Modelling the emergence of cities and urban patterning using coupled integro-differential equations.

Human residential population distributions show patterns of higher density clustering around local services such as shops and places of employment, displaying characteristic length scales; Fourier transforms and spatial autocorrelation show the length scale between UK cities is around 45 km. We use integro-differential equations to model the spatio-temporal dynamics of population and service density under the assumption that they benefit from spatial proximity, captured via spatial weight kernels. The system tends towards a well-mixed homogeneous state or a spatial pattern. Linear stability analysis around the homogeneous steady state predicts a modelled length-scale consistent with that observed in the data. Moreover, we show that spatial instability occurs only for perturbations with a sufficiently long wavelength and only where there is a sufficiently strong dependence of service potential on population density. Within urban centres, competition for space may cause services and population to be out of phase with one another, occupying separate parcels of land. By introducing competition, along with a preference for population to be located near, but not too near, to high service density areas, secondary out-of-phase patterns occur within the model, at a higher density and with a shorter length scale than in phase patterning. Thus, we show that a small set of core behavioural ingredients can generate aggregations of populations and services, and pattern formation within cities, with length scales consistent with real-world data. The analysis and results are valid across a wide range of parameter values and functional forms in the model.

C9ORF72-derived poly-GA DPRs undergo endocytic uptake in iAstrocytes and spread to motor neurons.

Dipeptide repeat (DPR) proteins are aggregation-prone polypeptides encoded by the pathogenic GGGGCC repeat expansion in the C9ORF72 gene, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. In this study, we focus on the role of poly-GA DPRs in disease spread. We demonstrate that recombinant poly-GA oligomers can directly convert into solid-like aggregates and form characteristic ß-sheet fibrils in vitro. To dissect the process of cell-to-cell DPR transmission, we closely follow the fate of poly-GA DPRs in either their oligomeric or fibrillized form after administration in the cell culture medium. We observe that poly-GA DPRs are taken up via dynamin-dependent and -independent endocytosis, eventually converging at the lysosomal compartment and leading to axonal swellings in neurons. We then use a co-culture system to demonstrate astrocyte-to-motor neuron DPR propagation, showing that astrocytes may internalise and release aberrant peptides in disease pathogenesis. Overall, our results shed light on the mechanisms of poly-GA cellular uptake and propagation, suggesting lysosomal impairment as a possible feature underlying the cellular pathogenicity of these DPR species.

The SUMO protease SENP3 regulates mitochondrial autophagy mediated by Fis1.

Mitochondria are unavoidably subject to organellar stress resulting from exposure to a range of reactive molecular species. Consequently, cells operate a poorly understood quality control programme of mitophagy to facilitate elimination of dysfunctional mitochondria. Here, we used a model stressor, deferiprone (DFP), to investigate the molecular basis for stress-induced mitophagy. We show that mitochondrial fission 1 protein (Fis1) is required for DFP-induced mitophagy and that Fis1 is SUMOylated at K149, an amino acid residue critical for Fis1 mitochondrial localization. We find that DFP treatment leads to the stabilization of the SUMO protease SENP3, which is mediated by downregulation of the E3 ubiquitin (Ub) ligase CHIP. SENP3 is responsible for Fis1 deSUMOylation and depletion of SENP3 abolishes DFP-induced mitophagy. Furthermore, preventing Fis1 SUMOylation by conservative K149R mutation enhances Fis1 mitochondrial localization. Critically, expressing a Fis1 K149R mutant restores DFP-induced mitophagy in SENP3-depleted cells. Thus, we propose a model in which SENP3-mediated deSUMOylation facilitates Fis1 mitochondrial localization to underpin stress-induced mitophagy.

Future improvements on performance of an EU landfill directive driven municipal solid waste management for a city in England.

Sustainable municipal solid waste (MSW) management is regarded as one of the key elements for achieving urban sustainability via mitigating global climate change, recycling resources and recovering energy. Landfill is considered as the least preferable disposal method and the EU Landfill Directive (ELD) announced in 1999 requires member countries to reduce the volume of landfilled biodegradable materials. The enforcement of ELD initiated the evolution of MSW management system UK. This study depicted and assessed the transition and performance of MSW management after the millennium in Nottingham via materials flow analysis (MFA), as well as appropriately selected indicators based on the concept of waste management hierarchy and targets set in waste management regulations. We observed improvements in waste reduction, material recycling, energy recovery, and landfill prevention. During the period 2001/02 to 2016/17, annual waste generation reduced from 463 kg/Ca to 361 kg/Ca, the recycling and composting share increased from 4.6% to 44.4%, and the landfill share reduced from 54.7% to 7.3%. These signs of progress are believed to be driven by the ELD and the associated policies and waste management targets established at the national and local levels. An alternative scenario with food waste and textile separation at source and utilizing anaerobic digestion to treat separately collected organic waste is proposed at the end of this paper to fulfil the high targets set by local government and we further suggest that the recycling share may be improved by educating and supporting the public on waste separation at the sources.

Anti-apoptotic Mutations Desensitize Human Pluripotent Stem Cells to Mitotic Stress and Enable Aneuploid Cell Survival.

Human pluripotent stem cells (hPSCs) are susceptible to numerical and structural chromosomal alterations during long-term culture. We show that mitotic errors occur frequently in hPSCs and that prometaphase arrest leads to very rapid apoptosis in undifferentiated but not in differentiated cells. hPSCs express high levels of proapoptotic protein NOXA in undifferentiated state. Knocking out NOXA by CRISPR or upregulation of the anti-apoptosis gene BCL-XL significantly reduced mitotic cell death, allowing the survival of aneuploid cells and the formation of teratomas significantly larger than their wild-type parental hPSCs. These results indicate that the normally low threshold of apoptosis in hPSCs can safeguard their genome integrity by clearing cells undergoing abnormal division. The amplification of BCL2L1 on chromosome 20q11.21, a frequent mutation in hPSCs, although not directly oncogenic, reduces the sensitivity of hPSCs to damage caused by erroneous mitosis and increases the risk of gaining aneuploidy.

Entropy and its Application to Urban Systems.

Since its conception over 150 years ago, entropy has enlightened and confused scholars and students alike, from its origins in physics and beyond. More recently, it has been considered within the urban context in a rather eclectic range of applications. The entropy maximization approach, as applied by Alan Wilson and others from the 1960s, contrasts with considerations from the 1990s of the city as a thermodynamic dissipative system, in the tradition of Ilya Prigogine. By reviewing the relevant mathematical theory, we draw the distinction among three interrelated definitions of entropy, the thermodynamic, the figurative, and the information statistical. The applications of these definitions to urban systems within the literature are explored, and the conflation of the thermodynamic and figurative interpretations are disentangled. We close this paper with an outlook on future uses of entropy in urban systems analysis.

Mitochondria-localising DNA-binding biscyclometalated phenyltriazole iridium(iii) dipyridophenazene complexes: syntheses and cellular imaging properties.

Two new biscyclometalated complexes [Ir(ptzR)2(dppz)]+ (dppz = dipyridophenazene; ptzRH = 4-phenyl-1-benzyl-1,2,3-triazole (1+) and 4-phenyl-1-propyl-1,2,3-triazole (2+)) have been prepared. The hexafluorophosphate salts of these complexes have been fully characterized and, in one case, the X-ray structure of a nitrate salt was obtained. The DNA binding properties of the chloride salts of the complexes were investigated, as well as their cellular uptake by A2780 and MCF7 cell lines. Both complexes display an increase in the intensity of phosphorescence upon titration with duplex DNA, indicating the intercalation of the dppz ligand and, given that they are monocations, the complexes exhibit appreciable DNA binding affinity. Optical microscopy studies reveal that both complexes are taken up by live cancer cell lines displaying cytosol based luminescence. Colocalization studies with commercial probes show high Pearson coefficients with mitotracker dyes confirming that the new complexes specifically localize on mitochondria.

Multimodal Super-resolution Optical Microscopy Using a Transition-Metal-Based Probe Provides Unprecedented Capabilities for Imaging Both Nuclear Chromatin and Mitochondria.

Detailed studies on the live cell uptake properties of a dinuclear membrane-permeable RuII cell probe show that, at low concentrations, the complex localizes and images mitochondria. At concentrations above ∼20 µM, the complex images nuclear DNA. Because the complex is extremely photostable, has a large Stokes shift, and displays intrinsic subcellular targeting, its compatibility with super-resolution techniques was investigated. It was found to be very well suited to image mitochondria and nuclear chromatin in two color, 2C-SIM, and STED and 3D-STED, both in fixed and live cells. In particular, due to its vastly improved photostability compared to that of conventional SR probes, it can provide images of nuclear DNA at unprecedented resolution.

Living with an autonomous spatiotemporal home heating system: Exploration of the user experiences (UX) through a longitudinal technology intervention-based mixed-methods approach.

Rising energy demands place pressure on domestic energy consumption, but savings can be delivered through home automation and engaging users with their heating and energy behaviours. The aim of this paper is to explore user experiences (UX) of living with an automated heating system regarding experiences of control, understanding of the system, emerging thermal behaviours, and interactions with the system as this area is not sufficiently researched in the existing homes setting through extended deployment. We present a longitudinal deployment of a quasi-autonomous spatiotemporal home heating system in three homes. Users were provided with a smartphone control application linked to a self-learning heating algorithm. Rich qualitative and quantitative data presented here enabled a holistic exploration of UX. The paper's contribution focuses on highlighting key aspects of UX living with an automated heating systems including (i) adoption of the control interface into the social context, (ii) how users' vigilance in maintaining preferred conditions prevailed as a better indicator of system over-ride than gross deviation from thermal comfort, (iii) limited but motivated proactivity in system-initiated communications as best strategy for soliciting user feedback when inference fails, and (iv) two main motivations for interacting with the interface - managing irregularities when absent from the house and maintaining immediate comfort, latter compromising of a checking behaviour that can transit to a system state alteration behaviour depending on mismatches. We conclude by highlighting the complex socio-technical context in which thermal decisions are made in a situated action manner, and by calling for a more holistic, UX-focused approach in the design of automated home systems involving user experiences.

Human PIF1 helicase supports DNA replication and cell growth under oncogenic-stress.

Unwinding duplex DNA is a critical processing step during replication, repair and transcription. Pif1 are highly conserved non-processive 5'->3' DNA helicases with well-established roles in maintenance of yeast genome stability. However, the function of the sole member of Pif1 family in humans remains unclear. Human PIF1 is essential for tumour cell viability, particularly during replication stress, but is dispensable in non-cancerous cells and Pif1 deficient mice. Here we report that suppression of PIF1 function slows replication fork rates and increases arrested forks during normal cycling conditions. Importantly, PIF1-dependent replication impediments impair S-phase progression and reduce proliferation rates of RAS oncogene-transformed fibroblasts, where replication fork slowing is exacerbated, but not parental, non-cancerous cells. Disrupted fork movement upon PIF1-depletion does not enhance double-stranded break formation or DNA damage responses but affects resumption of DNA synthesis after prolonged replication inhibitor exposure, accompanied by diminished new origin firing and mainly S-phase entry. Taken together, we characterised a functional role for human PIF1 in DNA replication that becomes important for cell growth under oncogenic stress. Given that oncogenes induce high levels of replication stress during the early stages of tumorigenesis, this function of PIF1 could become critical during cancer development.

Modelling occupants' personal characteristics for thermal comfort prediction.

Based on results from a field survey campaign conducted in Switzerand, we show that occupants' variations in clothing choices, which are relatively unconstrained, are best described by the daily mean outdoor temperature and that major clothing adjustments occur rarely during the day. We then develop an ordinal logistic model of the probability distribution of discretised clothing levels, which results in a concise and informative expression of occupants' clothing choices. Results from both cross-validation and independent verification suggest that this model formulation may be used with confidence. Furthermore, the form of the model is readily generalisable, given the requisite calibration data, to environments where dress codes are more specific. We also observe that, for these building occupants, the prevailing metabolic activity levels are mostly constant for the whole range of surveyed environmental conditions, as their activities are relatively constrained by the tasks in hand. Occupants may compensate for this constraint, however, through the consumption of cold and hot drinks, with corresponding impacts on metabolic heat production. Indeed, cold drink consumption was found to be highly correlated with indoor thermal conditions, whilst hot drink consumption is best described by a seasonal variable. These variables can be used for predictive purposes using binary logistic models.

New perspectives on epidermal barrier dysfunction in atopic dermatitis: gene-environment interactions.

Atopic dermatitis (AD) is a multifactorial, chronic inflammatory skin disorder in which genetic mutations and cutaneous hyperreactivity to environmental stimuli play a causative role. Genetic mutations alone might not be enough to cause clinical manifestations of AD, and this review will propose a new perspective on the importance of epidermal barrier dysfunction in genetically predisposed individuals, predisposing them to the harmful effects of environmental agents. The skin barrier is known to be damaged in patients with AD, both in acute eczematous lesions and also in clinically unaffected skin. Skin barrier function can be impaired first by a genetic predisposition to produce increased levels of stratum corneum chymotryptic enzyme. This protease enzyme causes premature breakdown of corneodesmosomes, leading to impairment of the epidermal barrier. The addition of environmental interactions, such as washing with soap and detergents, or long-term application of topical corticosteroids can further increase production of stratum corneum chymotryptic enzyme and impair epidermal barrier function. The epidermal barrier can also be damaged by exogenous proteases from house dust mites and Staphylococcus aureus. One or more of these factors in combination might lead to a defective barrier, thereby increasing the risk of allergen penetration and succeeding inflammatory reaction, thus contributing to exacerbations of this disease.

Predisposition to sensitive skin and atopic eczema.

Genes that control the thickness of our skin and its vulnerability to chemicals in the environment play a role in the development of contact dermatitis and atopic eczema. Sensitive skin manifests itself as a burning, stinging or itching sensation following the application of topical products such as soap, bubble baths and cosmetics. The skin may become red and dry after repeated application of these products. New insights into the skin barrier can help us improve treatment of the skin and prevent problems associated with atopic eczema and sensitive skin

Meta-analysis of genome-wide studies of psoriasis susceptibility reveals linkage to chromosomes 6p21 and 4q28-q31 in Caucasian and Chinese Hans population.

Ten genome-wide scans have been conducted over the past few years in the search for psoriasis susceptibility genes, but only one potential susceptibility region has been consistently replicated. A meta-analysis using the genome-search meta-analysis method was undertaken combining the results of six of these psoriasis genome-wide studies. The results of this analysis revealed linkage to the major histocompatibility complex on chromosome 6p21 that includes the PSORS1 locus. In addition, linkage was also recorded to a region on chromosome 4q28-q31 previously identified only in a Chinese Hans population. Both these regions were statistically significant even after correction for multiple testing. A possible reason for the erratic replication of findings could be the large effect of the PSORS1 locus (6p21) masking the effect of other loci involved in psoriasis. To overcome this problem, we suggest that future studies condition on the effect of the PSORS1 locus.

Chronic effects of fatty acids on pancreatic beta-cell function: new insights from functional genomics.

Type 2 diabetes can be viewed as a failure of the pancreatic beta-cell to compensate for peripheral insulin resistance with enhanced insulin secretion. This failure is explained by both a relative loss of beta-cell mass as well as secretory defects that include enhanced basal secretion and a selective loss of sensitivity to glucose. These features are reproduced by chronic exposure of beta-cells to fatty acids (FAs), suggesting that hyperlipidemia might contribute to decompensation. Using MIN6 cells pretreated for 48 h with oleate or palmitate, we have previously defined alterations in global gene expression by transcript profiling and described additional secretory changes to those already established (Busch A-K, Cordery D, Denyer G, Biden TJ: Diabetes 51:977-987, 2002). In contrast to a modest decoupling of glucose-stimulated insulin secretion, FA pretreatment markedly enhanced the secretory response to an acute subsequent challenge with FAs. We propose that this apparent switch in sensitivity from glucose to FAs would be an appropriate response to hyperlipidemia in vivo and thus plays a positive role in beta-cell compensation for insulin resistance. Altered expression of dozens of genes could contribute to this switch, and allelic variations in any of these genes could (to varying degrees) impair beta-cell compensation and thus contribute to conditions ranging from impaired glucose tolerance to frank diabetes.

Three-dimensional mapping of the lesions induced by beta-beta'-iminodiproprionitrile, methyl iodide and methyl methacrylate in the rat nasal cavity.

The nasal cavity is an important target organ for toxicity, and many chemicals induce site-specific lesions in this region. The factors responsible for this site-selectivity have not been unequivocally identified, but probably include regional dosimetry and bioactivation. The purpose of this study was to map, in 3 dimensions, the lesions induced by beta-beta'-iminodipropionitrile (IDPN), methyl iodide (MeI) and methyl methacrylate (MMA) in the rat nasal cavity. Animals were administered IDPN (150 mg/kg, IP) or exposed via inhalation to MeI (100 ppm, 2 hours) or MMA (400 ppm, 4 hours) and sacrificed after 24 hours. Heads were decalcified, step-sections (1 every 400 microm) cut and stained, and the severity of the epithelial lesion graded as mild (vacuolation and pyknosis), moderate (undulation and mild stripping), or marked (complete stripping). These grades were mapped onto a 3D-model of a rat nasal cavity using the KS400 imaging system (Imaging Associates, Thame, UK). Despite the different routes of exposure the lesions induced by the 3 compounds had very similar distributions, predominantly affecting the dorsal-medial aspects of the ethmoturbinates and, in the case of MMA, the organ of Rodolfo Masera. These results suggest that, with these chemicals, local bioactivation plays a more important role than dosimetry in determining lesion distribution.

Development of methodology for the three-dimensional modelling of the metabolic capacity of the rat nasal cavity using glutathione S-transferase M1 as an example.

A variety of chemicals induce site-specific lesions in the rodent nasal cavity. In order to explore the reasons for this site-selectivity, methodology for (a) creation of a 3-dimensional (3D) model of a rat nasal cavity, and (b) mapping of semiquantitative data onto the model has been developed. The head of a rat was fixed, decalcified, step-sectioned (every 100 microm) and stained with hematoxylin and eosin. Digital images of the sections were optically captured, and a KS400 image analysis system (Imaging Associates, Thame, Oxford, UK), attached to a standard personal computer, was used to align adjacent images and reconstruct the series in 3D. The final model was anatomically correct, and could be rotated in any plane and manipulated to display individual internal structures. The spatial localization of a glutathione S-transferase (rGSTM1, previously known as GST 3-3) within this model was investigated using immunohistochemistry. Step sections (every 400 microm) were stained, analyzed by imaging densitometry, and the results for the stained regions within the nasal cavity divided into 4 grades representing high to low expression of rGSTM1. The data was mapped onto the 3D model and showed that the highest expression of this enzyme was in the central regions of the nasal cavity at the transition between respiratory and olfactory epithelia. This methodology will allow investigation of the relationship between the in situ localization of bioactivating and detoxifying enzyme systems and the site-specificity of nasal lesions.

Antioxidant status of the rat nasal cavity.

Despite extensive interest in the rodent nasal cavity as a target organ for toxicity, there is very limited information regarding nasal defenses against oxidative stress and xenobiotic-derived oxidants. Using immunohistochemistry, we have examined the distribution of Cu,Zn and Mn superoxide dismutase (SOD), catalase, glutathione (GSH) peroxidase, and DT-diaphorase in rat nasal tissues. In addition, we have determined the concentrations of ascorbate and alpha-tocopherol and the activities of SOD (combined Cu,Zn and Mn forms), catalase, GSH peroxidase, GSH reductase, and DT-diaphorase in nasal respiratory epithelium (RE), olfactory epithelium (OE), and in lung. Immunohistochemistry demonstrated that all four enzymes were similarly distributed, with the greatest staining intensity in dorsal-medial regions of the nasal cavity. In respiratory epithelium, ciliated columnar cells and subepithelial glands stained positively, while in olfactory tissue the enzymes were detected in the sustentacular cells and Bowman's glands. With the exception of SOD, enzyme activities were higher in RE than OE, while concentrations of ascorbate and alpha-tocopherol were higher in OE than RE. With the exception of catalase, nasal activities were either higher than or comparable to those of the lung. Thus, the rat nasal cavity appears to be well protected against oxidative damage.

Histochemical localisation of carboxylesterase activity in rat and mouse oral cavity mucosa.

Vinyl acetate (VA) is widely used within the chemical industry, in the manufacture of polyvinyl alcohol, and as polyvinyl acetate emulsions in latex paints, adhesives, paper and paper board coatings. Chronic oral exposure of rodents to high concentrations of VA induces tumours within the oral cavity. Carboxylesterase-dependent hydrolysis of VA is thought to be critical in the development of nasal tumours following inhalation exposure of animals to VA. Therefore, carboxylesterase activity was determined histochemically in the oral cavities of male F344 rats and BDF mice in order to explore the potential role of carboxylesterase-dependent hydrolysis of VA in the development of oral tumours. Following fixation in 10% neutral buffered formalin heads were decalcified in neutral saturated EDTA, embedded in resin, sectioned at six levels (three each for the upper and lower jaws), and carboxylesterase activity revealed in the tissue using alpha-naphthyl butyrate as substrate. The localisation of carboxylesterase activity in freshly dissected rat oral tissue was compared to that of the resin sections and found to be identical, thus validating the decalcification process. A similar pattern of carboxylesterase activity was observed for the two species. Staining was low in areas surrounding the teeth, and medium/high in the buccal mucosa, the central/posterior upper palate and those regions of the lower jaw not proximal to the teeth. In general the intensity of staining was greater in sections from the rat compared to those from the mouse. By comparison, carboxylesterase activity was considerably higher in mouse nasal olfactory epithelium than in any of the oral tissues. Thus the mucosa of the oral cavity has the potential to hydrolyse VA to its metabolites, acetic acid and acetaldehyde, and the presence of carboxylesterases at this site is consistent with, and may be an important determining factor in, the development of oral cavity tumours following exposure to VA.