SummaryThe evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with >10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance.

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In a world where resources are scarce and urban areas consume the vast majority of these resources, it is vital to make cities greener and more sustainable. Advanced systems to improve and automate processes within a city will play a leading role in smart cities. From smart design of buildings, which capture rain water for later use, to intelligent control systems, which can monitor infrastructures autonomously, the possible improvements enabled by sensing technologies are immense. Ubiquitous sensing poses numerous challenges, which are of a technological or social nature. This paper presents an overview of the state of the art with regards to sensing in smart cities. Topics include sensing applications in smart cities, sensing platforms and technical challenges associated with these technologies. In an effort to provide a holistic view of how sensing technologies play a role in smart cities, a range of applications and technical challenges associated with these applications are discussed. As some of these applications and technologies belong to different disciplines, the material presented in this paper attempts to bridge these to provide a broad overview, which can be of help to researchers and developers in understanding how advanced sensing can play a role in smart cities.

Tumor necrosis factor (TNF)-␣ has been reported to modulate brain injury, but remarkably, little is known about its effects on neurogenesis. We report that TNF-␣ strongly influences survival, proliferation, and neuronal differentiation in cultured subventricular zone (SVZ) neural stem/progenitor cells derived from the neonatal P1-3 C57BL/6 mice. By using single-cell calcium imaging, we

Neurological impairments are frequently detected in children surviving cerebral malaria (CM), the most severe neurological complication of infection with Plasmodium falciparum. The pathophysiology and therapy of long lasting cognitive deficits in malaria patients after treatment of the parasitic disease is a critical area of investigation. In the present study we used several models of experimental malaria with differential features to investigate persistent cognitive damage after rescue treatment. Infection of C57BL/6 and Swiss (SW) mice with Plasmodium berghei ANKA (PbA) or a lethal strain of Plasmodium yoelii XL (PyXL), respectively, resulted in documented CM and sustained persistent cognitive damage detected by a battery of behavioral tests after cure of the acute parasitic disease with chloroquine therapy. Strikingly, cognitive impairment was still present 30 days after the initial infection. In contrast, BALB/c mice infected with PbA, C57BL6 infected with Plasmodium chabaudi chabaudi and SW infected with non lethal Plasmodium yoelii NXL (PyNXL) did not develop signs of CM, were cured of the acute parasitic infection by chloroquine, and showed no persistent cognitive impairment. Reactive oxygen species have been reported to mediate neurological injury in CM. Increased production of malondialdehyde (MDA) and conjugated dienes was detected in the brains of PbA-infected C57BL/6 mice with CM, indicating high oxidative stress. Treatment of PbA-infected C57BL/6 mice with additive antioxidants together with chloroquine at the first signs of CM prevented the development of persistent cognitive damage. These studies provide new insights into the natural history of cognitive dysfunction after rescue therapy for CM that may have clinical relevance, and may also be relevant to cerebral sequelae of sepsis and other disorders.

ABSTRACT

Subventricular zone (SVZ) cell cultures contain mixed populations of immature cells, neurons, astrocytes, and progenitors in different stages of development. In the present work, we examined whether cell types of the SVZ could be functionally discriminated on the basis of intracellular free calcium level ([Ca(2+)](i)) variations following KCl and histamine stimulation. For this purpose, [Ca(2+)](i) were measured in SVZ cell cultures from neonatal P1-3 C57Bl/6 donor mice, in single cells, after stimulation with 100 microM histamine or 50 mM KCl. MAP-2-positive neurons and doublecortin-positive neuroblasts were distinguished on the basis of their selective ratio of response to KCl and/or histamine stimulation. Moreover, we could distinguish immature cells on the basis of the selective response to histamine via the histamine 1 receptor activation. Exposure of SVZ cultures to the pro-neurogenic stem cell factor (SCF) induced an increase in the number of cells responding to KCl and a decrease in the number of cells responding to histamine, consistent with neuronal differentiation. The selective response to KCl/histamine in single cell calcium imaging analysis offers a rapid and efficient way for the functional discrimination of neuronal differentiation in SVZ cell cultures, opening new perspectives for the search of potential pro-neurogenic factors.

In the present study we investigated the effects of phenolic compounds present in Hypericum perforatum against neuronal excitotoxicity and mitochondrial dysfunction. Quercetin, kaempferol and biapigenin significantly reduced neuronal death caused by 100 microM kainate plus 100 microM N-methyl-D-aspartate. The observed neuroprotection was correlated with prevention of delayed calcium deregulation and with the maintenance of mitochondrial transmembrane electric potential. The three compounds were able to reduce mitochondrial lipid peroxidation and loss of mitochondrial transmembrane electric potential caused by oxidative stress induced by ADP plus iron. Moreover, biapigenin was also able to significantly affect mitochondrial bioenergetics and decrease the capacity of mitochondria to accumulate calcium. Taken together, the results suggest that the neuroprotective action induced by quercetin and kaempferol are mainly mediated by antioxidant effects, whereas biapigenin mainly affects mitochondrial bioenergetics and calcium uptake.