A crucial requirement for Hedgehog signaling in small cell lung cancer

Small-cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer for which there is no effective treatment. Using a mouse model in which deletion of Rb1 and Trp53 in the lung epithelium of adult mice induces SCLC, we found that the Hedgehog signaling pathway is activated in SCLC cells independently of the lung microenvironment. Constitutive activation of the Hedgehog signaling molecule Smoothened (Smo) promoted the clonogenicity of human SCLC in vitro and the initiation and progression of mouse SCLC in vivo. Reciprocally, deletion of Smo in Rb1 and Trp53-mutant lung epithelial cells strongly suppressed SCLC initiation and progression in mice. Furthermore, pharmacological blockade of Hedgehog signaling inhibited the growth of mouse and human SCLC, most notably following chemotherapy. These findings show a crucial cell-intrinsic role for Hedgehog signaling in the development and maintenance of SCLC and identify Hedgehog pathway inhibition as a therapeutic strategy to slow the progression of disease and delay cancer recurrence in individuals with SCLC.     

Cytochrome c-d regulates developmental apoptosis in the Drosophila retina

The role of cytochrome c (Cyt c) in caspase activation has largely been established from mammalian cell-culture studies, but much remains to be learned about its physiological relevance in situ. The role of Cyt c in invertebrates has been subject to considerable controversy. The Drosophila genome contains distinct cyt c genes: cyt c-p and cyt c-d. Loss of cyt c-p function causes embryonic lethality owing to a requirement of the gene for mitochondrial respiration. By contrast, cyt c-d mutants are viable but male sterile. Here, we show that cyt c-d regulates developmental apoptosis in the pupal eye. cyt c-d mutant retinas show a profound delay in the apoptosis of superfluous interommatidial cells and perimeter ommatidial cells. Furthermore, there is no apoptosis in mutant retinal tissues for the Drosophila homologues of apoptotic protease-activating factor 1 (Ark) and caspase 9 (Dronc). In addition, we found that cyt c-d--as with ark and dronc-regulates scutellar bristle number, which is known to depend on caspase activity. Collectively, our results indicate a role of Cyt c in caspase regulation of Drosophila somatic cells.     

Lis1 is an initiation factor for dynein-driven organelle transport

The molecular motor cytoplasmic dynein is responsible for most minus-end-directed, microtubule-based transport in eukaryotic cells. It is especially important in neurons, where defects in microtubule-based motility have been linked to neurological diseases. For example, lissencephaly is caused by mutations in the dynein-associated protein Lis1. In this paper, using the long, highly polarized hyphae of the filamentous fungus Aspergillus nidulans, we show that three morphologically and functionally distinct dynein cargos showed transport defects in the genetic absence of Lis1/nudF, raising the possibility that Lis1 is ubiquitously used for dynein-based transport. Surprisingly, both dynein and its cargo moved at normal speeds in the absence of Lis1 but with reduced frequency. Moreover, Lis1, unlike dynein and dynactin, was absent from moving dynein cargos, further suggesting that Lis1 is not required for dynein-based cargo motility once it has commenced. Based on these observations, we propose that Lis1 has a general role in initiating dynein-driven motility.     

Spatial and temporal variation of the ichthyoplankton in a subtropical river in Brazil

Studies that assess reproduction dynamics and ichthyoplankton distributions are scarce for the upper Uruguay River, especially in environments such as tributary mouths. Therefore, this study aimed to evaluate: (i) ichthyoplankton composition; (ii) spatial and temporal variation in ichthyoplankton abundance; and (iii) relationships between environmental variables and the abundance of ichthyoplankton during one annual cycle in this region. Monthly samples were collected from September 2001 to August 2002 in 48 h cycles at 6 h intervals between each sampling. Samples of eggs and larvae were collected from three of the main tributaries of the region (Ligeiro, Palomas and Chapecó rivers) and from three stretches of the Uruguay River near the confluence of these tributaries. Surface samples were collected with a 0.5 mm mesh cylindro-conical net. In general, reproductive seasonality was well-defined between October and February. It was most intense from November to January, when the photoperiod reached its highest values, flow was decreased, and the water temperature was increased. Based on egg and larval distributions, we found that spawning occurred mainly in the Ligeiro and Chapecó tributaries and in the Uruguay/Chapecó section. In contrast, fish spawning in the sites downstream of dams was more restricted. Finally, a difference was observed between the egg and larval distributions of the main river and its tributaries: the greatest reproductive activity in the tributaries occurred during periods of high flow and increased water temperature, while in the main river, more eggs and larvae were observed when the flow decreased and the water temperature increased.     

Brain Barrier Breakdown as a Cause and Consequence of Neuroinflammation in Sepsis

The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) are important for the maintenance of brain homeostasis. During sepsis, peripheral production of proinflammatory cytokines and reactive oxygen species are responsible for structural alterations in those brain barriers. Thus, an increasing permeability of these barriers can lead to the activation of glial cells such as microglia and the production of cytotoxic mediators which in turn act on the brain barriers, damaging them further. Thereby, in this review, we try to highlight how the brain barrier’s permeability is not only a cause but a consequence of brain injury in sepsis.     

Water relations of cassava cultivated under water-deficit levels

The tolerance of plants to water deficit involves a series of adaptive mechanisms; however, little is known about the physiological characteristics of cassava (Manihot esculenta Crantz), which is one of the most tolerant crops to adverse environmental conditions. The objective of this work was to evaluate the water relations in cassava plants subjected to different levels of water deficit. The treatments were conducted in three evaluation periods (0, 45 and 90 days after water deficit) and at three soil water tensions (? 10, ? 40 and ? 70 kPa), with five replicates. The plants were mainly affected at 45 days after the water deficit, with an increase of 42.9% in total chlorophyll content and 35.3% in carotenoid content in plants under a tension of ? 70 kPa; however, these plants reduced by 30.8% chlorophyll a content at 90 days of the treatments. The water potential, relative water content and electrolyte leakage in the leaf were not altered by the soil water tension. There was an increase of 35.4% in stomatal density independent of soil water status at 90 days and of 16.0% under tensions of ? 40 and ? 70 kPa; however, the effective quantum efficiency of photosystem II and rate of electron transport were reduced. Cassava can maintain a leaf water potential close to ? 0.3 MPa in the predawn and the integrity of the cell membranes in leaves under a soil water tension of up to ? 70 kPa.