Rai1 frees mice from the repression of active wake behaviors by light.

Besides its role in vision, light impacts physiology and behavior through circadian and direct (aka 'masking') mechanisms. In Smith-Magenis syndrome (SMS), the dysregulation of both sleep-wake behavior and melatonin production strongly suggests impaired non-visual light perception. We discovered that mice haploinsufficient for the SMS causal gene, Retinoic acid induced-1 (Rai1), were hypersensitive to light such that light eliminated alert and active-wake behaviors, while leaving time-spent-awake unaffected. Moreover, variables pertaining to circadian rhythm entrainment were activated more strongly by light. At the input level, the activation of rod/cone and suprachiasmatic nuclei (SCN) by light was paradoxically greatly reduced, while the downstream activation of the ventral-subparaventricular zone (vSPVZ) was increased. The vSPVZ integrates retinal and SCN input and, when activated, suppresses locomotor activity, consistent with the behavioral hypersensitivity to light we observed. Our results implicate Rai1 as a novel and central player in processing non-visual light information, from input to behavioral output

Oscillations and Episodic Memory: Addressing the Synchronization/Desynchronization Conundrum

Brain oscillations are one of the core mechanisms underlying episodic memory. However, while some studies highlight the role of synchronized oscillatory activity, others highlight the role of desynchronized activity. We here describe a framework to resolve this conundrum and integrate these two opposing oscillatory behaviors. Specifically, we argue that the synchronization and desynchronization reflect a division of labor between a hippocampal and a neocortical system, respectively. We describe a novel oscillatory framework that integrates synchronization and desynchronization mechanisms to explain how the two systems interact in the service of episodic memory

A Conserved Cysteine Motif Is Critical for Rice Ceramide Kinase Activity and Function

Ceramide kinase (CERK) is a key regulator of cell survival in dicotyledonous plants and animals. Much less is known about the roles of CERK and ceramides in mediating cellular processes in monocot plants. Here, we report the characterization of a ceramide kinase, OsCERK, from rice (Oryza sativa spp. Japonica cv. Nipponbare) and investigate the effects of ceramides on rice cell viability.OsCERK can complement the Arabidopsis CERK mutant acd5. Recombinant OsCERK has ceramide kinase activity with Michaelis-Menten kinetics and optimal activity at 7.0 pH and 40°C. Mg2+ activates OsCERK in a concentration-dependent manner. Importantly, a CXXXCXXC motif, conserved in all ceramide kinases and important for the activity of the human enzyme, is critical for OsCERK enzyme activity and in planta function. In a rice protoplast system, inhibition of CERK leads to cell death and the ratio of added ceramide and ceramide-1-phosphate, CERK's substrate and product, respectively, influences cell survival. Ceramide-induced rice cell death has apoptotic features and is an active process that requires both de novo protein synthesis and phosphorylation, respectively. Finally, mitochondria membrane potential loss previously associated with ceramide-induced cell death in Arabidopsis was also found in rice, but it occurred with different timing.OsCERK is a bona fide ceramide kinase with a functionally and evolutionarily conserved Cys-rich motif that plays an important role in modulating cell fate in plants. The vital function of the conserved motif in both human and rice CERKs suggests that the biochemical mechanism of CERKs is similar in animals and plants. Furthermore, ceramides induce cell death with similar features in monocot and dicot plants

GTPase regulator associated with the focal adhesion kinase (GRAF) transcript was down-regulated in patients with myeloid malignancies

<p>Abstract</p> <p>Background</p> <p>GTPase regulator associated with the focal adhesion kinase (<it>GRAF</it>), a putative tumor suppressor gene, is found inactivated in hematopoietic malignancies by either genetic or epigenetic abnormalities. However, the expression level of <it>GRAF </it>gene has not yet been studied in leukemia. The aim of this study was to investigate the expression level of <it>GRAF </it>gene in those patients with myeloid malignancies including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and chronic myeloid leukemia (CML).</p> <p>Methods</p> <p>The expression levels of <it>GRAF </it>transcript were determined in 94 patients using real-time quantitative PCR (RQ-PCR). Clinical and laboratory data of these patients were collected and analyzed.</p> <p>Results</p> <p>The significantly decreased level of <it>GRAF </it>transcript was observed in three myeloid malignancies compared to controls. Within AML, there was no difference in the level of <it>GRAF </it>transcript among different FAB subtypes (<it>P </it>> 0.05). Difference was not observed in the amount of <it>GRAF </it>mRNA between CML at chronic phase and controls. As CML progressed, <it>GRAF </it>transcript significantly decreased. In MDS, three cases with 5q deletion had lower <it>GRAF </it>transcript than four without 5q deletion (median 0.76 vs 2.99) (<it>P </it>> 0.05).</p> <p>Conclusion</p> <p>our results demonstrate that the <it>GRAF </it>transcript is decreased in myeloid malignancies.</p

ER stress drives Lipocalin 2 upregulation in prostate cancer cells in an NF-κB-dependent manner

<p>Abstract</p> <p>Background</p> <p>Tumor cells adapt to endoplasmic reticulum (ER) stress through a set of conserved intracellular pathways, as part of a process termed the unfolded protein response (UPR). The expression of UPR genes/proteins correlates with increasing progression and poor clinical outcome of several tumor types, including prostate cancer. UPR signaling can activate NF-κB, a master regulator of transcription of pro-inflammatory, tumorigenic cytokines. Previous studies have shown that Lipocalin 2 (Lcn2) is upregulated in several epithelial cancers, including prostate cancer, and recently Lcn2 was implicated as a key mediator of breast cancer progression. Here, we hypothesize that the tumor cell UPR regulates Lcn2 production.</p> <p>Methods</p> <p>We interrogated Lcn2 regulation in murine and human prostate cancer cells undergoing pharmacological and physiological ER stress, and tested UPR and NF-κB dependence by using pharmacological inhibitors of these signaling pathways.</p> <p>Results</p> <p>Induction of ER stress using thapsigargin (Tg), a canonical pharmacologic ER stress inducer, or via glucose deprivation, a physiologic ER stressor present in the tumor microenvironment, upregulates LCN2 production in murine and human prostate cancer cells. Inhibition of the UPR using 4-phenylbutyric acid (PBA) dramatically decreases Lcn2 transcription and translation. Inhibition of NF-κB in prostate cancer cells undergoing Tg-mediated ER stress by BAY 11-7082 abrogates Lcn2 upregulation.</p> <p>Conclusions</p> <p>We conclude that the UPR activates Lcn2 production in prostate cancer cells in an NF-κB-dependent manner. Our results imply that the observed upregulation of Lipocalin 2 in various types of cancer cells may be the direct consequence of concomitant UPR activation, and that the ER stress/Lipocalin 2 axis is a potential new target for intervention in cancer progression.</p

A review of the epidemiology of oral and pharyngeal carcinoma: update

Oral and pharyngeal cancers are the sixth most common cancers internationally. In the United States, there are about 30,000 new cases of oral and pharyngeal cancers diagnosed each year. Furthermore, survival rates for oral and pharyngeal cancers have not significantly improved over the last three decades. This review examines the scientific literature surrounding the epidemiology of oral and pharyngeal cancers, including but not limited to risk factors, disparities, preventative factors, and the epidemiology in countries outside the United States. The literature review revealed that much of the research in this field has been focused on alcohol, tobacco, and their combined effects on oral and pharyngeal cancers. The literature on oral and pharyngeal cancer disparities among racial groups also appears to be growing. However, less literature is available on the influence of dietary factors on these cancers. Finally, effective interventions for the reduction of oral and pharyngeal cancers are discussed

Vitamin A deficiency during pregnancy of HIV infected and non-infected women in tropical settings of Northwest Ethiopia

<p>Abstract</p> <p>Background</p> <p>Vitamin A deficiency (VAD) is known to be a major public health problem among women of reproductive age in South East Asia and Africa. In Ethiopia, there are no studies conducted on serum vitamin A status of HIV-infected pregnant women. Therefore, the present study was aimed at determining the level of serum vitamin A and VAD among pregnant women with and without HIV infection in tropical settings of Northwest Ethiopia.</p> <p>Methods</p> <p>In this cross-sectional study, blood samples were collected from 423 pregnant women and from 55 healthy volunteers who visited the University of Gondar Hospital. Serum concentration of vitamin A was measured by high performance liquid chromatography.</p> <p>Results</p> <p>After controlling for total serum protein, albumin and demographic variables, the mean ± SD serum vitamin A in HIV seropositive pregnant women (0.96 ± 0.42 μmol/L) was significantly lower than that in pregnant women without HIV infection (1.10 ± 0.45 μmol/L, P < 0.05). Likewise, the level of serum vitamin A in HIV seropositive non-pregnant women (0.74 ± 0.39) was significantly lower than that in HIV negative non-pregnant women (1.18 ± 0.59 μmol/L, P < 0.004). VAD (serum retinol < 0.7 μmol/L) was observed in 18.4% and 17.7% of HIV infected and uninfected pregnant women, respectively. Forty six percent of non-pregnant women with HIV infection had VAD while only 28% controls were deficient for vitamin A (P = 0.002).</p> <p>Conclusion</p> <p>The present study shows that VAD is a major public health problem among pregnant women in the tropical settings of Northwest Ethiopia. Considering the possible implications of VAD during pregnancy, we recommend multivitamin (which has a lower level of vitamin A) supplementation in the care and management of pregnant women with or without HIV infection.</p

A Glucose Fuel Cell for Implantable Brain–Machine Interfaces

We have developed an implantable fuel cell that generates power through glucose oxidation, producing steady-state power and up to peak power. The fuel cell is manufactured using a novel approach, employing semiconductor fabrication techniques, and is therefore well suited for manufacture together with integrated circuits on a single silicon wafer. Thus, it can help enable implantable microelectronic systems with long-lifetime power sources that harvest energy from their surrounds. The fuel reactions are mediated by robust, solid state catalysts. Glucose is oxidized at the nanostructured surface of an activated platinum anode. Oxygen is reduced to water at the surface of a self-assembled network of single-walled carbon nanotubes, embedded in a Nafion film that forms the cathode and is exposed to the biological environment. The catalytic electrodes are separated by a Nafion membrane. The availability of fuel cell reactants, oxygen and glucose, only as a mixture in the physiologic environment, has traditionally posed a design challenge: Net current production requires oxidation and reduction to occur separately and selectively at the anode and cathode, respectively, to prevent electrochemical short circuits. Our fuel cell is configured in a half-open geometry that shields the anode while exposing the cathode, resulting in an oxygen gradient that strongly favors oxygen reduction at the cathode. Glucose reaches the shielded anode by diffusing through the nanotube mesh, which does not catalyze glucose oxidation, and the Nafion layers, which are permeable to small neutral and cationic species. We demonstrate computationally that the natural recirculation of cerebrospinal fluid around the human brain theoretically permits glucose energy harvesting at a rate on the order of at least 1 mW with no adverse physiologic effects. Low-power brain–machine interfaces can thus potentially benefit from having their implanted units powered or recharged by glucose fuel cells