Heat-shock factor 1 (HSF1) orchestrates the heat-shock response in eukaryotes. Although this pathway has been evolved to help cells adapt in the presence of challenging conditions, it is co-opted in cancer to support malignancy. However, the mechanisms that regulate HSF1 and thus cellular stress response are poorly understood. Here we show that the ubiquitin ligase FBXW7 α interacts with HSF1 through a conserved motif phosphorylated by GSK3β and ERK1. FBXW7α ubiquitylates HSF1 and loss of FBXW7α results in impaired degradation of nuclear HSF1 and defective heat-shock response attenuation. FBXW7α is either mutated or transcriptionally downregulated in melanoma and HSF1 nuclear stabilization correlates with increased metastatic potential and disease progression. FBXW7α deficiency and subsequent HSF1 accumulation activates an invasion-supportive transcriptional program and enhances the metastatic potential of human melanoma cells. These findings identify a post-translational mechanism of regulation of the HSF1 transcriptional program both in the presence of exogenous stress and in cancer.

Background: Functional characterization of a novel mitochondrial protein, CHCM1/CHCHD6, is reported. Results: CHCM1 interacts with Mitofilin, DISC1, and CHCHD3, and its deficiency leads to severe defects in mitochondrial cristae morphology, reduction in cell growth, ATP production, and oxygen consumption. Conclusion: CHCM1/CHCHD6 is a novel player linked to mitochondrial cristae morphology. Significance: Results provide valuable insights into molecular events controlling the structural integrity and biogenesis of mitochondrial cristae.

Abstract-Routing is a process of finding a network path from a source node to a destination node. The execution time and the memory requirement of a routing algorithm increase with the size of the network. In order to deal with the scalability problem, large networks are often structured hierarchically by grouping nodes into different domains. The internal topology of each domain is then aggregated into a simple topology that reflects the cost of routing across that domain. This process is called topology aggregation. For delay-bandwidth sensitive networks, traditional approaches represent the property of each link in the aggregated topology as a delay-bandwidth pair, which corresponds to a point on the delay-bandwidth plane. Since each link after aggregation may be the abstraction of many physical paths, a single delay-bandwidth pair results in significant information loss. The major contribution of this paper is a novel quality-of-service (QoS) parameter representation with a new aggregation algorithm and a QoS-aware routing protocol. Our QoS representation captures the state information about the network with much greater accuracy than the existing algorithms. Our simulation results show that the new approach achieves very good performance in terms of delay deviation, success ratio, and crankback ratio.

Tumor infiltrating lymphocytes (TILs) in primary melanomas are thought to represent the host anti-tumor immune response, but controversy exists over whether TILs offer independent prognostication of survival. We studied a cohort of 1,241 primary melanoma patients to assess the association of absent, non-brisk, and brisk TIL grade with survival outcomes. We tested whether quantitative TIL counts using immunohistochemical lymphocyte markers CD3, CD45, and FOXP3 add prognostic value to TIL grading compared to histology alone in 15% of the cohort. To assess for inter-group immunologic heterogeneity among TIL grades, we investigated differential expression of 594 immunoregulatory genes in 67 primary melanomas. On histologic evaluation of 1,241 primary melanomas, TILs were graded as absent (n=388, 31%), non-brisk (n=330, 27%), and brisk (n=523, 42%). Patients with brisk TILs had improved recurrence-free survival (RFS) (p=0.025) and overall survival (OS) (p=0.006) compared to patients with non-brisk and absent TILs, for which there were no differences in RFS (p=0.40) or OS (p=0.41). TIL quantitation by immunohistochemistry did not improve prognostication compared to TIL grading on hematoxylin and eosin stained sections. Melanomas with non-brisk and absent TILs share similar immunoregulatory gene expression profiles. In contrast, melanomas with brisk TILs demonstrate upregulation of T-cell activation pathways and inhibition of upstream immune checkpoint regulators. The presence of TILs in primary melanomas represents a heterogeneous group and caution in prognostic interpretation is warranted. Melanomas with brisk TILs are defined by an immunostimulatory gene expression profile and improved prognosis compared to melanomas with non-brisk or absent TILs.

Deployment of data generation devices such as sensors and smart meters have been accelerating toward the vision of smart grid. The volume of data to be collected increases tremendously. Secure, efficient, and scalable data collection becomes a challenging task. In this paper, we present a secure and scalable data communications protocol for smart grid data collection. Under a hierarchical architecture, relay nodes [also known as data collectors (DCs)] collect and convey the data securely from measurement devices to the power operator. While the DCs can verify the integrity, they are not given access to the content, which may pave the way for third party providers to deliver value-added services or even the data collection itself. We further present optimization solutions for minimizing the total data collection time.Index Terms-Data collection with time minimization in the smart grid, scalable data collection in the smart grid, secure data collection in the smart grid.

Recently, we reported the identification of a novel gene named RBEL1 (Rab-like protein 1) and characterized its two encoded isoforms, RBEL1A and RBEL1B, that function as novel GTPases of Ras superfamily. Here we report the identification of two additional splice variants of RBEL1 that we have named RBEL1C and -D. All four RBEL1 isoforms (A, B, C, and D) have identical N termini harboring the Rab-like GTPase domains but contain variable C termini. Although all isoforms can be detected in both cytoplasm and nucleus, RBEL1A is predominantly cytoplasmic, whereas RBEL1B is mostly nuclear. RBEL1C and -D, by contrast, are evenly distributed between the cytoplasm and nucleus. Furthermore, all four RBEL1 proteins are also capable of associating with cellular membrane. The RBEL1 proteins also exhibit a unique nucleotide-binding potential and, whereas the larger A and B isoforms are mainly GTP-bound, the smaller C and D variants bind to both GTP and GDP. Furthermore, a regulatory region at amino acid position 236 -302 immediately adjacent to the GTP-binding domain is important for GTP-binding potential of RBEL1A, because deletion of this region converts RBEL1A from predominantly GTP-bound to GDP-bound. RBEL1 knockdown via RNA interference results in marked cell growth suppression, which is associated with morphological and biochemical features of apoptosis as well as inhibition of extracellular signal-regulated kinase phosphorylation. Taken together, our results indicate that RBEL1 proteins are linked to cell growth and survival and possess unique biochemical, cellular, and functional characteristics and, therefore, appear to form a novel subfamily of GTPases within the Ras superfamily.

Human Monoglyceride Lipase (MGL) is a recently identified lipase and very little is known about its regulation and function in cellular regulatory processes, particularly in context to human malignancy. In this study, we investigated the regulation and function of Monoglyceride Lipase in human cancer(s) and report that MGL expression was either absent or reduced in the majority of primary colorectal cancers. Immunohistochemical studies showed that reduction of MGL expression in the colorectal tumor tissues predominantly occurred in the cancerous epithelial cells. MGL was found to reside in the core surface of a cellular organelle named “lipid body”. Furthermore, it was found to selectively interact with a number of phospholipids including phosphotidic acid and phosphoinositol(3,4,5)P3, phosphoinositol(3,5)P2, phosphoinositol(3,4)P2 and several other phosphoinositides, and among all phosphoinositides analyzed, its interaction with PI(3,4,5)P3 was found to be the strongest. In addition, overexpression of MGL suppressed colony formation in tumor cell lines and knockdown of MGL resulted in increased Akt phosphorylation. Together, our results suggest that MGL plays a negative regulatory role in PI3-K/Akt signaling and tumor cell growth.

The transmission of energy is monitored in the smart grid through deploying sensors in all the components, including the overhead transmission lines. There are many poles/towers supporting a long overhead transmission line. Naturally, sensors are deployed on the location close to the poles/towers on each span. Due to the limited transmission range of the wireless transceiver module of a sensor, researchers generally assume that data generated by a sensor have to be delivered to the substation through a set of sensors in-between. This results in a linear network model. In this paper, we first analyze the performance of this model in handling the traffics extracted from an existing testbed. We realize that the linear network model may not be sufficient to support future smart grid applications which may have diversified requirements on data delivery. We then study a new network model in which sensor/relay nodes can also communicate with other nodes using a wide area network such as the cellular network. In this new model, the network formed can be reconfigured based on the application requirements to deliver information to the substations efficiently and effectively.