Plant IsomiR Atlas : Large Scale Detection, Profiling, and Target Repertoire of IsomiRs in Plants

microRNAs (miRNAs) play an important role as key regulators controlling the post-transcriptional events in plants across development, abiotic and biotic stress, tissue polarity and also in defining the evolutionary basis of the origin of the post-transcriptional machinery. Identifying patterns of regulated and co-regulated small RNAs, in particular miRNAs and their sequence variants with the availability of next generation sequencing approaches has widely demonstrated the role of miRNAs and their temporal regulation in maintaining plant development and their response to stress conditions. Although the role of canonical miRNAs has been widely explored and functional diversity is revealed, those works for isomiRs are still limited and urgent to be carried out across plants. This relative lack of information with respect to isomiRs might be attributed to the non-availability of large-scale detection of isomiRs across wide plant species. In the present research, we addressed this by developing Plant isomiR Atlas, which provides large-scale detection of isomiRs across 23 plant species utilizing 677 smallRNAs datasets and reveals a total of 98,374 templated and non-templated isomiRs from 6,167 precursors. Plant isomiR Atlas provides several visualization features such as species specific isomiRs, isomiRs and canonical miRNAs overlap, terminal modification classifications, target identification using psRNATarget and TargetFinder and also canonical miRNAs: target interactions. Plant isomiR Atlas will play a key role in understanding the regulatory nature of miRNAome and will accelerate to understand the functional role of isomiRs. ONE SENTENCE SUMMARY Plant isomiR Atlas will play a key role in understanding the regulatory nature of miRNAome and will accelerate the understanding and diversity of functional targets of plants isomiRs.Peer reviewe

Upregulation of CPT1A Is Essential for the Tumor-Promoting Effect of Adipocytes in Colon Cancer

Colon tumors grow in an adipose tissue-enriched microenvironment. Locally advanced colon cancers often invade into surrounding adipose tissue with a direct contact with adipocytes. We have previously shown that adipocytes promote tumor growth by modulating cellular metabolism. Here we demonstrate that carnitine palmitoyltransferase I (CPT1A), a key enzyme controlling fatty acid oxidation (FAO), was upregulated in colon cancer cells upon exposure to adipocytes or fatty acids. In addition, CPT1A expression was increased in invasive tumor cells within the adipose tissue compared to tumors without direct contact with adipocytes. Silencing CPT1A abolished the protective effect provided by fatty acids against nutrient deprivation and reduced tumor organoid formation in 3D culture and the expression of genes associated with cancer stem cells downstream of Wnt/β-catenin. Mechanistically, CPT1A-dependent FAO promoted the acetylation and nuclear translocation of β-catenin. Furthermore, knockdown of CPT1A blocked the tumor-promoting effect of adipocytes in vivo and inhibited xenograft tumor initiation. Taken together, our findings identify CPT1A-depedent FAO as an essential metabolic pathway that enables the interaction between adipocytes and colon cancer cells

Sugihara Causality Analysis of Scalp EEG for Detection of Early Alzheimer\u27s Disease

Recently, Sugihara proposed an innovative causality concept, which, in contrast to statistical predictability in Granger sense, characterizes underlying deterministic causation of the system. This work exploits Sugihara causality analysis to develop novel EEG biomarkers for discriminating normal aging from mild cognitive impairment (MCI) and early Alzheimer\u27s disease (AD). The hypothesis of this work is that scalp EEG based causality measurements have different distributions for different cognitive groups and hence the causality measurements can be used to distinguish between NC, MCI, and AD participants. The current results are based on 30-channel resting EEG records from 48 age-matched participants (mean age 75.7 years) - 15 normal controls (NCs), 16 MCI, and 17 early-stage AD. First, a reconstruction model is developed for each EEG channel, which predicts the signal in the current channel using data of the other 29 channels. The reconstruction model of the target channel is trained using NC, MCI, or AD records to generate an NC-, MCI-, or AD-specific model, respectively. To avoid over fitting, the training is based on the leave-one-out principle. Sugihara causality between the channels is described by a quality score based on comparison between the reconstructed signal and the original signal. The quality scores are studied for their potential as biomarkers to distinguish between the different cognitive groups. First, the dimension of the quality scores is reduced to two principal components. Then, a three-way classification based on the principal components is conducted. Accuracies of 95.8%, 95.8%, and 97.9% are achieved for resting eyes open, counting eyes closed, and resting eyes closed protocols, respectively. This work presents a novel application of Sugihara causality analysis to capture characteristic changes in EEG activity due to cognitive deficits. The developed method has excellent potential as individualized biomarkers in the detection of pathophysiological changes in early-stage AD

Functional Association of Gdown1 with RNA Polymerase II Poised on Human Genes

Most human genes are loaded with promoter-proximally paused RNA polymerase II (Pol II) molecules that are poised for release into productive elongation by P-TEFb. We present evidence that Gdown1, the product of the POLR2M gene that renders Pol II responsive to Mediator, is involved in Pol II elongation control. During in vitro transcription, Gdown1 specifically blocked elongation stimulation by TFIIF, inhibited the termination activity of TTF2, and influenced pausing factors NELF and DSIF, but did not affect the function of TFIIS or the mRNA capping enzyme. Without P-TEFb, Gdown1 led to the production of stably paused polymerases in the presence of nuclear extract. Supporting these mechanistic insights, ChIP-Seq demonstrated that Gdown1 mapped over essentially all poised polymerases across the human genome. Our results establish that Gdown1 stabilizes poised polymerases while maintaining their responsiveness to P-TEFb and suggest that Mediator overcomes a Gdown1-mediated block of initiation by allowing TFIIF function.National Human Genome Research Institute (U.S.) (Grant HG002668-05

GPU-based ultra-fast direct aperture optimization for online adaptive radiation therapy

Online adaptive radiation therapy (ART) has great promise to significantly reduce normal tissue toxicity and/or improve tumor control through real-time treatment adaptations based on the current patient anatomy. However, the major technical obstacle for clinical realization of online ART, namely the inability to achieve real-time efficiency in treatment re-planning, has yet to be solved. To overcome this challenge, this paper presents our work on the implementation of an intensity modulated radiation therapy (IMRT) direct aperture optimization (DAO) algorithm on graphics processing unit (GPU) based on our previous work on CPU. We formulate the DAO problem as a large-scale convex programming problem, and use an exact method called column generation approach to deal with its extremely large dimensionality on GPU. Five 9-field prostate and five 5-field head-and-neck IMRT clinical cases with 5\times5 mm2 beamlet size and 2.5\times2.5\times2.5 mm3 voxel size were used to evaluate our algorithm on GPU. It takes only 0.7~2.5 seconds for our implementation to generate optimal treatment plans using 50 MLC apertures on an NVIDIA Tesla C1060 GPU card. Our work has therefore solved a major problem in developing ultra-fast (re-)planning technologies for online ART

Adipocytes Activate Mitochondrial Fatty Acid Oxidation and Autophagy to Promote Tumor Growth in Colon Cancer

Obesity has been associated with increased incidence and mortality of a wide variety of human cancers including colorectal cancer. However, the molecular mechanism by which adipocytes regulate the metabolism of colon cancer cells remains elusive. In this study, we showed that adipocytes isolated from adipose tissues of colon cancer patients have an important role in modulating cellular metabolism to support tumor growth and survival. Abundant adipocytes were found in close association with invasive tumor cells in colon cancer patients. Co-culture of adipocytes with colon cancer cells led to a transfer of free fatty acids that released from the adipocytes to the cancer cells. Uptake of fatty acids allowed the cancer cells to survive nutrient deprivation conditions by upregulating mitochondrial fatty acid β-oxidation. Mechanistically, co-culture of adipocytes or treating cells with fatty acids induced autophagy in colon cancer cells as a result of AMPK activation. Inhibition of autophagy attenuated the ability of cancer cells to utilize fatty acids and blocked the growth-promoting effect of adipocytes. In addition, we found that adipocytes stimulated the expression of genes associated with cancer stem cells and downregulated genes associated with intestinal epithelial cell differentiation in primary colon cancer cells and mouse tumor organoids. Importantly, the presence of adipocytes promoted the growth of xenograft tumors in vivo. Taken together, our results show that adipocytes in the tumor microenvironment serve as an energy provider and a metabolic regulator to promote the growth and survival of colon cancer cells

Downregulation of SREBP Inhibits Tumor Growth and Initiation by Altering Cellular Metabolism in Colon Cancer

Sterol regulatory element-binding proteins (SREBPs) belong to a family of transcription factors that regulate the expression of genes required for the synthesis of fatty acids and cholesterol. Three SREBP isoforms, SREBP1a, SREBP1c, and SREBP2, have been identified in mammalian cells. SREBP1a and SREBP1c are derived from a single gene through the use of alternative transcription start sites. Here we investigated the role of SREBP-mediated lipogenesis in regulating tumor growth and initiation in colon cancer. Knockdown of either SREBP1 or SREBP2 decreased levels of fatty acids as a result of decreased expression of SREBP target genes required for lipid biosynthesis in colon cancer cells. Bioenergetic analysis revealed that silencing SREBP1 or SREBP2 expression reduced the mitochondrial respiration, glycolysis, as well as fatty acid oxidation indicating an alteration in cellular metabolism. Consequently, the rate of cell proliferation and the ability of cancer cells to form tumor spheroids in suspension culture were significantly decreased. Similar results were obtained in colon cancer cells in which the proteolytic activation of SREBP was blocked. Importantly, knockdown of either SREBP1 or SREBP2 inhibited xenograft tumor growth in vivo and decreased the expression of genes associated with cancer stem cells. Taken together, our findings establish the molecular basis of SREBP-dependent metabolic regulation and provide a rationale for targeting lipid biosynthesis as a promising approach in colon cancer treatment

Spatial repellency, antifeedant activity and toxicity of three medium chain fatty acids and their methyl esters of coconut fatty acid against stable flies

BACKGROUND: Stable flies are one of the most detrimental arthropod pests to livestock. With changing climates and agronomic practices, they expand their roles as pests and disease vectors as well. Their painful bites reduce livestock productivity, annoy companion animals, and interfere with human recreational activities. Current management technologies are unable to effectively control stable flies. The present study reports new results concerning the contact, spatial repellency, and toxicity of a bio-based product, coconut fatty acid and their methyl ester derivatives of free fatty acids of C8:0, C10:0 and C12:0 to stable flies. RESULTS: Three medium chain fatty acid methyl esters (C8:0 , C10:0 and C12:0 ) showed strong antifeedant activity against stable flies and their strengths were dose-dependent. Only the C8:0 acid, C8:0 - and C10:0 methyl esters elicited significant antennal responses. Laboratory single cage olfactometer bioassays revealed that coconut fatty acid and C8:0 methyl ester displayed active spatial repellency. All three methyl esters showed strong toxicity against stable flies. CONCLUSION: Antifeedant activity is the main method through which coconut fatty acid deters stable fly blood-feeding. The C8:0, C10:0 and C12:0 methyl esters act not only as strong antifeedants, but also possess strong toxicity against stable fly adults. Limited spatial repellency was observed from coconut fatty acid and C8:0 methyl ester

Spatial repellency, antifeedant activity and toxicity of three medium chain fatty acids and their methyl esters of coconut fatty acid against stable flies

BACKGROUND: Stable flies are one of the most detrimental arthropod pests to livestock. With changing climates and agronomic practices, they expand their roles as pests and disease vectors as well. Their painful bites reduce livestock productivity, annoy companion animals, and interfere with human recreational activities. Current management technologies are unable to effectively control stable flies. The present study reports new results concerning the contact, spatial repellency, and toxicity of a bio-based product, coconut fatty acid and their methyl ester derivatives of free fatty acids of C8:0, C10:0 and C12:0 to stable flies. RESULTS: Three medium chain fatty acid methyl esters (C8:0 , C10:0 and C12:0 ) showed strong antifeedant activity against stable flies and their strengths were dose-dependent. Only the C8:0 acid, C8:0 - and C10:0 methyl esters elicited significant antennal responses. Laboratory single cage olfactometer bioassays revealed that coconut fatty acid and C8:0 methyl ester displayed active spatial repellency. All three methyl esters showed strong toxicity against stable flies. CONCLUSION: Antifeedant activity is the main method through which coconut fatty acid deters stable fly blood-feeding. The C8:0, C10:0 and C12:0 methyl esters act not only as strong antifeedants, but also possess strong toxicity against stable fly adults. Limited spatial repellency was observed from coconut fatty acid and C8:0 methyl ester

Design and Performance of the Hotrod Melt-Tip Ice-Drilling System

We introduce the design and performance of a melt-tip ice-drilling system designed to insert a temperature sensor cable into ice. The melt tip is relatively simple and low cost, designed for a one-way trip to the ice-bed interface. The drilling system consists of a melt tip, umbilical cable, winch, interface, power supply, and support items. The melt tip and the winch are the most novel elements of the drilling system, and we make the hardware and electrical designs of these components available open access. Tests conducted in a laboratory ice well indicate that the melt tip has an electrical energy to forward melting heat transfer efficiency of ~35 % with a theoretical maximum penetration rate of ~12 m/hr at maximum 6.0 kW power. In contrast, ice-sheet testing suggests the melt tip has an analogous heat transfer efficiency of ~15 % with a theoretical maximum penetration rate of ~6 m/hr. We expect the efficiency gap between laboratory and field performance to decrease with increasing operator experience. Umbilical freeze-in due to borehole refreezing is the primary depth-limiting factor of the drilling system. Enthalpy-based borehole refreezing assessments predict refreezing below critical umbilical diameter in ~4 hours at -20 ˚C ice temperatures and ~20 hours at -2 ˚C. This corresponds to a theoretical depth limit of up to ~200 m, depending on firn thickness, ice temperature and operator experience.</p