Quantitative model for inferring dynamic regulation of the tumour suppressor gene p53

Background: The availability of various "omics" datasets creates a prospect of performing the study of genome-wide genetic regulatory networks. However, one of the major challenges of using mathematical models to infer genetic regulation from microarray datasets is the lack of information for protein concentrations and activities. Most of the previous researches were based on an assumption that the mRNA levels of a gene are consistent with its protein activities, though it is not always the case. Therefore, a more sophisticated modelling framework together with the corresponding inference methods is needed to accurately estimate genetic regulation from "omics" datasets. Results: This work developed a novel approach, which is based on a nonlinear mathematical model, to infer genetic regulation from microarray gene expression data. By using the p53 network as a test system, we used the nonlinear model to estimate the activities of transcription factor (TF) p53 from the expression levels of its target genes, and to identify the activation/inhibition status of p53 to its target genes. The predicted top 317 putative p53 target genes were supported by DNA sequence analysis. A comparison between our prediction and the other published predictions of p53 targets suggests that most of putative p53 targets may share a common depleted or enriched sequence signal on their upstream non-coding region. Conclusions: The proposed quantitative model can not only be used to infer the regulatory relationship between TF and its down-stream genes, but also be applied to estimate the protein activities of TF from the expression levels of its target genes

How Local is the Local Diversity? Reinforcing Sequential Determinantal Point Processes with Dynamic Ground Sets for Supervised Video Summarization

The large volume of video content and high viewing frequency demand automatic video summarization algorithms, of which a key property is the capability of modeling diversity. If videos are lengthy like hours-long egocentric videos, it is necessary to track the temporal structures of the videos and enforce local diversity. The local diversity refers to that the shots selected from a short time duration are diverse but visually similar shots are allowed to co-exist in the summary if they appear far apart in the video. In this paper, we propose a novel probabilistic model, built upon SeqDPP, to dynamically control the time span of a video segment upon which the local diversity is imposed. In particular, we enable SeqDPP to learn to automatically infer how local the local diversity is supposed to be from the input video. The resulting model is extremely involved to train by the hallmark maximum likelihood estimation (MLE), which further suffers from the exposure bias and non-differentiable evaluation metrics. To tackle these problems, we instead devise a reinforcement learning algorithm for training the proposed model. Extensive experiments verify the advantages of our model and the new learning algorithm over MLE-based methods

Abnormal function of the vasopressin-cyclic-AMP-aquaporin2 axis during urine concentrating and diluting in patients with reduced renal function. A case control study

<p>Abstract</p> <p>Background</p> <p>The kidneys ability to concentrate and dilute urine is deteriorated during progressive renal insufficiency. We wanted to test the hypothesis that these phenomena could be attributed to an abnormal function of the principal cells in the distal part of the nephron.</p> <p>Methods</p> <p>Healthy control subjects and patients with chronic kidney diseases were studied. Group 1 comprised healthy subjects, n = 10. Groups 2-4 comprised patients with chronic kidney disease (Group 2, n = 14, e-GFR ? 90 m1/min; Group 3, n = 11, 60 m1/min ? e-GFR < 90 ml/min; and Group 4, n = 16, 15 ml/min ? e-GFR < 60 ml/min). The subjects collected urine during 24 hours. A urine concentrating test was done by thirsting during the following 12 hours. Thereafter, a urine diluting test was performed with a water load of 20 ml/kg body weight. The effect variables were urinary excretions of aquaporin2 (u-AQP2), cyclic-AMP (u-c-AMP), urine volume (UV), free water clearance (C_H2O), urine osmolarity (u-Osm), and plasma arginine vasopressin (p-AVP).</p> <p>Results</p> <p>After fluid deprivation, u-Osm increased. In all groups, UV and C_H2Odecreased and u-AQP2 and u-c-AMP increased in Groups 1 and 2, but were unchanged in Group 3 and 4. P-AVP was significantly higher in Group 4 than in the other groups. During urine diluting, UV and C_H2Oreached significantly higher levels in Groups 1-3 than Group 4. Both before and after water loading, u-AQP2 and p-AVP were significantly higher and u-c-AMP was significantly lower in Group 4 than the other groups. Estimated-GFR was correlated negatively to p-AVP and positively to u-c-AMP.</p> <p>Conclusions</p> <p>Patients with moderately severe chronic kidney disease have a reduced renal concentrating and diluting capacity compared to both patients with milder chronic kidney disease and healthy control subjects. These phenomena can be attributed, at least partly, to an abnormally decreased response in the AVP-c-AMP-AQP2 axis.</p> <p>ClinicalTrials.Gov Identifier: NCT00313430</p

JCMT POL-2 and BISTRO Survey Observations of Magnetic Fields in the L1689 Molecular Cloud

We present 850 μm polarization observations of the L1689 molecular cloud, part of the nearby Ophiuchus molecular cloud complex, taken with the POL-2 polarimeter on the James Clerk Maxwell Telescope (JCMT). We observe three regions of L1689: the clump L1689N which houses the IRAS 16293-2433 protostellar system, the starless clump SMM-16, and the starless core L1689B. We use the Davis–Chandrasekhar–Fermi method to estimate plane-of-sky field strengths of 366 ± 55 μG in L1689N, 284 ± 34 μG in SMM-16, and 72 ± 33 μG in L1689B, for our fiducial value of dust opacity. These values indicate that all three regions are likely to be magnetically transcritical with sub-Alfvénic turbulence. In all three regions, the inferred mean magnetic field direction is approximately perpendicular to the local filament direction identified in Herschel Space Telescope observations. The core-scale field morphologies for L1689N and L1689B are consistent with the cloud-scale field morphology measured by the Planck Space Observatory, suggesting that material can flow freely from large to small scales for these sources. Based on these magnetic field measurements, we posit that accretion from the cloud onto L1689N and L1689B may be magnetically regulated. However, in SMM-16, the clump-scale field is nearly perpendicular to the field seen on cloud scales by Planck, suggesting that it may be unable to efficiently accrete further material from its surroundings

Microwave studies of the fractional Josephson effect in HgTe-based Josephson junctions

The rise of topological phases of matter is strongly connected to their potential to host Majorana bound states, a powerful ingredient in the search for a robust, topologically protected, quantum information processing. In order to produce such states, a method of choice is to induce superconductivity in topological insulators. The engineering of the interplay between superconductivity and the electronic properties of a topological insulator is a challenging task and it is consequently very important to understand the physics of simple superconducting devices such as Josephson junctions, in which new topological properties are expected to emerge. In this article, we review recent experiments investigating topological superconductivity in topological insulators, using microwave excitation and detection techniques. More precisely, we have fabricated and studied topological Josephson junctions made of HgTe weak links in contact with two Al or Nb contacts. In such devices, we have observed two signatures of the fractional Josephson effect, which is expected to emerge from topologically-protected gapless Andreev bound states. We first recall the theoretical background on topological Josephson junctions, then move to the experimental observations. Then, we assess the topological origin of the observed features and conclude with an outlook towards more advanced microwave spectroscopy experiments, currently under development.Comment: Lectures given at the San Sebastian Topological Matter School 2017, published in "Topological Matter. Springer Series in Solid-State Sciences, vol 190. Springer

Preconditioning of mesenchymal stromal cells with low-intensity ultrasound: influence on chondrogenesis and directed SOX9 signaling pathways

Background: Continuous low-intensity ultrasound (cLIUS) facilitates the chondrogenic differentiation of human mesenchymal stromal cells (MSCs) in the absence of exogenously added transforming growth factor-beta (TGFβ) by upregulating the expression of transcription factor SOX9, a master regulator of chondrogenesis. The present study evaluated the molecular events associated with the signaling pathways impacting SOX9 gene and protein expression under cLIUS. Methods: Human bone marrow-derived MSCs were exposed to cLIUS stimulation at 14 kPa (5 MHz, 2.5 Vpp) for 5 min. The gene and protein expression of SOX9 was evaluated. The specificity of SOX9 upregulation under cLIUS was determined by treating the MSCs with small molecule inhibitors of select signaling molecules, followed by cLIUS treatment. Signaling events regulating SOX9 expression under cLIUS were analyzed by gene expression, immunofluorescence staining, and western blotting. Results: cLIUS upregulated the gene expression of SOX9 and enhanced the nuclear localization of SOX9 protein when compared to non-cLIUS-stimulated control. cLIUS was noted to enhance the phosphorylation of the signaling molecule ERK1/2. Inhibition of MEK/ERK1/2 by PD98059 resulted in the effective abrogation of cLIUS-induced SOX9 expression, indicating that cLIUS-induced SOX9 upregulation was dependent on the phosphorylation of ERK1/2. Inhibition of integrin and TRPV4, the upstream cell-surface effectors of ERK1/2, did not inhibit the phosphorylation of ERK1/2 and therefore did not abrogate cLIUS-induced SOX9 expression, thereby suggesting the involvement of other mechanoreceptors. Consequently, the effect of cLIUS on the actin cytoskeleton, a mechanosensitive receptor regulating SOX9, was evaluated. Diffused and disrupted actin fibers observed in MSCs under cLIUS closely resembled actin disruption by treatment with cytoskeletal drug Y27632, which is known to increase the gene expression of SOX9. The upregulation of SOX9 under cLIUS was, therefore, related to cLIUS-induced actin reorganization. SOX9 upregulation induced by actin reorganization was also found to be dependent on the phosphorylation of ERK1/2. Conclusions: Collectively, preconditioning of MSCs by cLIUS resulted in the nuclear localization of SOX9, phosphorylation of ERK1/2 and disruption of actin filaments, and the expression of SOX9 was dependent on the phosphorylation of ERK1/2 under cLIUS

Pancreatic adenocarcinoma in a patient with Situs Inversus: a case report of this rare coincidence

<p>Abstract</p> <p>Background</p> <p><it>Situs inversus </it>(SI) is a relatively rare occurrence in patients with pancreatic adenocarcinoma. Pancreatic resection in these patients has rarely been described. CT scan imaging is a principle modality for detecting pancreatic cancer and its use in SI patients is seldom reported.</p> <p>Case Presentation</p> <p>We report a 48 year old woman with SI who, despite normal CT scan 8 months earlier, presented with obstructive jaundice and a pancreatic head mass requiring a pancreaticoduodenectomy. The surgical pathology report demonstrated pancreatic adenocarcinoma.</p> <p>Conclusion</p> <p>SI is a rare condition with concurrent pancreatic cancer being even rarer. Despite the rarity, pancreaticoduodenectomy in these patients for resectable lesions is safe as long as special consideration to the anatomy is taken. Additionally, radiographic imaging has significantly improved detection of early pancreatic cancer; however, there continues to be a need for improved detection of small neoplasms.</p

Localisation of RNAs into the germ plasm of vitellogenic xenopus oocytes

We have studied the localisation of mRNAs in full-grown Xenopus laevis oocytes by injecting fluorescent RNAs, followed by confocal microscopy of the oocyte cortex. Concentrating on RNA encoding the Xenopus Nanos homologue, nanos1 (formerly Xcat2), we find that it consistently localised into aggregated germ plasm ribonucleoprotein (RNP) particles, independently of cytoskeletal integrity. This implies that a diffusion/entrapment-mediated mechanism is active, as previously reported for previtellogenic oocytes. Sometimes this was accompanied by localisation into scattered particles of the “late”, Vg1/VegT pathway; occasionally only late pathway localisation was seen. The Xpat RNA behaved in an identical fashion and for neither RNA was the localisation changed by any culture conditions tested. The identity of the labelled RNP aggregates as definitive germ plasm was confirmed by their inclusion of abundant mitochondria and co-localisation with the germ plasm protein Hermes. Further, the nanos1/Hermes RNP particles are interspersed with those containing the germ plasm protein Xpat. These aggregates may be followed into the germ plasm of unfertilized eggs, but with a notable reduction in its quantity, both in terms of injected molecules and endogenous structures. Our results conflict with previous reports that there is no RNA localisation in large oocytes, and that during mid-oogenesis even germ plasm RNAs localise exclusively by the late pathway. We find that in mid oogenesis nanos1 RNA also localises to germ plasm but also by the late pathway. Late pathway RNAs, Vg1 and VegT, also may localise into germ plasm. Our results support the view that mechanistically the two modes of localisation are extremely similar, and that in an injection experiment RNAs might utilise either pathway, the distinction in fates being very subtle and subject to variation. We discuss these results in relation to their biological significance and the results of others

The JCMT BISTRO-2 Survey: The Magnetic Field in the Center of the Rosette Molecular Cloud

We present the first 850 μm polarization observations in the most active star-forming site of the Rosette Molecular Cloud (d ~ 1.6 kpc) in the wall of the Rosette Nebula, imaged with the SCUBA-2/POL-2 instruments of the James Clerk Maxwell telescope, as part of the B-Fields In Star-forming Region Observations 2 (BISTRO-2) survey. From the POL-2 data we find that the polarization fraction decreases with the 850 μm continuum intensity with α = 0.49 ± 0.08 in the p ∝ I−α relation, which suggests that some fraction of the dust grains remain aligned at high densities. The north of our 850 μm image reveals a "gemstone ring" morphology, which is a ~1 pc diameter ring-like structure with extended emission in the "head" to the southwest. We hypothesize that it might have been blown by feedback in its interior, while the B-field is parallel to its circumference in most places. In the south of our SCUBA-2 field the clumps are apparently connected with filaments that follow infrared dark clouds. Here, the POL-2 magnetic field orientations appear bimodal with respect to the large-scale Planck field. The mass of our effective mapped area is ~174 M⊙, which we calculate from 850 μm flux densities. We compare our results with masses from large-scale emission-subtracted Herschel 250 μm data and find agreement within 30%. We estimate the plane-of-sky B-field strength in one typical subregion using the Davis–Chandrasekhar–Fermi technique and find 80 ± 30 μG toward a clump and its outskirts. The estimated mass-to-flux ratio of λ = 2.3 ± 1.0 suggests that the B-field is not sufficiently strong to prevent gravitational collapse in this subregion