Gaussian Process (GP) models are extensively used in data analysis given their flexible modeling capabilities and interpretability. The fully Bayesian treatment of GP models is analytically ...intractable, and therefore it is necessary to resort to either deterministic or stochastic approximations. This paper focuses on stochastic-based inference techniques. After discussing the challenges associated with the fully Bayesian treatment of GP models, a number of inference strategies based on Markov chain Monte Carlo methods are presented and rigorously assessed. In particular, strategies based on efficient parameterizations and efficient proposal mechanisms are extensively compared on simulated and real data on the basis of convergence speed, sampling efficiency, and computational cost.
The Hall effect, which originates from the motion of charged particles in magnetic fields, has deep consequences for the description of materials, extending far beyond condensed matter. Understanding ...such an effect in interacting systems represents a fundamental challenge, even for small magnetic fields. In this work, we used an atomic quantum simulator in which we tracked the motion of ultracold fermions in two-leg ribbons threaded by artificial magnetic fields. Through controllable quench dynamics, we measured the Hall response for a range of synthetic tunneling and atomic interaction strengths. We unveil a universal interaction-independent behavior above an interaction threshold, in agreement with theoretical analyses. The ability to reach hard-to-compute regimes demonstrates the power of quantum simulation to describe strongly correlated topological states of matter.
Cyclin-dependent kinase 12 (CDK12) overexpression is implicated in breast cancer, but whether it has a primary or only a cooperative tumorigenic role is unclear. Here, we show that transgenic CDK12 ...overexpression in the mouse mammary gland per se is sufficient to drive the emergence of multiple and multifocal tumors, while, in cooperation with known oncogenes, it promotes earlier tumor onset and metastasis. Integrative transcriptomic, metabolomic and functional data reveal that hyperactivation of the serine-glycine-one-carbon network is a metabolic hallmark inherent to CDK12-induced tumorigenesis. Consistently, in retrospective patient cohort studies and in patient-derived xenografts, CDK12-overexpressing breast tumors show positive response to methotrexate-based chemotherapy targeting CDK12-induced metabolic alterations, while being intrinsically refractory to other types of chemotherapy. In a retrospective analysis of hormone receptor-negative and lymph node-positive breast cancer patients randomized in an adjuvant phase III trial to 1-year low-dose metronomic methotrexate-based chemotherapy or no maintenance chemotherapy, a high CDK12 status predicts a dramatic reduction in distant metastasis rate in the chemotherapy-treated vs. not-treated arm. Thus, by coupling tumor progression with metabolic reprogramming, CDK12 creates an actionable vulnerability for breast cancer therapy and might represent a suitable companion biomarker for targeted antimetabolite therapies in human breast cancers.
Hemophagocytic lymphohistiocytosis in the ED Cesarine, Joseph, MD; Filippone, Lisa M., MD; Filippone, Edward J., MD
The American journal of emergency medicine,
10/2016, Letnik:
34, Številka:
10
Journal Article
Recenzirano
A previously oriented 72-year-old man with a history of hypertension, coronary artery disease, and chronic obstructive pulmonary disease presented to the emergency department (ED) with a change in ...mental status and jaundice. ...the patient satisfied Histiocyte Society criteria for diagnosing HLH in the pediatric age range (6 of 8 criteria, see Table 2) as well criteria developed for diagnosing reactive sHLH in adults (H-score of 224 giving a 97% chance of having sHLH).  Presentation Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Hemoglobin (14.0-18.0 g/dL)/hematocrit (42%-52%) 12.2/36.4 11.6/33.910.0/29.010.1/29.7 9.3/27.09.5/27.39.4/27.3 10.0/30.310.1/30.69.3/27.2 8.6/25.17.9/23.6 8.4/24.6 8.1/23.9 8.3/24.8 8.1/23.8 WBC (4.5-11.0 x 103/μL) 0.98 0.910.710.68 0.490.500.43 0.590.510.49 0.380.37 0.38 0.67 1.97 3.24 Platelets (150-400 x 103/μL) 86 605440 333431 323232 2853a 49 65 95 147 Ferritin (15-400 ng/mL) 1826 4836  12596   14995   Fibrinogen (134-351 mg/dL) 257   119      d-Dimer (<0.50 μg/mL) 11.9         AST (10-35 U/L)/ALT (6-45 U/L) 75/39   106/38      Total bilirubin (0.0-1.2 mg/dL)/direct bilirubin (0.0-0.3 mg/dL) 2.9/0.7   2.1/0.8      LDH (110-230 U/L) 466   732      Triglycerides (<50.0 mg/dL)  123        Sodium (135-145 mmol/L) 134 134 135 135 134135 136 135 138 139 Bicarbonate (23-30 mmol/L) 21 20 21 22 2323 24 23 24 24 Creatinine (0.6-1.2 mg/dL) 1.53 1.54 1.36 1.21 1.301.34 1.35 1.26 1.09 1.04 Table 1 Laboratory values HLH2004 diagnostic criteriaa H-score diagnostic criteriab Macrophage activation syndromec The diagnosis of HLH can be established by a molecular diagnosis consistent with HLH or by meeting >=5 of the following 8 clinical and laboratory diagnostic criteria: A higher score is associated with a higher risk for HLH, as calculated based on the following criteria and scoring system A patient with known or suspected systemic juvenile idiopathic arthritis is classified as having macrophage activation syndrome if the following criteria are met: 1.
The transcription factor Pax8, a member of the Paired-box gene family, is a critical regulator required for proper development and differentiation of thyroid follicular cells. Despite being Pax8 well ...characterized with respect to its role in regulating genes responsible for thyroid differentiation, its involvement in cell survival and proliferation has been hypothesized but remains unclear. Here, we show that Pax8 overexpression significantly increases proliferation and colony-forming efficiency of Fischer rat thyroid line 5 epithelial cells, although it is not sufficient to overcome their hormone dependence. More interestingly, we show that Pax8-specific silencing induces apoptosis through a p53-dependent pathway that involves caspase-3 activation and cleavage of poly(ADP)ribose polymerase. Our data indicate that tumor protein 53 induced nuclear protein 1 (tp53inp1), a positive regulator of p53-dependent cell cycle arrest and apoptosis, is a transcriptional target of Pax8 and is upregulated by Pax8 knockdown. Remarkably, tp53inp1 silencing significantly abolishes Pax8-induced apoptosis thus suggesting that tp53inp1 may be the mediator of the observed effects. In conclusion, our data highlight that Pax8 is required for the survival of differentiated epithelial cells and its expression levels are able to modulate the proliferation rate of such cells.
The interplay of interactions and strong disorder can lead to an exotic quantum many-body localized (MBL) phase of matter. Beyond the absence of transport, the MBL phase has distinctive signatures, ...such as slow dephasing and logarithmic entanglement growth; they commonly result in slow and subtle modifications of the dynamics, rendering their measurement challenging. Here, we experimentally characterize these properties of the MBL phase in a system of coupled superconducting qubits. By implementing phase sensitive techniques, we map out the structure of local integrals of motion in the MBL phase. Tomographic reconstruction of single and two-qubit density matrices allows us to determine the spatial and temporal entanglement growth between the localized sites. In addition, we study the preservation of entanglement in the MBL phase. The interferometric protocols implemented here detect affirmative quantum correlations and exclude artifacts due to the imperfect isolation of the system. By measuring elusive MBL quantities, our work highlights the advantages of phase sensitive measurements in studying novel phases of matter.
Persistent activation of mTOR (mammalian target of rapamycin) in diabetes increases the vulnerability of the heart to ischemia/reperfusion (I/R) injury. We show here that infusion of rapamycin (mTOR ...inhibitor) at reperfusion following ischemia reduced myocardial infarct size and apoptosis with restoration of cardiac function in type 1 diabetic rabbits. Likewise, treatment with rapamycin protected hyperglycemic human-pluripotent-stem-cells-derived cardiomyocytes (HG-hiPSC-CMs) following simulated ischemia (SI) and reoxygenation (RO). Phosphorylation of S6 (mTORC1 marker) was increased, whereas AKT phosphorylation (mTORC2 marker) and microRNA-302a were reduced with concomitant increase of its target, PTEN, following I/R injury in diabetic heart and HG-hiPSC-CMs. Rapamycin inhibited mTORC1 and PTEN, but augmented mTORC2 with restoration of miRNA-302a under diabetic conditions. Inhibition of miRNA-302a blocked mTORC2 and abolished rapamycin-induced protection against SI/RO injury in HG-hiPSC-CMs. We conclude that rapamycin attenuates reperfusion injury in diabetic heart through inhibition of PTEN and mTORC1 with restoration of miR-302a-mTORC2 signaling.
Display omitted
•miR-302a and AKT phosphorylation are suppressed in post-ischemic diabetic heart•Negative regulator of insulin signaling, PTEN, is induced after ischemia reperfusion•miRNA-302a-mimic abolishes ischemic injury in hyperglycemic human iPS cardiocytes•Rapamycin treatment restores miR-302a-mTORC2 cardioprotective signaling in diabetes
Human Metabolism; Molecular Biology
Sugarcane is known for its highly complex genetics and more knowledge is needed for better use and conservation of genetic materials. In order to identify genotypes and to assess genetic diversity, ...diverse data sets such as morphological and molecular markers are used as a general approach. To evaluate the usefulness of different markers, important sugarcane genotypes in Argentina were characterized by AFLP, SSR and morphological traits. All genotypes characterized were grouped in one main cluster in dendrograms using two independent softwares. Interestingly, local genotypes grouped together with USA varieties and no clear genetic differentiation could be found probably due to intensive germplasm exchange between these breeding programs. The molecular markers tested were useful for genetic diversity assessment as well as for genotype identification. These markers should be included in the internationally established characters for sugarcane variety protection as they give a better view on whole genome complexity. Additionally, genetic similarities obtained from molecular markers will provide more accurate information to breeders than the pedigree method, especially when considering the asymmetric genetic inheritance of sugarcane. Morphological traits are valuable tools to identify genotypes since they reflect external resemblance more than genetic relatedness. When they were combined with molecular markers the dendogram obtained revealed genetic relationships and the genetic diversity was better estimated. In summary, both methods appear to be useful, complementing each other and should be used together to assist sugarcane breeders in estimating genetic diversity, electing parents for crossings, identifying superior lines and to protect intellectual property rights.
PDF
