We introduce an approach for sketch classification based on Fisher vectors that significantly outperforms existing techniques. For the TU-Berlin sketch benchmark Eitz et al. 2012a, our recognition ...rate is close to human performance on the same task. Motivated by these results, we propose a different benchmark for the evaluation of sketch classification algorithms. Our key idea is that the relevant aspect when recognizing a sketch is not the intention of the person who made the drawing, but the information that was effectively expressed. We modify the original benchmark to capture this concept more precisely and, as such, to provide a more adequate tool for the evaluation of sketch classification techniques. Finally, we perform a classification-driven analysis which is able to recover semantic aspects of the individual sketches, such as the quality of the drawing and the importance of each part of the sketch for the recognition.
Pancreatic ductal adenocarcinoma (PDAC) is almost universally fatal. The annual number of deaths equals the number of newly diagnosed cases, despite maximal treatment. The overall 5-year survival ...rate of <5% has remained stubbornly unchanged over the last 30 years, despite tremendous efforts in preclinical and clinical science. There is unquestionably an urgent need to further improve our understanding of pancreatic cancer biology, treatment response and relapse, and to identify novel therapeutic targets. Rigorous research in the field has uncovered genetic aberrations that occur during PDAC development and progression. In most cases, PDAC is initiated by oncogenic mutant KRAS, which has been shown to drive pancreatic neoplasia. However, all attempts to target KRAS directly have failed in the clinic and KRAS is widely assumed to be undruggable. This has led to intense efforts to identify druggable critical downstream targets and nodes orchestrated by mutationally activated KRAS. This includes context-specific KRAS effector pathways, synthetic lethal interaction partners and KRAS-driven metabolic changes. Here, we review recent advances in oncogenic KRAS signalling and discuss how these might benefit PDAC treatment in the future.
Active machine learning puts artificial intelligence in charge of a sequential, feedback-driven discovery process. We present the application of a multi-objective active learning scheme for ...identifying small molecules that inhibit the protein-protein interaction between the anti-cancer target CXC chemokine receptor 4 (CXCR4) and its endogenous ligand CXCL-12 (SDF-1). Experimental design by active learning was used to retrieve informative active compounds that continuously improved the adaptive structure-activity model. The balanced character of the compound selection function rapidly delivered new molecular structures with the desired inhibitory activity and at the same time allowed us to focus on informative compounds for model adjustment. The results of our study validate active learning for prospective ligand finding by adaptive, focused screening of large compound repositories and virtual compound libraries.
Gene expression in eukaryotes requires the effective separation of nuclear transcription and RNA processing from cytosolic translation
. This separation is achieved by the nuclear envelope, which ...controls the exchange of macromolecules through nuclear pores
. During mitosis, however, the nuclear envelope in animal and plant cells disassembles, allowing cytoplasmic and nuclear components to intermix
. When the nuclear envelope is reformed, cytoplasmic components are removed from the nucleus by receptor-mediated transport through nuclear pores
. These pores have a size limit of 39 nanometres
, which raises the question of how larger cytoplasmic molecules are cleared from the nucleus. Here we show in HeLa cells that large cytoplasmic components are displaced before nuclear envelope assembly by the movement of chromosomes to a dense cluster. This clustering occurs when chromosomes approach the poles of anaphase spindles, and is mediated by a microtubule-independent mechanism that involves the surfactant-like protein Ki-67. Ki-67 forms repulsive molecular brushes during the early stages of mitosis
, but during mitotic exit the brushes collapse and Ki-67 promotes chromosome clustering. We show that the exclusion of mature ribosomes from the nucleus after mitosis depends on Ki-67-regulated chromosome clustering. Thus, our study reveals that chromosome mechanics help to re-establish the compartmentalization of eukaryotic cells after open mitosis.
Regional citrate anticoagulation (RCA) is now recommended over systemic heparin for continuous renal replacement therapy in patients without contraindications. Its use is likely to increase ...throughout the world. However, in the absence of citrate blood level monitoring, the diagnosis of citrate accumulation, the most feared complication of RCA, remains relatively complex. It is therefore commonly mistaken with other conditions. This review aims at providing clarifications on RCA-associated acid-base disturbances and their management at the bedside. In particular, the authors wish to propose a clear distinction between citrate accumulation and net citrate overload.
High-frequency stimulation of the globus pallidus internus (GPi) is a highly effective therapy in primary dystonia. Recent reports have also demonstrated almost immediate improvement of motor ...symptoms in patients with tardive dystonia after pallidal deep brain stimulation (DBS). Here, we show the long-term effect of continuous bilateral GPi DBS in tardive dystonia on motor function, quality of life (QoL), and mood.
Nine consecutive patients undergoing DBS for tardive dystonia were assessed during continuous DBS at 3 time points: 1 week, 3 to 6 months, and last follow-up at the mean of 41 (range 18-80) months after surgery using established and validated movement disorder and neuropsychological scales. Clinical assessment was performed by a neurologist not blinded to the stimulation settings.
One week and 3 to 6 months after pallidal DBS, Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) motor scores were ameliorated by 56.4 +/- 26.7% and 74.1 +/- 15.8%, BFMDRS disability scores by 62.5 +/- 21.0% and 88.9 +/- 10.3%, and Abnormal Involuntary Movement Scale (AIMS) scores by 52.3 +/- 24.1% and 69.5 +/- 27.6%, respectively. At last follow-up, this improvement compared with the presurgical assessment was maintained as reflected by a reduction of BFMDRS motor scores by 83.0 +/- 12.2%, BFMDRS disability scores by 67.7 +/- 28.0%, and AIMS scores by 78.7 +/- 19.9%. QoL improved significantly in physical components, and there was a significant improvement in affective state. Furthermore, cognitive functions remained unchanged compared with presurgical status in the long-term follow-up. No permanent adverse effects were observed.
Pallidal deep brain stimulation is a safe and effective long-term treatment in patients with medically refractory tardive dystonia.
Exocometary Gas in the HD 181327 Debris Ring Marino, S.; Matra, L.; Stark, C. ...
Monthly notices of the Royal Astronomical Society,
08/2016, Volume:
460, Issue:
3
Journal Article
Peer reviewed
Open access
An increasing number of observations have shown that gaseous debris discs are not an exception. However, until now, we only knew of cases around A stars. Here we present the first detection of 12CO ...(2-1) disc emission around an F star, HD 181327, obtained with the Atacama Large Millimeter/submillimeter Array (ALMA) observations at 1.3 mm. The continuum and CO emission are resolved into an axisymmetric disc with ring-like morphology. Using a Markov chain Monte Carlo method coupled with radiative transfer calculations, we study the dust and CO mass distribution. We find the dust is distributed in a ring with a radius of 86.0 +/- 0.4 au and a radial width of 23.2 +/- 1.0 au. At this frequency, the ring radius is smaller than in the optical, revealing grain size segregation expected due to radiation pressure. We also report on the detection of low-level continuum emission beyond the main ring out to approximately 200 au. We model the CO emission in the non-local thermodynamic equilibrium regime and we find that the CO is co-located with the dust, with a total CO gas mass ranging between 1.2 x 10(exp -6) solar mass and 2.9 x 10(exp -6) solar mass, depending on the gas kinetic temperature and collisional partners densities. The CO densities and location suggest a secondary origin, i.e. released from icy planetesimals in the ring. We derive a CO+CO2 cometary composition that is consistent with Solar system comets. Due to the low gas densities, it is unlikely that the gas is shaping the dust distribution.
Precise comparisons of the fundamental properties of matter-antimatter conjugates provide sensitive tests of charge-parity-time (CPT) invariance, which is an important symmetry that rests on basic ...assumptions of the standard model of particle physics. Experiments on mesons, leptons and baryons have compared different properties of matter-antimatter conjugates with fractional uncertainties at the parts-per-billion level or better. One specific quantity, however, has so far only been known to a fractional uncertainty at the parts-per-million level: the magnetic moment of the antiproton, . The extraordinary difficulty in measuring with high precision is caused by its intrinsic smallness; for example, it is 660 times smaller than the magnetic moment of the positron. Here we report a high-precision measurement of in units of the nuclear magneton μ
with a fractional precision of 1.5 parts per billion (68% confidence level). We use a two-particle spectroscopy method in an advanced cryogenic multi-Penning trap system. Our result = -2.7928473441(42)μ
(where the number in parentheses represents the 68% confidence interval on the last digits of the value) improves the precision of the previous best measurement by a factor of approximately 350. The measured value is consistent with the proton magnetic moment, μ
= 2.792847350(9)μ
, and is in agreement with CPT invariance. Consequently, this measurement constrains the magnitude of certain CPT-violating effects to below 1.8 × 10
gigaelectronvolts, and a possible splitting of the proton-antiproton magnetic moments by CPT-odd dimension-five interactions to below 6 × 10
Bohr magnetons.
The promiscuous binding behavior of bioactive compounds forms a mechanistic basis for understanding polypharmacological drug action. We present the development and prospective application of a ...computational tool for identifying potential promiscuous drug-like ligands. In combination with computational target prediction methods, the approach provides a working concept for rationally designing such molecular structures. We could confirm the multi-target binding of a de novo generated compound in a proof-of-concept study relying on the new method.
For patients with recurrent SCLC, topotecan remains the only approved second-line treatment, and the outcomes are poor. CheckMate 032 is a phase 1/2, multicenter, open-label study of nivolumab or ...nivolumab plus ipilimumab in SCLC or other advanced/metastatic solid tumors previously treated with one or more platinum-based chemotherapies. We report results of third- or later-line nivolumab monotherapy treatment in SCLC.
In this analysis, patients with limited-stage or extensive-stage SCLC and disease progression after two or more chemotherapy regimens received nivolumab monotherapy, 3 mg/kg every 2 weeks, until disease progression or unacceptable toxicity. The primary end point was objective response rate. Secondary end points included duration of response, progression-free survival, overall survival, and safety.
Between December 4, 2013, and November 30, 2016, 109 patients began receiving third- or later-line nivolumab monotherapy. At a median follow-up of 28.3 months (from first dose to database lock), the objective response rate was 11.9% (95% confidence interval: 6.5–19.5) with a median duration of response of 17.9 months (range 3.0–42.1). At 6 months, 17.2% of patients were progression-free. The 12-month and 18-month overall survival rates were 28.3% and 20.0%, respectively. Grade 3 to 4 treatment-related adverse events occurred in 11.9% of patients. Three patients (2.8%) discontinued because of treatment-related adverse events.
Nivolumab monotherapy provided durable responses and was well tolerated as a third- or later-line treatment for recurrent SCLC. These results suggest that nivolumab monotherapy is an effective third- or later-line treatment for this patient population.
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