Improved unfolding by detrending of statistical fluctuations in quantum spectra

Accepted for publication in Physical Review EA fundamental relation exists between the statistical properties of the fluctuations of the energy level spectrum of a Hamiltonian and the chaotic properties of the physical system it describes. This relationship has been addressed previously as a signature of chaos in quantum dynamical systems. In order to properly analyze these fluctuations, however, it is necessary to separate them from the general tendency, namely, its secular part. Unfortunately this process, called unfolding, is not trivial and can lead to erroneous conclusions about the chaoticity of a system. In this paper we propose a technique to improve the unfolding procedure for the purpose of minimizing the dependence on the particular procedure. This technique is based on detrending the fluctuations of the unfolded spectra through the empirical mode decomposition method

Insights into gliomagenesis: systems biology unravels key pathways

Technological advances have enabled a better characterization of all the genetic alterations in tumors. A picture that emerges is that tumor cells are much more genetically heterogeneous than originally expected. Thus, a critical issue in cancer genomics is the identification of the genetic alterations that drive the genesis of a tumor. Recently, a systems biology approach has been used to characterize such alterations and find associations between them and the process of gliomagenesis. Here, we discuss some implications of this strategy for the development of new therapeutic and diagnostic protocols for cancer

Dopamine Modulation of Choice Behavior Following Unexpected Reward Omission

Being able identify decreases in resource availability and alter motivated behavior accordingly is evolutionarily adaptive. Additionally, the neurobiological mechanisms that facilitate these basic foraging skills in animals are thought to be utilized in other forms of goal directed cognition in humans. To study how the brain mediates such behaviors, we adapt an operant behavioral task in which laboratory rats can earn food rewards from two distinct levers. We find that when one lever is extinguished, while the other lever continues to be reinforced, both male and female rats quickly identify this contingency change and develop a choice preference for the rewarded lever. Previous electrophysiology studies of putative midbrain dopamine (DA) neurons have revealed brief pauses in neuronal activity when an expected reward is omitted, which is thought to briefly decrease DA transmission in terminal regions, such as the nucleus accumbens (NAc). Additionally, decreases in DA transmission have been hypothesized to be signaled preferentially through D2 receptors. Other studies, however, have proposed that extra-cellular DA levels over longer periods of time may play a role in motivation and behavioral flexibility. To test these hypotheses, we employ one-minute sampling microdialysis and fast-scan cyclic voltammetry (FSCV) in the NAc. Microdialysis experiments reveal an increase in DA concentration, lasting multiple minutes, following the omission of an expected rewarded. These increases in DA concentration correlate to observed increases in motivational vigor and exploratory behaviors. In contrast, FSCV reveals brief decreases in DA transmission when the expected reward is omitted, consistent with previous electrophysiology studies. Furthermore, holding D2 receptor tone, through site-specific microinfusion of a D2-like agonist into the NAc, attenuates the behavioral preference for the rewarded option. Together, these experiments reveal dynamic changes in DA transmission over multiple time scales when an expected reward is omitted. Tonic increases in DA concentration may motivate the animal to employ alternate behavioral strategies, while the phasic decreases are likely involved in redirecting choice behavior away from the non-rewarded option. This series of experiments provides novel insight into the complex relationships between DA transmission and motivated behavior during negative changes in reward availability.PhDPsychologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/109040/1/stransky_1.pd

Development of behavioral preferences for the optimal choice following unexpected reward omission is mediated by a reduction of D 2‐like receptor tone in the nucleus accumbens

To survive in a dynamic environment, animals must identify changes in resource availability and rapidly apply adaptive strategies to obtain resources that promote survival. We have utilised a behavioral paradigm to assess differences in foraging strategy when resource (reward) availability unexpectedly changes. When reward magnitude was reduced by 50% (receive one reward pellet instead of two), male and female rats developed a preference for the optimal choice by the second session. However, when an expected reward was omitted (receive no reward pellets instead of one), subjects displayed a robust preference for the optimal choice during the very first session. Previous research shows that, when an expected reward is omitted, dopamine neurons phasically decrease their firing rate, which is hypothesised to decrease dopamine release preferentially affecting D 2‐like receptors. As robust changes in behavioral preference were specific to reward omission, we tested this hypothesis and the functional role of D 1‐ and D 2‐like receptors in the nucleus accumbens in mediating the rapid development of a behavioral preference for the rewarded option during reward omission in male rats. Blockade of both receptor types had no effect on this behavior; however, holding D 2‐like, but not D 1‐like, receptor tone via infusion of dopamine receptor agonists prevented the development of the preference for the rewarded option during reward omission. These results demonstrate that avoiding an outcome that has been tagged with aversive motivational properties is facilitated through decreased dopamine transmission and subsequent functional disruption of D 2‐like, but not D 1‐like, receptor tone in the nucleus accumbens. This study investigates the role of dopamine receptors in the nucleus accumbens in altering behavior in response to the omission of an expected reward. Similarly to controls, multiple doses of a D 1‐like receptor agonist, D 1‐like receptor antagonist, and D 2‐like receptor antagonist do not prevent subjects from developing a robust behavioral preference for the rewarded lever and avoiding the omitted‐reward lever during the first session of reward omission. However, the D 2‐like agonist quinpirole dose‐dependently blocks a behavioral preference for the rewarded lever, suggesting that reductions in D 2‐like receptor tone are necessary for altering behavior away from an aversive option and toward the optimal choice.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99645/1/ejn12253.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/99645/2/ejn12253-sup-0001-Supplement.pd

A Key Silencing Histone Mark on Chromatin Is Lost When Colorectal Adenocarcinoma Cells Are Depleted of Methionine by Methionine γ-Lyase

Methionine is an essential amino acid used, beyond protein synthesis, for polyamine formation and DNA/RNA/protein methylation. Cancer cells require particularly high methionine supply for their homeostasis. A successful approach for decreasing methionine concentration is based on the systemic delivery of methionine γ-lyase (MGL), with in vitro and in vivo studies demonstrating its efficacy in cancer therapy. However, the mechanisms explaining how cancer cells suffer from the absence of methionine more significantly than non-malignant cells are still unclear. We analyzed the outcome of the human colorectal adenocarcinoma cancer cell line HT29 to the exposure of MGL for up to 72 h by monitoring cell viability, proteome expression, histone post-translational modifications, and presence of spurious transcription. The rationale of this study was to verify whether reduced methionine supply would affect chromatin decondensation by changing the levels of histone methylation and therefore increasing genomic instability. MGL treatment showed a time-dependent cytotoxic effect on HT29 cancer cells, with an IC50 of 30 µg/ml, while Hs27 normal cells were less affected, with an IC50 of >460 µg/ml. Although the levels of total histone methylation were not altered, a loss of the silencing histone mark H3K9me2 was observed, as well as a decrease in H4K20me3. Since H3K9me2/3 decorate repetitive DNA elements, we proved by qRT-PCR that MGL treatment leads to an increased expression of major satellite units. Our data indicate that selected histone methylation marks may play major roles in the mechanism of methionine starvation in cancer cells, proving that MGL treatment directly impacts chromatin homeostasis

Effects of radiation damage and inelastic scattering on single-particle imaging of hydrated proteins with an X-ray Free-Electron Laser

We present a computational case study of X-ray single-particle imaging of hydrated proteins on an example of 2-Nitrogenase–Iron protein covered with water layers of various thickness, using a start-to-end simulation platform and experimental parameters of the SPB/SFX instrument at the European X-ray Free-Electron Laser facility. The simulations identify an optimal thickness of the water layer at which the effective resolution for imaging the hydrated sample becomes significantly higher than for the non-hydrated sample. This effect is lost when the water layer becomes too thick. Even though the detailed results presented pertain to the specific sample studied, the trends which we identify should also hold in a general case. We expect these findings will guide future single-particle imaging experiments using hydrated proteins

Preoperative FDG-PET/CT Is an Important Tool in the Management of Patients with Thick (T4) Melanoma

The yield of preoperative PET/CT (PET/CT) for regional and distant metastases for thin/intermediate thickness melanoma is low. Objective of this study is to determine if PET/CT performed for T4 melanomas helps guide management and alter treatment plans. Methods. Retrospective cohort of 216 patients with T4 melanomas treated at two tertiary institutions. Fifty-six patients met our inclusion criteria (T4 lesion, PET/CT and no clinical evidence of metastatic disease). Results. Fifty-six patients (M: 32, F: 24) with median tumor thickness of 6 mm were identified. PET/CT recognized twelve with regional and four patients with metastatic disease. Melanoma-related treatment plan was altered in 11% of the cases based on PET/CT findings. PET/CT was negative 60% of the time, in 35% of the cases; it identified incidental findings that required further evaluation. Conclusion. Patients with T4 lesions, PET/CT changed the treatment plan 18% of the time. Regional findings changed the surgical treatment plan in 11% and the adjuvant plan in 7% of our cases due to the finding of metastatic disease. Additionally 20 patients had incidental findings that required further workup. In this subset of patients, we feel there is a benefit to PET/CT, and further studies should be performed to validate our findings