Quantifying the CDK inhibitor VMY-1-103\u27s activity and tissue levels in an in vivo tumor model by LC-MS/MS and by MRI.

The development of new small molecule-based therapeutic drugs requires accurate quantification of drug bioavailability, biological activity and treatment efficacy. Rapidly measuring these endpoints is often hampered by the lack of efficient assay platforms with high sensitivity and specificity. Using an in vivo model system, we report a simple and sensitive liquid chromatography-tandem mass spectrometry assay to quantify the bioavailability of a recently developed novel cyclin-dependent kinase inhibitor VMY-1-103, a purvalanol B-based analog whose biological activity is enhanced via dansylation. We developed a rapid organic phase extraction technique and validated wide and functional VMY-1-103 distribution in various mouse tissues, consistent with its enhanced potency previously observed in a variety of human cancer cell lines. More importantly, in vivo MRI and single voxel proton MR-Spectroscopy further established that VMY-1-103 inhibited disease progression and affected key metabolites in a mouse model of hedgehog-driven medulloblastoma

In planta function of compatible solute transporters of the AtProT family

The three proline transporters of Arabidopsis thaliana (AtProTs) transport the compatible solutes proline and glycine betaine and the stress-induced compound γ-aminobutyric acid when expressed in heterologous systems. The aim of the present study was to show transport and physiological relevance of these three AtProTs in planta. Using single, double, and triple knockout mutants and AtProT-overexpressing lines, proline content, growth on proline, transport of radiolabelled betaine, and expression of AtProT genes and enzymes of proline metabolism were analysed. AtProT2 was shown to facilitate uptake of L- and D-proline as well as [14C]glycine betaine in planta, indicating a role in the import of compatible solutes into the root. Toxic concentrations of L- and D-proline resulted in a drastic growth retardation of AtProT-overexpressing plants, demonstrating the need for a precise regulation of proline uptake and/or distribution. Furthermore evidence is provided that AtProT genes are highly expressed in tissues with elevated proline content—that is, pollen and leaf epidermis

Image-guided Placement of Magnetic Neuroparticles as a Potential High-Resolution Brain-Machine Interface

We are developing methods of noninvasively delivering magnetic neuroparticles™ via intranasal administration followed by image-guided magnetic propulsion to selected locations in the brain. Once placed, the particles can activate neurons via vibrational motion or magnetoelectric stimulation. Similar particles might be used to read out neuronal electrical pulses via spintronic or liquid-crystal magnetic interactions, for fast bidirectional brain-machine interface. We have shown that particles containing liquid crystals can be read out with magnetic resonance imaging (MRI) using embedded magnetic nanoparticles and that the signal is visible even for voltages comparable to physiological characteristics. Such particles can be moved within the brain (e.g., across midline) without causing changes to neurological firing

On the origin of endemic species in the Red Sea

Aim: The geological and palaeo-climatic forces that produced the unique biodiversity in the Red Sea are a subject of vigorous debate. Here, we review evidence for and against the hypotheses that: (1) Red Sea fauna was extirpated during glacial cycles of the Pleistocene and (2) coral reef fauna found refuge within or just outside the Red Sea during low sea level stands when conditions were inhospitable. Location: Red Sea and Western Indian Ocean. Methods: We review the literature on palaeontological, geological, biological and genetic evidence that allow us to explore competing hypotheses on the origins and maintenance of shallow-water reef fauna in the Red Sea. Results: Palaeontological (microfossil) evidence indicates that some areas of the central Red Sea were devoid of most plankton during low sea level stands due to hypersaline conditions caused by almost complete isolation from the Indian Ocean. However, two areas may have retained conditions adequate for survival: the Gulf of Aqaba and the southern Red Sea. In addition to isolation within the Red Sea, which separated the northern and southern faunas, a strong barrier may also operate in the region: the cold, nutrient-rich water upwelling at the boundary of the Gulf of Aden and the Arabian Sea. Biological data are either inconclusive or support these putative barriers and refugia, but no data set, that we know of rejects them. Genetic evidence suggests that many endemic lineages diverged from their Indian Ocean counterparts long before the most recent glaciations and/or are restricted to narrow areas, especially in the northern Red Sea. Main conclusions: High endemism observed in the Red Sea and Gulf of Aden appears to have multiple origins. A cold, nutrient-rich water barrier separates the Gulf of Aden from the rest of the Arabian Sea, whereas a narrow strait separates the Red Sea from the Gulf of Aden, each providing potential isolating barriers. Additional barriers may arise from environmental gradients, circulation patterns and the constriction at the mouth of the Gulf of Aqaba. Endemics that evolved within the Red Sea basin had to survive glacial cycles in relatively low salinity refugia. It therefore appears that the unique conditions in the Red Sea, in addition to those characteristics of the Arabian Peninsula region as a whole, drive the divergence of populations via a combination of isolation and selection

Parasympathetic Activity and Blood Catecholamine Responses Following a Single Partial-Body Cryostimulation and a Whole-Body Cryostimulation

The aim of this study was to compare the effects of a single whole-body cryostimulation (WBC) and a partial-body cryostimulation (PBC) (i.e., not exposing the head to cold) on indices of parasympathetic activity and blood catecholamines. Two groups of 15 participants were assigned either to a 3-min WBC or PBC session, while 10 participants constituted a control group (CON) not receiving any cryostimulation. Changes in thermal, physiological and subjective variables were recorded before and during the 20-min after each cryostimulation. According to a qualitative statistical analysis, an almost certain decrease in skin temperature was reported for all body regions immediately after the WBC (mean decrease±90% CL, -13.7±0.7°C) and PBC (-8.3±0.3°C), which persisted up to 20-min after the session. The tympanic temperature almost certainly decreased only after the WBC session (-0.32±0.04°C). Systolic and diastolic blood pressures were very likely increased after the WBC session, whereas these changes were trivial in the other groups. In addition, heart rate almost certainly decreased after PBC (-10.9%) and WBC (-15.2%) sessions, in a likely greater proportion for WBC compared to PBC. Resting vagal-related heart rate variability indices (the root-mean square difference of successive normal R-R intervals, RMSSD, and high frequency band, HF) were very likely increased after PBC (RMSSD: +54.4%, HF: +138%) and WBC (RMSSD: +85.2%, HF: +632%) sessions without any marked difference between groups. Plasma norepinephrine concentrations were likely to very likely increased after PBC (+57.4%) and WBC (+76.2%), respectively. Finally, cold and comfort sensations were almost certainly altered after WBC and PBC, sensation of discomfort being likely more pronounced after WBC than PBC. Both acute cryostimulation techniques effectively stimulated the autonomic nervous system (ANS), with a predominance of parasympathetic tone activation. The results of this study also suggest that a whole-body cold exposure induced a larger stimulation of the ANS compared to partial-body cold exposure

Integrating neuroimaging biomarkers into the multicentre, high-dose erythropoietin for asphyxia and encephalopathy (HEAL) trial: rationale, protocol and harmonisation

Introduction: MRI and MR spectroscopy (MRS) provide early biomarkers of brain injury and treatment response in neonates with hypoxic-ischaemic encephalopathy). Still, there are challenges to incorporating neuroimaging biomarkers into multisite randomised controlled trials. In this paper, we provide the rationale for incorporating MRI and MRS biomarkers into the multisite, phase III high-dose erythropoietin for asphyxia and encephalopathy (HEAL) Trial, the MRI/S protocol and describe the strategies used for harmonisation across multiple MRI platforms. Methods and analysis: Neonates with moderate or severe encephalopathy enrolled in the multisite HEAL trial undergo MRI and MRS between 96 and 144 hours of age using standardised neuroimaging protocols. MRI and MRS data are processed centrally and used to determine a brain injury score and quantitative measures of lactate and n-acetylaspartate. Harmonisation is achieved through standardisation-thereby reducing intrasite and intersite variance, real-time quality assurance monitoring and phantom scans. Ethics and dissemination: IRB approval was obtained at each participating site and written consent obtained from parents prior to participation in HEAL. Additional oversight is provided by an National Institutes of Health-appointed data safety monitoring board and medical monitor

Probabilistic Prediction of Separation Buffer to Compensate for the Closing Effect on Final Approach

The air traffic is mainly divided into en-route flight segments, arrival and departure segments inside the terminal maneuvering area, and ground operations at the airport. To support utilizing available capacity more efficiently, in our contribution we focus on the prediction of arrival procedures, in particular, the time-to-fly from the turn onto the final approach course to the threshold. The predictions are then used to determine advice for the controller regarding time-to-lose or time-to-gain for optimizing the separation within a sequence of aircraft. Most prediction methods developed so far provide only a point estimate for the time-to-fly. Complementary, we see the need to further account for the uncertain nature of aircraft movement based on a probabilistic prediction approach. This becomes very important in cases where the air traffic system is operated at its limits to prevent safety-critical incidents, e.g., separation infringements due to very tight separation. Our approach is based on the Quantile Regression Forest technique that can provide a measure of uncertainty of the prediction not only in form of a prediction interval but also by generating a probability distribution over the dependent variable. While the data preparation, model training, and tuning steps are identical to classic Random Forest methods, in the prediction phase, Quantile Regression Forests provide a quantile function to express the uncertainty of the prediction. After developing the model, we further investigate the interpretation of the results and provide a way for deriving advice to the controller from it. With this contribution, there is now a tool available that allows a more sophisticated prediction of time-to-fly, depending on the specific needs of the use case and which helps to separate arriving aircraft more efficiently

Structural Brain Defects.

Up to 14% of patients with congenital metabolic disease may show structural brain abnormalities from perturbation of cell proliferation, migration, and/or organization. Most inborn errors of metabolism have a postnatal onset. Abnormalities from genetic disease processes have a prenatal onset. Energy impairment, substrate insufficiency, cell membrane receptor and cell signaling abnormalities, and toxic byproduct accumulation are associations between genetic disorders and structural brain anomalies. Collective imaging patterns of brain abnormalities can provide clues to the underlying etiology. We review selected metabolic diseases associated with brain malformations and highlight characteristic clinical and imaging manifestations that help narrow the differential diagnosis