Coreleased orexin and glutamate evoke nonredundant spike outputs and computations in histamine neurons.

Stable wakefulness requires orexin/hypocretin neurons (OHNs) and OHR2 receptors. OHNs sense diverse environmental cues and control arousal accordingly. For unknown reasons, OHNs contain multiple excitatory transmitters, including OH peptides and glutamate. To analyze their cotransmission within computational frameworks for control, we optogenetically stimulated OHNs and examined resulting outputs (spike patterns) in a downstream arousal regulator, the histamine neurons (HANs). OHR2s were essential for sustained HAN outputs. OHR2-dependent HAN output increased linearly during constant OHN input, suggesting that the OHN→HAN(OHR2) module may function as an integral controller. OHN stimulation evoked OHR2-dependent slow postsynaptic currents, similar to midnanomolar OH concentrations. Conversely, glutamate-dependent output transiently communicated OHN input onset, peaking rapidly then decaying alongside OHN→HAN glutamate currents. Blocking glutamate-driven spiking did not affect OH-driven spiking and vice versa, suggesting isolation (low cross-modulation) of outputs. Therefore, in arousal regulators, cotransmitters may translate distinct features of OHN activity into parallel, nonredundant control signals for downstream effectors.

Traffic Routes and Signals for the Tonoplast

Tonoplast, the membrane delimiting plant vacuoles, regulates ion, water and nutrient movement between the cytosol and the vacuolar lumen through the activity of its membrane proteins. Correct traffic of proteins from the endoplasmic reticulum (ER) to the tonoplast requires (i) approval by the ER quality control, (ii) motifs for exit from the ER and (iii) motifs that promote sorting to the tonoplast. Recent evidence suggests that this traffic follows different pathways that are protein-specific and could also reflect vacuole specialization for lytic or storage function. The routes can be distinguished based on their sensitivity to drugs such as brefeldin A and C834 as well as using mutant plants that are defective in adaptor proteins of vesicle coats, or dominant-negative mutants of Rab GTPases.

Opposing RA and FGF signals control proximodistal vertebrate limb development through regulation of Meis genes.

Vertebrate limbs develop in a temporal proximodistal sequence, with proximal regions specified and generated earlier than distal ones. Whereas considerable information is available on the mechanisms promoting limb growth, those involved in determining the proximodistal identity of limb parts remain largely unknown. We show here that retinoic acid (RA) is an upstream activator of the proximal determinant genes Meis1 and Meis2. RA promotes proximalization of limb cells and endogenous RA signaling is required to maintain the proximal Meis domain in the limb. RA synthesis and signaling range, which initially span the entire lateral plate mesoderm, become restricted to proximal limb domains by the apical ectodermal ridge (AER) activity following limb initiation. We identify fibroblast growth factor (FGF) as the main molecule responsible for this AER activity and propose a model integrating the role of FGF in limb cell proliferation, with a specific function in promoting distalization through inhibition of RA production and signaling.

Screening and testing for endocrine disruption in fish-biomarkers as "signposts," not "traffic lights," in risk assessment

Biomarkers are currently best used as mechanistic "signposts" rather than as "traffic lights" in the environmental risk assessment of endocrine-disrupting chemicals (EDCs). In field studies, biomarkers of exposure [e.g., vitellogenin (VTG) induction in male fish] are powerful tools for tracking single substances and mixtures of concern. Biomarkers also provide linkage between field and laboratory data, thereby playing an important role in directing the need for and design of fish chronic tests for EDCs. It is the adverse effect end points (e.g., altered development, growth, and/or reproduction) from such tests that are most valuable for calculating adverseNOEC (no observed effect concentration) or adverseEC10 (effective concentration for a 10% response) and subsequently deriving predicted no effect concentrations (PNECs). With current uncertainties, biomarkerNOEC or biomarkerEC10 data should not be used in isolation to derive PNECs. In the future, however, there may be scope to increasingly use biomarker data in environmental decision making, if plausible linkages can be made across levels of organization such that adverse outcomes might be envisaged relative to biomarker responses. For biomarkers to fulfil their potential, they should be mechanistically relevant and reproducible (as measured by interlaboratory comparisons of the same protocol). VTG is a good example of such a biomarker in that it provides an insight to the mode of action (estrogenicity) that is vital to fish reproductive health. Interlaboratory reproducibility data for VTG are also encouraging; recent comparisons (using the same immunoassay protocol) have provided coefficients of variation (CVs) of 38-55% (comparable to published CVs of 19-58% for fish survival and growth end points used in regulatory test guidelines). While concern over environmental xenoestrogens has led to the evaluation of reproductive biomarkers in fish, it must be remembered that many substances act via diverse mechanisms of action such that the environmental risk assessment for EDCs is a broad and complex issue. Also, biomarkers such as secondary sexual characteristics, gonadosomatic indices, plasma steroids, and gonadal histology have significant potential for guiding interspecies assessments of EDCs and designing fish chronic tests. To strengthen the utility of EDC biomarkers in fish, we need to establish a historical control database (also considering natural variability) to help differentiate between statistically detectable versus biologically significant responses. In conclusion, as research continues to develop a range of useful EDC biomarkers, environmental decision-making needs to move forward, and it is proposed that the "biomarkers as signposts" approach is a pragmatic way forward in the current risk assessment of EDCs.

Reliability of intraoperative high-resolution 2D ultrasound as an alternative to high-field strength MR imaging for tumor resection control: a prospective comparative study

OBJECT: Ultrasound may be a reliable but simpler alternative to intraoperative MR imaging (iMR imaging) for tumor resection control. However, its reliability in the detection of tumor remnants has not been definitely proven. The aim of the study was to compare high-field iMR imaging (1.5 T) and high-resolution 2D ultrasound in terms of tumor resection control. METHODS: A prospective comparative study of 26 consecutive patients was performed. The following parameters were compared: the existence of tumor remnants after presumed radical removal and the quality of the images. Tumor remnants were categorized as: detectable with both imaging modalities or visible only with 1 modality. RESULTS: Tumor remnants were detected in 21 cases (80.8%) with iMR imaging. All large remnants were demonstrated with both modalities, and their image quality was good. Two-dimensional ultrasound was not as effective in detecting remnants<1 cm. Two remnants detected with iMR imaging were missed by ultrasound. In 2 cases suspicious signals visible only on ultrasound images were misinterpreted as remnants but turned out to be a blood clot and peritumoral parenchyma. The average time for acquisition of an ultrasound image was 2 minutes, whereas that for an iMR image was approximately 10 minutes. Neither modality resulted in any procedure-related complications or morbidity. CONCLUSIONS: Intraoperative MR imaging is more precise in detecting small tumor remnants than 2D ultrasound. Nevertheless, the latter may be used as a less expensive and less time-consuming alternative that provides almost real-time feedback information. Its accuracy is highest in case of more confined, deeply located remnants. In cases of more superficially located remnants, its role is more limited.

A genome-to-genome analysis of associations between human genetic variation, HIV-1 sequence diversity, and viral control

HIV-1 sequence diversity is affected by selection pressures arising from host genomic factors. Using paired human and viral data from 1071 individuals, we ran >3000 genome-wide scans, testing for associations between host DNA polymorphisms, HIV-1 sequence variation and plasma viral load (VL), while considering human and viral population structure. We observed significant human SNP associations to a total of 48 HIV-1 amino acid variants (p<2.4 × 10−12). All associated SNPs mapped to the HLA class I region. Clinical relevance of host and pathogen variation was assessed using VL results. We identified two critical advantages to the use of viral variation for identifying host factors: (1) association signals are much stronger for HIV-1 sequence variants than VL, reflecting the ‘intermediate phenotype’ nature of viral variation; (2) association testing can be run without any clinical data. The proposed genome-to-genome approach highlights sites of genomic conflict and is a strategy generally applicable to studies of host–pathogen interaction.

A reliable, traffic-adaptive and energy-efficient link layer for wireless sensor networks

The paper presents a link layer stack for wireless sensor networks, which consists of the Burst-aware Energy-efficient Adaptive Medium access control (BEAM) and the Hop-to-Hop Reliability (H2HR) protocol. BEAM can operate with short beacons to announce data transmissions or include data within the beacons. Duty cycles can be adapted by a traffic prediction mechanism indicating pending packets destined for a node and by estimating its wake-up times. H2HR takes advantage of information provided by BEAM such as neighbour information and transmission information to perform per-hop congestion control. We justify the design decisions by measurements in a real-world wireless sensor network testbed and compare the performance with other link layer protocols.

Personalized Tuning of a Reinforcement Learning Control Algorithm for Glucose Regulation

Artificial pancreas is in the forefront of research towards the automatic insulin infusion for patients with type 1 diabetes. Due to the high inter- and intra-variability of the diabetic population, the need for personalized approaches has been raised. This study presents an adaptive, patient-specific control strategy for glucose regulation based on reinforcement learning and more specifically on the Actor-Critic (AC) learning approach. The control algorithm provides daily updates of the basal rate and insulin-to-carbohydrate (IC) ratio in order to optimize glucose regulation. A method for the automatic and personalized initialization of the control algorithm is designed based on the estimation of the transfer entropy (TE) between insulin and glucose signals. The algorithm has been evaluated in silico in adults, adolescents and children for 10 days. Three scenarios of initialization to i) zero values, ii) random values and iii) TE-based values have been comparatively assessed. The results have shown that when the TE-based initialization is used, the algorithm achieves faster learning with 98%, 90% and 73% in the A+B zones of the Control Variability Grid Analysis for adults, adolescents and children respectively after five days compared to 95%, 78%, 41% for random initialization and 93%, 88%, 41% for zero initial values. Furthermore, in the case of children, the daily Low Blood Glucose Index reduces much faster when the TE-based tuning is applied. The results imply that automatic and personalized tuning based on TE reduces the learning period and improves the overall performance of the AC algorithm.

Spatial cognition, body representation and affective processes: the role of vestibular information beyond ocular reflexes and control of posture

A growing number of studies in humans demonstrate the involvement of vestibular information in tasks that are seemingly remote from well-known functions such as space constancy or postural control. In this review article we point out three emerging streams of research highlighting the importance of vestibular input: (1) Spatial Cognition: Modulation of vestibular signals can induce specific changes in spatial cognitive tasks like mental imagery and the processing of numbers. This has been shown in studies manipulating body orientation (changing the input from the otoliths), body rotation (changing the input from the semicircular canals), in clinical findings with vestibular patients, and in studies carried out in microgravity. There is also an effect in the reverse direction; top-down processes can affect perception of vestibular stimuli. (2) Body Representation: Numerous studies demonstrate that vestibular stimulation changes the representation of body parts, and sensitivity to tactile input or pain. Thus, the vestibular system plays an integral role in multisensory coordination of body representation. (3) Affective Processes and Disorders: Studies in psychiatric patients and patients with a vestibular disorder report a high comorbidity of vestibular dysfunctions and psychiatric symptoms. Recent studies investigated the beneficial effect of vestibular stimulation on psychiatric disorders, and how vestibular input can change mood and affect. These three emerging streams of research in vestibular science are—at least in part—associated with different neuronal core mechanisms. Spatial transformations draw on parietal areas, body representation is associated with somatosensory areas, and affective processes involve insular and cingulate cortices, all of which receive vestibular input. Even though a wide range of different vestibular cortical projection areas has been ascertained, their functionality still is scarcely understood.

Estimating the uptake of traffic-derived NO2 from 15N abundance in Norway spruce needles

The 15N ratio of nitrogen oxides (NOx) emitted from vehicles, measured in the air adjacent to a highway in the Swiss Middle Land, was very high [δ15N(NO2) = +5.7‰]. This high 15N abundance was used to estimate long-term NO2 dry deposition into a forest ecosystem by measuring δ15N in the needles and the soil of potted and autochthonous spruce trees [Picea abies (L.) Karst] exposed to NO2 in a transect orthogonal to the highway. δ15N in the current-year needles of potted trees was 2.0‰ higher than that of the control after 4 months of exposure close to the highway, suggesting a 25% contribution to the N-nutrition of these needles. Needle fall into the pots was prevented by grids placed above the soil, while the continuous decomposition of needle litter below the autochthonous trees over previous years has increased δ15N values in the soil, resulting in parallel gradients of δ15N in soil and needles with distance from the highway. Estimates of NO2 uptake into needles obtained from the δ15N data were significantly correlated with the inputs calculated with a shoot gas exchange model based on a parameterisation widely used in deposition modelling. Therefore, we provide an indication of estimated N inputs to forest ecosystems via dry deposition of NO2 at the receptor level under field conditions.