Study protocol : the empirical investigation of methods to correct for measurement error in biobanks with dietary assessment

Peer reviewedPublisher PD

Synthesis and evaluation of designed PKC modulators for enhanced cancer immunotherapy.

Bryostatin 1 is a marine natural product under investigation for HIV/AIDS eradication, the treatment of neurological disorders, and enhanced CAR T/NK cell immunotherapy. Despite its promising activity, bryostatin 1 is neither evolved nor optimized for the treatment of human disease. Here we report the design, synthesis, and biological evaluation of several close-in analogs of bryostatin 1. Using a function-oriented synthesis approach, we synthesize a series of bryostatin analogs designed to maintain affinity for bryostatin's target protein kinase C (PKC) while enabling exploration of their divergent biological functions. Our late-stage diversification strategy provides efficient access to a library of bryostatin analogs, which per our design retain affinity for PKC but exhibit variable PKC translocation kinetics. We further demonstrate that select analogs potently increase cell surface expression of CD22, a promising CAR T cell target for the treatment of leukemias, highlighting the clinical potential of bryostatin analogs for enhancing targeted immunotherapies

A Workflow for Probabilistic Calibration of Models of Left Atrial Electrophysiology

Atrial fibrillation is an increasingly common condition. Computational models that describe left atrial electrophysiology have the potential to be used to guide interventions such as catheter ablation. Calibration of these models to faithfully represent left atrial structure and function in a particular patient is challenging because electrophysiology observations obtained in the clinical setting are typically sparse and noisy, and can be difficult to register to a mesh obtained from imaging. Probabilistic approaches show promise as a way to obtain personalised models while taking account of noise, sparseness, and uncertainty. We have developed a workflow in which parameter fields are represented as Gaussian processes, and the posterior distribution is inferred using MCMC. Our workflow has been tested using synthetic data, generated from simulations where the spatial variation in model parameters is known, and we have shown that both features and parameters can be recovered from simulated sparse measurements

Decadal changes of the Western Arabian sea ecosystem

Historical data from oceanographic expeditions and remotely sensed data on outgoing longwave radiation, temperature, wind speed and ocean color in the western Arabian Sea (1950–2010) were used to investigate decadal trends in the physical and biochemical properties of the upper 300 m. 72 % of the 29,043 vertical profiles retrieved originated from USA and UK expeditions. Increasing outgoing longwave radiation, surface air temperatures and sea surface temperature were identified on decadal timescales. These were well correlated with decreasing wind speeds associated with a reduced Siberian High atmospheric anomaly. Shoaling of the oxycline and nitracline was observed as well as acidification of the upper 300 m. These physical and chemical changes were accompanied by declining chlorophyll-a concentrations, vertical macrofaunal habitat compression, declining sardine landings and an increase of fish kill incidents along the Omani coast

Young children do not require perceptual-motor feedback to solve Aesop's Fable tasks

Aesop's Fable tasks-in which subjects drop objects into a water-filled tube to raise the water level and obtain out-of-reach floating rewards -have been used to test for causal understanding of water displacement in both young children and non-human animals. However, a number of alternative explanations for success on these tasks have yet to be ruled out. One hypothesis is that subjects may respond to perceptual-motor feedback: repeating those actions that bring the reward incrementally closer. Here, we devised a novel, forced-choice version of the Aesop's Fable task to assess whether subjects can solve water displacement tasks when this type of feedback is removed. Subjects had to select only one set of objects, or one type of tube, into which all objects were dropped at once, and the effect the objects had on the water level was visually concealed. In the current experiment, fifty-five 5-9 year old children were tested in six different conditions in which we either varied object properties (floating vs. sinking, hollow vs. solid, large vs. small and too large vs. small objects), the water level (high vs. low) and/or the tube size (narrow vs. wide). We found that children aged 8-9 years old were able to solve most of the water displacement tasks on their first trial, without any opportunity for feedback, suggesting that they mentally simulated the results of their actions before making a choice. Children aged 5-7 years solved two conditions on their first trial (large vs. small objects and high- vs. low-water levels), and learnt to solve most of the remaining conditions over five trials. The developmental pattern shown here is comparable to previous studies using the standard Aesop's Fable task, where eight year olds are typically successful from their first trial and 5-7 year olds learn to pass over five trials. Thus, our results indicate that children do not depend on perceptual-motor feedback to solve these water displacement tasks. The forced-choice paradigm we describe could be used comparatively to test whether or not non-human animals require visual feedback to solve water displacement tasks

Large-scale air mass characteristics observed over the remote tropical Pacific Ocean during March-April 1999: Results from PEM-Tropics B field experiment

Eighteen long-range flights over the Pacific Ocean between 38° S to 20° N and 166° E to 90° W were made by the NASA DC-8 aircraft during the NASA Pacific Exploratory Mission (PEM) Tropics B conducted from March 6 to April 18, 1999. Two lidar systems were flown on the DC-8 to remotely measure vertical profiles of ozone (O3), water vapor (H2O), aerosols, and clouds from near the surface to the upper troposphere along their flight track. In situ measurements of a wide range of gases and aerosols were made on the DC-8 for comprehensive characterization of the air and for correlation with the lidar remote measurements. The transition from northeasterly flow of Northern Hemispheric (NH) air on the northern side of the Intertropical Convergence Zone (ITCZ) to generally easterly flow of Southern Hemispheric (SH) air south of the ITCZ was accompanied by a significant decrease in O3, carbon monoxide, hydrocarbons, and aerosols and an increase in H2O. Trajectory analyses indicate that air north of the ITCZ came from Asia and/or the United States, while the air south of the ITCZ had a long residence time over the Pacific, perhaps originating over South America several weeks earlier. Air south of the South Pacific Convergence Zone (SPCZ) came rapidly from the west originating over Australia or Africa. This air had enhanced O3 and aerosols and an associated decrease in H2O. Average latitudinal and longitudinal distributions of O3 and H2O were constructed from the remote and in situ O3 and H2O data, and these distributions are compared with results from PEM-Tropics A conducted in August-October 1996. During PEM-Tropics B, low O3 air was found in the SH across the entire Pacific Basin at low latitudes. This was in strong contrast to the photochemically enhanced O3 levels found across the central and eastern Pacific low latitudes during PEM-Tropics A. Nine air mass types were identified for PEM-Tropics B based on their O3, aerosols, clouds, and potential vorticity characteristics. The data from each flight were binned by altitude according to air mass type, and these results showed the relative observational frequency of the different air masses as a function of altitude in seven regions over the Pacific. The average chemical composition of the major air mass types was determined from in situ measurements in the NH and SH, and these results provided insight into the origin, lifetime, and chemistry of the air in these regions. Copyright 2001 by the American Geophysical Union

Viscous placebo and carbohydrate breakfasts similarly decrease appetite and increase resistance exercise performance compared to a control breakfast in trained males

Given the common view that pre-exercise nutrition/breakfast is important for performance, the present study investigated whether breakfast influences resistance exercise performance via a physiological or psychological effect. Twenty-two resistance trained, breakfast-consuming men completed three experimental trials, consuming water-only (WAT), or semi-solid breakfasts containing 0 g/kg (PLA) or 1.5 g/kg (CHO) maltodextrin. PLA and CHO meals contained xanthan gum and low-energy flavouring (~29 kcal) and subjects were told both ‘contained energy’. Two hours post-meal, subjects completed 4 sets of back squat and bench press to failure at 90% 10 repetition maximum. Blood samples were taken pre-meal, 45 min and 105 min post-meal to measure serum/plasma glucose, insulin, ghrelin, GLP-1 and PYY concentrations. Subjective hunger/fullness were also measured. Total back squat repetitions were greater in CHO (44 (SD 10) repetitions) and PLA (43 ± 10 repetitions) than WAT (38 (SD 10) repetitions; P < 0.001). Total bench press repetitions were similar between trials (WAT 37 (SD 7) repetitions; CHO 39 ± 7 repetitions; PLA 38 (SD 7) repetitions; P = 0.130). Performance was similar between CHO and PLA trials. Hunger was suppressed and fullness increased similarly in PLA and CHO, relative to WAT (P < 0.001). During CHO, plasma glucose was elevated at 45 min (P < 0.05), whilst serum insulin was elevated (P < 0.05) and plasma ghrelin supressed at 45 and 105 min (P < 0.05). These results suggest that breakfast/pre-exercise nutrition enhances resistance exercise performance via a psychological effect, although a potential mediating role of hunger cannot be discounted

Key Physiological Parameters Dictate Triggering of Activity-Dependent Bulk Endocytosis in Hippocampal Synapses

To maintain neurotransmission in central neurons, several mechanisms are employed to retrieve synaptically exocytosed membrane. The two major modes of synaptic vesicle (SV) retrieval are clathrin-mediated endocytosis and activity-dependent bulk endocytosis (ADBE). ADBE is the dominant SV retrieval mode during intense stimulation, however the precise physiological conditions that trigger this mode are not resolved. To determine these parameters we manipulated rat hippocampal neurons using a wide spectrum of stimuli by varying both the pattern and duration of stimulation. Using live-cell fluorescence imaging and electron microscopy approaches, we established that stimulation frequency, rather than the stimulation load, was critical in the triggering of ADBE. Thus two hundred action potentials, when delivered at high frequency, were sufficient to induce near maximal bulk formation. Furthermore we observed a strong correlation between SV pool size and ability to perform ADBE. We also identified that inhibitory nerve terminals were more likely to utilize ADBE and had a larger SV recycling pool. Thus ADBE in hippocampal synaptic terminals is tightly coupled to stimulation frequency and is more likely to occur in terminals with large SV pools. These results implicate ADBE as a key modulator of both hippocampal neurotransmission and plasticity

A Minimal Model of Metabolism Based Chemotaxis

Since the pioneering work by Julius Adler in the 1960's, bacterial chemotaxis has been predominantly studied as metabolism-independent. All available simulation models of bacterial chemotaxis endorse this assumption. Recent studies have shown, however, that many metabolism-dependent chemotactic patterns occur in bacteria. We hereby present the simplest artificial protocell model capable of performing metabolism-based chemotaxis. The model serves as a proof of concept to show how even the simplest metabolism can sustain chemotactic patterns of varying sophistication. It also reproduces a set of phenomena that have recently attracted attention on bacterial chemotaxis and provides insights about alternative mechanisms that could instantiate them. We conclude that relaxing the metabolism-independent assumption provides important theoretical advances, forces us to rethink some established pre-conceptions and may help us better understand unexplored and poorly understood aspects of bacterial chemotaxis