Activation of IRE1, PERK and salt-inducible kinases leads to Sec body formation in Drosophila S2 cells

The phase separation of the non-membrane bound Sec bodies occurs in Drosophila S2 cells by coalescence of components of the endoplasmic reticulum (ER) exit sites under the stress of amino acid starvation. Here, we address which signaling pathways cause Sec body formation and find that two pathways are critical. The first is the activation of the salt-inducible kinases (SIKs; SIK2 and SIK3) by Na(+) stress, which, when it is strong, is sufficient. The second is activation of IRE1 and PERK (also known as PEK in flies) downstream of ER stress induced by the absence of amino acids, which needs to be combined with moderate salt stress to induce Sec body formation. SIK, and IRE1 and PERK activation appear to potentiate each other through the stimulation of the unfolded protein response, a key parameter in Sec body formation. This work shows the role of SIKs in phase transition and re-enforces the role of IRE1 and PERK as a metabolic sensor for the level of circulating amino acids and salt. This article has an associated First Person interview with the first author of the paper

HOW RELIABLE IS IN SITU SATURATION MONITORING (ISSM) USING X-RAY?

ABSTRACT In core flooding studies, where fluids are injected to mobilize hydrocarbons, X-ray measurements are often used to monitor the hydrocarbon saturations in the core. This is done as a function of the position in the core and as a function of time. The goal is to understand how effective the injected fluids can displace the hydrocarbons, and to measure how much hydrocarbons are left behind in the core. The calculation of in place saturations from X-ray, however, is not straightforward, and it is often unclear what the uncertainties in the calculated saturations are. In this paper, we compare calculated saturations from X-ray with saturations from direct measurement of produced hydrocarbon volumes from the core. The direct measurement is obtained using a novel apparatus which measures the production of oil using a balance under a back pressure. We show that differences between the two methods can be quite substantial and we discuss what may be the reasons causing these differences. The paper ends with a discussion on how we can improve the use of in situ saturation monitoring for unsteady state experiments

The origin of non-thermal fluctuations in multiphase flow in porous media

Core flooding experiments to determine multiphase flow in properties of rock such as relative permeability can show significant fluctuations in terms of pressure, saturation, and electrical conductivity. That is typically not considered in the Darcy scale interpretation but treated as noise. However, in recent years, flow regimes that exhibit spatio-temporal variations in pore scale occupancy related to fluid phase pressure changes have been identified. They are associated with topological changes in the fluid configurations caused by pore-scale instabilities such as snap-off. The common understanding of Darcy-scale flow regimes is that pore-scale phenomena and their signature should have averaged out at the scale of representative elementary volumes (REV) and above. In this work, it is demonstrated that pressure fluctuations observed in centimeter-scale experiments commonly considered Darcy-scale at fractional flow conditions, where wetting and non-wetting phases are co-injected into porous rock at small (<10−6) capillary numbers are ultimately caused by pore-scale processes, but there is also a Darcy-scale fractional flow theory aspect. We compare fluctuations in fractional flow experiments conducted on samples of few centimeters size with respective experiments and in-situ micro-CT imaging at pore-scale resolution using synchrotron-based X-ray computed micro-tomography. On that basis we can establish a systematic causality from pore to Darcy scale. At the pore scale, dynamic imaging allows to directly observe the associated breakup and coalescence processes of non-wetting phase clusters, which follow “trajectories” in a “phase diagram” defined by fractional flow and capillary number and can be used to categorize flow regimes. Connected pathway flow would be represented by a fixed point, whereas processes such as ganglion dynamics follow trajectories but are still overall capillary-dominated. That suggests that the origin of the pressure fluctuations observed in centimeter-sized fractional flow experiments are capillary effects. The energy scale of the pressure fluctuations corresponds to 105-106 times the thermal energy scale. This means the fluctuations are non-thermal. At the centimeter scale, there are non-monotonic and even oscillatory solutions permissible by the fractional flow theory, which allow the fluctuations to be visible and—depending on exact conditions—significant at centimeter scale, within the viscous limit of classical (Darcy scale) fractional flow theory. That also means that the phenomenon involves both capillary aspects from the pore or cluster scale and viscous aspects of fractional flow and occurs right at the transition, where the physical description concept changes from pore to Darcy scale

Design and synthesis of novel small molecule CCR2 antagonists: evaluation of 4-aminopiperidine derivatives

Medicinal Chemistr

Predicting CYP3A-mediated midazolam metabolism in critically ill neonates, infants, children and adults with inflammation and organ failure.

Aims: Inflammation and organ failure have been reported to have an impact on cytochrome P450 (CYP) 3A-mediated clearance of midazolam in critically ill children. Our aim was to evaluate a previously developed population pharmacokinetic model both in critically ill children and other populations, in order to allow the model to be used to guide dosing in clinical practice. Methods: The model was evaluated externally in 136 individuals, including (pre)term neonates, infants, children and adults (body weight 0.77–90 kg, C-reactive protein level 0.1–341 mg l–1 and 0–4 failing organs) using graphical and numerical diagnostics. Results: The pharmacokinetic model predicted midazolam clearance and plasma concentrations without bias in postoperative or critically ill paediatric patients and term neonates [median prediction error (MPE) 180%). Conclusion: The recently published pharmacokinetic model for midazolam, quantifying the influence of maturation, inflammation and organ failure in children, yields unbiased clearance predictions and can therefore be used for dosing instructions in term neonates, children and adults with varying levels of critical illness, including healthy adults, but not for extrapolation to preterm neonates

Are mice good models for human neuromuscular disease? Comparing muscle excursions in walking between mice and humans

The mouse is one of the most widely used animal models to study neuromuscular diseases and test new therapeutic strategies. However, findings from successful pre-clinical studies using mouse models frequently fail to translate to humans due to various factors. Differences in muscle function between the two species could be crucial but often have been overlooked. The purpose of this study was to evaluate and compare muscle excursions in walking between mice and humans

How to select a chiropractor for the management of athletic conditions

<p>Abstract</p> <p>Background</p> <p>Chiropractors are an integral part of the management of musculoskeletal injuries. A considerable communication gap between the chiropractic and medical professions exists. Subsequently referring allopathic practitioners lack confidence in picking a chiropractic practitioner with appropriate management strategies to adequately resolve sporting injuries. Subsequently, the question is often raised: "how do you find a good chiropractor?".</p> <p>Discussion</p> <p>Best practice guidelines are increasingly suggesting that musculoskeletal injuries should be managed with multimodal active and passive care strategies. Broadly speaking chiropractors may be subdivided into "modern multimodal" or "classical" (unimodal) in nature. The modern multimodal practitioner is better suited to managing sporting injuries by incorporating passive and active care management strategies to address three important phases of care in the continuum of injury from the acute inflammation/pain phase to the chronic/rehabilitation phase to the injury prevention phase. In contrast, the unimodal, manipulation only and typically spine only approach of the classical practitioner seems less suited to the challenges of the injured athlete. Identifying what part of the philosophical management spectrum a chiropractor falls is important as it is clearly not easily evident in most published material such as Yellow Pages advertisements.</p> <p>Summary</p> <p>Identifying a chiropractic practitioner who uses multimodal treatment of adequate duration, who incorporates active and passive components of therapy including exercise prescription whilst using medical terminology and diagnosis without mandatory x-rays or predetermined treatment schedules or prepaid contracts of care will likely result in selection of a chiropractor with the approach and philosophy suited to appropriately managing athletic conditions. Sporting organizations and associations should consider using similar criteria as a minimum standard to allow participation in health care team selections.</p

Agonists for the adenosine A(1) receptor with tunable residence time: a case for nonribose 4-Amino-6-aryl-5-cyano-2-thiopyrimidines

Medicinal Chemistr