A multi-objective combinatorial optimisation framework for large scale hierarchical population synthesis

In agent-based simulations, synthetic populations of agents are commonly used to represent the structure, behaviour, and interactions of individuals. However, generating a synthetic population that accurately reflects real population statistics is a challenging task, particularly when performed at scale. In this paper, we propose a multi objective combinatorial optimisation technique for large scale population synthesis. We demonstrate the effectiveness of our approach by generating a synthetic population for selected regions and validating it on contingency tables from real population data. Our approach supports complex hierarchical structures between individuals and households, is scalable to large populations and achieves minimal contigency table reconstruction error. Hence, it provides a useful tool for policymakers and researchers for simulating the dynamics of complex populations

A Novel Peptide Prevents Enterotoxin- and Inflammation-Induced Intestinal Fluid Secretion by Stimulating Sodium-Hydrogen Exchanger 3 Activity.

BACKGROUND & AIMS: Acute diarrheal diseases are the second most common cause of infant mortality in developing countries. This is contributed to by lack of effective drug therapy that shortens the duration or lessens the volume of diarrhea. The epithelial brush border sodium (Na+)/hydrogen (H+) exchanger 3 (NHE3) accounts for a major component of intestinal Na+ absorption and is inhibited in most diarrheas. Because increased intestinal Na+ absorption can rehydrate patients with diarrhea, NHE3 has been suggested as a potential druggable target for drug therapy for diarrhea. METHODS: A peptide (sodium-hydrogen exchanger 3 stimulatory peptide [N3SP]) was synthesized to mimic the part of the NHE3 C-terminus that forms a multiprotein complex that inhibits NHE3 activity. The effect of N3SP on NHE3 activity was evaluated in NHE3-transfected fibroblasts null for other plasma membrane NHEs, a human colon cancer cell line that models intestinal absorptive enterocytes (Caco-2/BBe), human enteroids, and mouse intestine in vitro and in vivo. N3SP was delivered into cells via a hydrophobic fluorescent maleimide or nanoparticles. RESULTS: N3SP uptake stimulated NHE3 activity at nmol/L concentrations under basal conditions and partially reversed the reduced NHE3 activity caused by elevated adenosine 3,5-cyclic monophosphate, guanosine 3,5-cyclic monophosphate, and Ca2+ in cell lines and in in vitro mouse intestine. N3SP also stimulated intestinal fluid absorption in the mouse small intestine in vivo and prevented cholera toxin-, Escherichia coli heat-stable enterotoxin-, and cluster of differentiation 3 inflammation-induced fluid secretion in a live mouse intestinal loop model. CONCLUSIONS: These findings suggest pharmacologic stimulation of NHE3 activity as an efficacious approach for the treatment of moderate/severe diarrheal diseases

Considerations on the Numerical Modeling and Performance of Axial Swirlers Under Relight Conditions

Numerical modeling of aero engine combustors under relight conditions is a matter of continuously increasing importance due to the demanding engine certification regulations. In order to reduce the complexity and the cost of the numerical modeling, common practice is to replace the atomizer's swirlers with velocity profiles boundary conditions, very often scaled down from nominal operating conditions assuming similarity of the swirler flowfield. The current numerical study focuses on the flowfield characteristics of an axially swirled atomizer operating within a windmilling engine environment. The scalability of the velocity profile from higher power settings is examined. Observations on the performance of the axial swirler under relight conditions are also made. Experimental data was used as a validation platform for the numerical solver, after a grid sensitivity study and a turbulence model selection process. Boundary conditions for simulating the windmilling environment were extracted from experimental work. The swirler axial and tangential velocity profiles were normalized using the swirler inlet velocity. Results showed that both profiles are only scalable for windmilling conditions of high flight Mach number (! 0.5). At low flight Mach numbers, the actual profile had a lower velocity than that predicted through scaling. The swirl number was found to deteriorate significantly with the flight velocity following a linear trend, reducing significantly the expected flame quality. As a consequence the burner is forced to operate at the edge of its stability loop with low certainty regarding its successful relight

Elevated Intracellular Calcium Stimulates NHE3 Activity by an IKEPP (NHERF4) Dependent Mechanism

The ileal brush border (BB) contains four evolutionarily related multi-PDZ domain proteins including NHERF1, NHERF2, PDZK1 (NHERF3) and IKEPP (NHERF4). Why multiple related PDZ proteins are in a similar location in the same cell is unknown. However, some specificity in regulation of NHE3 activity has been identified. For example, elevated intracellular Ca2+ ([Ca2+]i) inhibition of NHE3 is reconstituted by NHERF2 but not NHERF1, and involves the formation of large NHE3 complexes. To further evaluate the specificity of the NHERF family in calcium regulation of NHE3 activity, the current study determined whether the four PDZ domain containing protein IKEPP reconstitutes elevated [Ca2+]i regulation of NHE3. In vitro, IKEPP bound to the F2 region (aa 590-667) of NHE3 in overlay assays, which is the same region where NHERF1 and NHERF2 bind. PS120 cells lack endogenous NHE3 and IKEPP. Treatment of PS120/NHE3/IKEPP cells (stably transfected with NHE3 and IKEPP) with the Ca2+ ionophore, 4-Br-{"type":"entrez-nucleotide","attrs":{"text":"A23187","term_id":"833253","term_text":"A23187"}}A23187 (0.5μM), stimulated NHE3 Vmax activity by ∼40%. This was associated with an increase in plasma membrane expression of NHE3 by a similar amount. NHE3 activity and surface expression were unaffected by {"type":"entrez-nucleotide","attrs":{"text":"A23187","term_id":"833253","term_text":"A23187"}}A23187 in PS120/NHE3 cells lacking IKEPP. Based on sucrose density gradient centrifugation, IKEPP was also shown to exist in large complexes, some of which overlap in size with NHE3, and the size of both NHE3 and IKEPP complexes decreased in parallel after [Ca2+]i elevation. FRET experiments on fixed cells demonstrated that IKEPP and NHE3 directly associated at an intracellular site. Elevating [Ca2+]i decreased this intracellular NHE3 and IKEPP association. In summary: (1) In the presence of IKEPP, elevated [Ca2+]i stimulates NHE3 activity. This was associated with increased expression of NHE3 in the plasma membrane as well as a shift to smaller sizes of NHE3 and IKEPP containing complexes. (2) IKEPP directly binds NHE3 at its F2 C-terminal domain and directly associates with NHE3 in vivo (FRET). (3) Elevated [Ca2+]i decreased the association of IKEPP and NHE3 in an intracellular compartment. Based on which NHERF family member is expressed in PS120 cells, elevated [Ca2+]i stimulates (IKEPP), inhibits (NHERF2) or does not affect (NHERF1) NHE3 activity. This demonstrates that regulation of NHE3 depends on the nature of the NHERF family member associating with NHE3 and the accompanying NHE3 complexes

Intestinal in vitro and ex vivo Models to Study Host-Microbiome Interactions and Acute Stressors

The gut microbiome is extremely important for maintaining homeostasis with host intestinal epithelial, neuronal, and immune cells and this host-microbe interaction is critical during times of stress or disease. Environmental, nutritional, and cognitive stress are just a few factors known to influence the gut microbiota and are thought to induce microbial dysbiosis. Research on this bidirectional relationship as it pertains to health and disease is extensive and rapidly expanding in both in vivo and in vitro/ex vivo models. However, far less work has been devoted to studying effects of host-microbe interactions on acute stressors and performance, the underlying mechanisms, and the modulatory effects of different stressors on both the host and the microbiome. Additionally, the use of in vitro/ex vivo models to study the gut microbiome and human performance has not been researched extensively nor reviewed. Therefore, this review aims to examine current evidence concerning the current status of in vitro and ex vivo host models, the impact of acute stressors on gut physiology/microbiota as well as potential impacts on human performance and how we can parlay this information for DoD relevance as well as the broader scientific community. Models reviewed include widely utilized intestinal cell models from human and animal models that have been applied in the past for stress or microbiology research as well as ex vivo organ/tissue culture models and new innovative models including organ-on-a-chip and co-culture models

Freezing of ridges and water networks preserves the Gamburtsev Subglacial Mountains for millions of years

Once an ice sheet grows beyond a critical thickness, the basal thermal regime favors melting and development of subglacial water networks. Subglacial water is necessary for bedrock erosion, but the exact mechanisms that lead to preservation of subglacial topography are unclear. Here we resolve the freezing mechanisms that lead to long-term, high-altitude preservation across the Gamburtsev Subglacial Mountains in East Antarctica. Analyses of a comprehensive geophysical data set reveal a large-scale water network along valley floors. The ice sheet often drives subglacial water up steep topography where it freezes along high ridges beneath thinner ice. Statistical tests of hypsometry show the Gamburtsevs resemble younger midlatitude mountains, indicating exceptional preservation. We conclude that the Gamburtsevs have been shielded from erosion since the latest Eocene (∼34 Ma). These freezing mechanisms likely account for the spatial and temporal patterns of erosion and preservation seen in other glaciated mountain ranges

Human enteroids: Preclinical models of non-inflammatory diarrhea

Researchers need an available and easy-to-use model of the human intestine to better understand human intestinal physiology and pathophysiology of diseases, and to offer an enhanced platform for developing drug therapy. Our work employs human enteroids derived from each of the major intestinal sections to advance understanding of several diarrheal diseases, including those caused by cholera, rotavirus and enterohemorrhagic Escherichia coli. An enteroid bank is being established to facilitate comparison of segmental, developmental, and regulatory differences in transport proteins that can influence therapy efficacy. Basic characterization of major ion transport protein expression, localization and function in the human enteroid model sets the stage to study the effects of enteric infection at the transport level, as well as to monitor potential responses to pharmacological intervention

Advancements on the use of Filtered Rayleigh Scattering (FRS) with machine learning methods for flow distortion in aero-engine intakes

In-flight measurements of aerodynamic quantities are a requirement to ensure the correct scaling of Reynolds and Mach number and for the airworthiness certification of an aircraft. The ability to obtain such measurement is subject to several challenges such as instrument installation, environment, type of measurand, and spatial and temporal resolution. Given expected, more frequent use of embedded propulsion systems in the near future, the measurement technology needs to adapt for the characterization of multi-type flow distortion in complex flow, to assess the operability of air-breathing propulsion systems. To meet this increasing demand for high-fidelity experimental data, the Filtered Rayleigh Scattering (FRS) method is identified as a promising technology, as it can provide measurements of pressure, temperature and 3D velocities simultaneously, across a full Aerodynamic Interface Plane (AIP). Τhis work demonstrates the application of a novel FRS instrument, to assess the flow distortion in an S-duct diffuser, in a ground testing facility. A comparison of FRS results with Stereo-Particle Image Velocimetry (S-PIV) measurements reveals good agreement of the out of plane velocities, within 3.3 % at the AIP. Furthermore, the introduction of machine learning methods significantly accelerates the processing of the FRS data by up to 200 times, offering a substantial prospect towards real time data analysis. This study demonstrates the further development of the FRS technique, with the ultimate goal of inlet flow distortion measurements for in-flight environments.European CommissionThe SINATRA project leading to this publication has received funding from the Clean Sky 2 Joint Undertaking (JU) under grant agreement No 886521. The JU receives support from the European Union’s Horizon 2020 research and innovation programme and the Clean Sky 2 JU members other than the Union.Experimental Thermal and Fluid Scienc

Non-intrusive flow diagnostics for unsteady inlet flow distortion measurements in novel aircraft architectures

Inlet flow distortion is expected to play a major role in future aircraft architectures where complex air induction systems are required to couple the engine with the airframe. The highly unsteady distortions generated by such intake systems can be detrimental to engine performance and were previously linked with loss of engine stability and potentially catastrophic consequences. During aircraft design, inlet flow distortion is typically evaluated at the aerodynamic interface plane, which is defined as a cross-flow plane located at a specific upstream distance from the engine fan. Industrial testing currently puts more emphasis on steady state distortions despite the fact that, historically, unsteady distortions were acknowledged as equally important. This was partially due to the limitations of intrusive measurement methods to deliver unsteady data of high spatial resolution in combination with their high cost and complexity. However, as the development of aircraft with fuselage-integrated engine concepts progresses, the combination of different types of flow distortions is expected to have a strong impact on the engine’s stability margin. Therefore, the need for novel measurement methods able to meet the anticipated demand for more comprehensive flow information is now more critical than ever. In reviewing the capabilities of various non-intrusive methods for inlet distortion measurements, Filtered Rayleigh Scattering (FRS) is found to have the highest potential for synchronously characterising multiple types of inlet flow distortions, since the method has the proven ability to simultaneously measure velocity, static pressure and temperature fields in challenging experimental environments. The attributes of the FRS method are further analysed aiming to deliver a roadmap for its application on ground-based and in-flight measurement environments.European Union funding: 88652

Epac1 mediates protein kinase A–independent mechanism of forskolin-activated intestinal chloride secretion

Intestinal Cl− secretion is stimulated by cyclic AMP (cAMP) and intracellular calcium ([Ca2+]i). Recent studies show that protein kinase A (PKA) and the exchange protein directly activated by cAMP (Epac) are downstream targets of cAMP. Therefore, we tested whether both PKA and Epac are involved in forskolin (FSK)/cAMP-stimulated Cl− secretion. Human intestinal T84 cells and mouse small intestine were used for short circuit current (Isc) measurement in response to agonist-stimulated Cl− secretion. FSK-stimulated Cl− secretion was completely inhibited by the additive effects of the PKA inhibitor, H89 (1 µM), and the [Ca2+]i chelator, 1,2-bis-(o-aminophenoxy)-ethane-N,N,N’,N’-tetraacetic acid, tetraacetoxymethyl ester (BAPTA-AM; 25 µM). Both FSK and the Epac activator 8-pCPT-2’-O-Me-cAMP (50 µM) elevated [Ca2+]i, activated Ras-related protein 2, and induced Cl− secretion in intact or basolateral membrane–permeabilized T84 cells and mouse ileal sheets. The effects of 8-pCPT-2’-O-Me-cAMP were completely abolished by BAPTA-AM, but not by H89. In contrast, T84 cells with silenced Epac1 had a reduced Isc response to FSK, and this response was completely inhibited by H89, but not by the phospholipase C inhibitor U73122 or BAPTA-AM. The stimulatory effect of 8-pCPT-2’-O-Me-cAMP on Cl− secretion was not abolished by cystic fibrosis transmembrane conductance (CFTR) inhibitor 172 or glibenclamide, suggesting that CFTR channels are not involved. This was confirmed by lack of effect of 8-pCPT-2’-O-Me-cAMP on whole cell patch clamp recordings of CFTR currents in Chinese hamster ovary cells transiently expressing the human CFTR channel. Furthermore, biophysical characterization of the Epac1-dependent Cl− conductance of T84 cells mounted in Ussing chambers suggested that this conductance was hyperpolarization activated, inwardly rectifying, and displayed a Cl−>Br−>I− permeability sequence. These results led us to conclude that the Epac-Rap-PLC-[Ca2+]i signaling pathway is involved in cAMP-stimulated Cl− secretion, which is carried by a novel, previously undescribed Cl− channel