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Within the scope of the European Horizon 2020 project ACDC – Artificial Cells with Distributed Cores to Decipher Protein Function, we aim at the development of a chemical compiler governing the three-dimensional arrangement of droplets, which are filled with various chemicals. Neighboring droplets form bilayers containing pores through which chemicals can move from one droplet to its neighbors. When achieving a desired three-dimensional configuration of droplets, we can thus enable gradual biochemical reaction schemes for various purposes, e.g., for the production of some desired macromolecules for pharmaceutical purposes. In this paper, we focus on geometric restrictions to possible arrangements of droplets. We present analytic results for the buttercup problem and a heuristic optimization method for the kissing number problem, which we then apply to find (quasi) optimum values for a bidisperse kissing number problem, in which the center sphere exhibits a larger radius.

We aim at planning and creating specific agglomerations of droplets to study synergic communication using these as programmable units. In this paper, we give an overview of preliminary obstacles for the various research issues, namely of how to create droplets, how to set up droplet agglomerations using DNA technology, how to prepare them for confocal microscopy, how to make a computer see droplets on photos, how to analyze networks of droplets, how to perform simulations mimicking experiments, and how to plan specific agglomerations of droplets.

We simulate the movement and agglomeration of oil droplets in water under constraints, like confinement, using a simplified stochastic-hydrodynamic model. In the analysis of the network created by the droplets in the agglomeration, we focus on the paths between pairs of droplets and compare the computational results for various system sizes.

Within the context of the European Horizon 2020 project ACDC, we intend to develop a probabilistic chemical compiler, to aid the construction of three-dimensional agglomerations of artificial hierarchical cellular constructs. These programmable discrete units offer a wide variety of technical innovations, like a portable biochemical laboratory that e.g. produces macromolecular medicine on demand. For this purpose, we have to investigate the agglomeration process of droplets and vesicles under proposed constraints, like confinement. This paper focuses on the influence of the geometry of the initialization and of the container on the agglomeration.

Anticancer drug development is a crucial step toward cancer treatment, that requires realistic predictions of malignant tissue development and sophisticated drug delivery. Tumors often acquire drug resistance and drug efficacy, hence cannot be accurately predicted in 2D tumor cell cultures. On the other hand, 3D cultures, including multicellular tumor spheroids (MCTSs), mimic the in vivo cellular arrangement and provide robust platforms for drug testing when grown in hydrogels with characteristics similar to the living body. Microparticles and liposomes are considered smart drug delivery vehicles, are able to target cancerous tissue, and can release entrapped drugs on demand. Microfluidics serve as a high‐throughput tool for reproducible, flexible, and automated production of droplet‐based microscale constructs, tailored to the desired final application. In this review, it is described how natural hydrogels in combination with droplet microfluidics can generate MCTSs, and the use of microfluidics to produce tumor targeting microparticles and liposomes. One of the highlights of the review documents the use of the bottom‐up construction methodologies of synthetic biology for the formation of artificial cellular assemblies, which may additionally incorporate both target cancer cells and prospective drug candidates, as an integrated “droplet incubator” drug assay platform., This review summarizes the recent progress of droplet technologies in anticancer drug development. Microfluidic‐formed droplets are utilized in both tumor spheroid formation and smart drug delivery. This work also highlights the current trend of using artificial cells materials for drug metabolism studies. Finally, a novel ‘droplet incubator’ concept as a prospective anticancer drug screening platform is introduced.

The bottom‐up construction of synthetic cells with user‐defined chemical organization holds considerable promise in the creation of bioinspired materials. Complex emulsions, droplet networks, and nested vesicles all represent platforms for the engineering of segregated chemistries with controlled communication, analogous to biological cells. Microfluidic manufacture of such droplet‐based materials typically results in radial or axisymmetric structures. In contrast, biological cells frequently display chemical polarity or gradients, which enable the determination of directionality, and inform higher‐order interactions. Here, a dual‐material, 3D‐printing methodology to produce microfluidic architectures that enable the construction of functional, asymmetric, hierarchical, emulsion‐based artificial cellular chassis is developed. These materials incorporate droplet networks, lipid membranes, and nanoparticle components. Microfluidic 3D‐channel arrangements enable symmetry‐breaking and the spatial patterning of droplet hierarchies. This approach can produce internal gradients and hemispherically patterned, multilayered shells alongside chemical compartmentalization. Such organization enables incorporation of organic and inorganic components, including lipid bilayers, within the same entity. In this way, functional polarization, that imparts individual and collective directionality on the resulting artificial cells, is demonstrated. This approach enables exploitation of polarity and asymmetry, in conjunction with compartmentalized and networked chemistry, in single and higher‐order organized structures, thereby increasing the palette of functionality in artificial cellular materials., Polarized artificial cells are created by 3D‐microfluidics. Multi‐material 3D‐printed microfluidics is used to create hierarchical droplet assemblies, where 3D‐channel geometries enable asymmetric and polarized patterning in droplet assemblies. These materials contain lipid‐bilayer‐segregated droplet networks and integrate patterned organic and inorganic components. Polarized patterning with magnetic microparticles bestows directional properties and motion in aqueous environments, with constructs exhibiting simple group‐level behaviors.

In article number https://doi.org/10.1002/advs.201901719, David Anthony Barrow, Oliver Kieran Castell, and co‐workers create polarized artificial cells from compartmentalized droplet networks and nanomaterials, using multi‐material, 3D‐printed fluidics. Polarized patterning with magnetic microparticles bestow directional properties and motion in aqueous environments, with artificial cells exhibiting simple group‐level behaviors.

PURPOSE: Obesity may alter mononuclear phagocyte system (MPS) function and the pharmacology and efficacy of nanoparticles therapies, such as PEGylated liposomal doxorubicin (PLD). We aimed to evaluate relationships between hormone and chemokine mediators of MPS function and the pharmacokinetic (PK) exposure of PLD in obese and normal weight patients with ovarian and endometrial cancer. METHODS: Hormone and chemokine mediators in obese and normal weight ovarian and endometrial cancer patients were measured. A separate pharmacology study was performed that evaluated the relationship between serum hormone concentrations, MPS function, and PK disposition of PLD in refractory ovarian cancer patients. RESULTS: Univariate analysis revealed a significant relationship between serum estradiol and body mass index (OR: 8.64, 95% CI: 2.67–28.0, p

Summary Objective Our study analyzes the association between chemokine-ligand-2 (CCL2) serum concentrations at baseline and knee radiographic osteoarthritis (OA) (knee-rOA), knee-rOA progression, individual radiographic features and knee symptomatic OA at 5-year follow-up. Design OA outcomes were analyzed in a community-based cohort including a baseline enrollment and a 5-year follow-up. Baseline CCL2 serum concentrations were assessed by multiplex assay and associated with presence or progression of individual radiographic features at 5-year follow-up. Separate multiple logistic regression models were used to examine adjusted associations between baseline CCL2 and each of the knee OA variables at follow-up. CCL2 at baseline was modeled as an explanatory variable, whereas each of the knee OA variables at follow-up served as the response variables. Models were adjusted for age, BMI, race, and sex. Trend tests were conducted to assess any linear effect on outcomes across CCL2 tertiles. Results Participants (n = 168) had a median age of 57-years and median BMI of 29 kg/m2. About 63% of all participants were women, and 58% Caucasian (42% African American). In adjusted logistic models, continuous log-CCL2 was significantly associated with knee-rOA. For each unit increase in log CCL2, the odds of having knee-rOA at follow-up was increased by 72%. CCL2 tertiles showed significant linear associations with presence and progression of knee-rOA and medial joint space narrowing (JSN), but not with presence or progression of osteophytes, bone sclerosis, knee symptoms, or symptomatic knee-rOA. Conclusions Serum CCL2 may help to elucidate some mechanisms of joint destruction and identify individuals with higher odds of structural knee changes.

Objective To determine whether dietary interventions that increase n-3 fatty acids with and without reduction in n-6 linoleic acid can alter circulating lipid mediators implicated in headache pathogenesis, and decrease headache in adults with migraine. Design Three arm, parallel group, randomized, modified double blind, controlled trial. Setting Ambulatory, academic medical center in the United States over 16 weeks. Participants 182 participants (88% women, mean age 38 years) with migraines on 5-20 days per month (67% met criteria for chronic migraine). Interventions Three diets designed with eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and linoleic acid altered as controlled variables: H3 diet (n=61)—increase EPA+DHA to 1.5 g/day and maintain linoleic acid at around 7% of energy; H3-L6 diet (n=61)—increase n-3 EPA+DHA to 1.5 g/day and decrease linoleic acid to ≤1.8% of energy; control diet (n=60)—maintain EPA+DHA at Main outcome measures The primary endpoints (week 16) were the antinociceptive mediator 17-hydroxydocosahexaenoic acid (17-HDHA) in blood and the headache impact test (HIT-6), a six item questionnaire assessing headache impact on quality of life. Headache frequency was assessed daily with an electronic diary. Results In intention-to-treat analyses (n=182), the H3-L6 and H3 diets increased circulating 17-HDHA (log ng/mL) compared with the control diet (baseline-adjusted mean difference 0.6, 95% confidence interval 0.2 to 0.9; 0.7, 0.4 to 1.1, respectively). The observed improvement in HIT-6 scores in the H3-L6 and H3 groups was not statistically significant (−1.6, −4.2 to 1.0, and −1.5, −4.2 to 1.2, respectively). Compared with the control diet, the H3-L6 and H3 diets decreased total headache hours per day (−1.7, −2.5 to −0.9, and −1.3, −2.1 to −0.5, respectively), moderate to severe headache hours per day (−0.8, −1.2 to −0.4, and −0.7, −1.1 to −0.3, respectively), and headache days per month (−4.0, −5.2 to −2.7, and −2.0, −3.3 to −0.7, respectively). The H3-L6 diet decreased headache days per month more than the H3 diet (−2.0, −3.2 to −0.8), suggesting additional benefit from lowering dietary linoleic acid. The H3-L6 and H3 diets altered n-3 and n-6 fatty acids and several of their nociceptive oxylipin derivatives in plasma, serum, erythrocytes or immune cells, but did not alter classic headache mediators calcitonin gene related peptide and prostaglandin E2. Conclusions The H3-L6 and H3 interventions altered bioactive mediators implicated in headache pathogenesis and decreased frequency and severity of headaches, but did not significantly improve quality of life. Trial registration ClinicalTrials.gov NCT02012790

The ability to make artificial lipid bilayers compatible with a wide range of environments, and with sufficient structural rigidity for manual handling, would open up a wealth of opportunities for their more routine use in real‐world applications. Although droplet interface bilayers (DIBs) have been demonstrated in a host of laboratory applications, from chemical logic to biosynthesis reaction vessels, their wider use is hampered by a lack of mechanical stability and the largely manual methods employed in their production. Multiphase microfluidics has enabled us to construct hierarchical triple emulsions with a semipermeable shell, in order to form robust, bilayer‐bound, droplet networks capable of communication with their external surroundings. These constructs are stable in air, water, and oil environments and overcome a critical obstacle of achieving structural rigidity without compromising environmental interaction. This paves the way for practical application of artificial membranes or droplet networks in diverse areas such as medical applications, drug testing, biophysical studies and their use as synthetic cells.

Computerized tomography scan (CT scan) imaging and finite element analysis were employed to investigate how the geometric composition of microneedles affects their mechanical strength and penetration characteristics. Simulations of microneedle arrays, comprising triangular, square and hexagonal microneedle base, revealed a linear dependence of the mechanical strength to the number of vertices in the polygon base. A laser-enabled, micromoulding technique was then used to fabricate 3 × 3 microneedle arrays, each individual microneedle having triangular, square or hexagonal base geometries. Their penetration characteristics into ex-vivo porcine skin, were investigated for the first time by CT scan imaging. This revealed greater penetration depths for the triangular and square-based microneedles, demonstrating CT scan as a powerful and reliable technique for studying microneedle skin penetration.

Background Serum levels of pro-inflammatory cytokines tend to be increased in irritable bowel syndrome (IBS) patients, or subgroups thereof. Still, the link between cytokine levels and IBS symptoms is unclear. We aim to determine systemic cytokine levels in IBS patients and healthy subjects (HS), confirm the presence of a subset of patients with an increased immune activity and to establish if cytokines are linked to IBS symptoms and pathophysiological factors. Methods Serum levels of interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF), and IL-10 were measured. All subjects reported IBS symptoms using validated questionnaires and underwent colonic sensorimotor testing. Multivariate supervised orthogonal partial least squares-discriminant analysis (OPLS-DA) and unsupervised principal component analysis (PCA) and hierarchical cluster analysis (HCA) were implemented. Key results Irritable bowel syndrome patients (n = 246) had higher serum levels of IL-1β, IL-6, IL-8, TNF, and IL-10 compared to HS (n = 21); however, serum cytokine profiles could not discriminate patients from HS. Moreover, cytokine levels were not correlated with symptoms among patients. Supervised OPLS-DA identified 104 patients (40% of patients) and unsupervised HCA analysis identified 49 patients (20%) with an increased immune activity indicated by elevated levels of serum cytokines compared to HS and the other patients. However, irrespective of how patients with increased immune activity were identified they were symptomatically similar to patients with no indication of increased immune activity. Conclusions & inferences Serum cytokines are elevated in IBS patients compared to HS. Immune activation characterizes a subset of patients, but modest associations between cytokine profile and symptoms suggest immune activity does not directly influence symptoms in IBS.

In this paper, a new type of microwave microfluidic sensor is proposed to detect and determine the dielectric properties of common liquids. The technique is based on perturbation theory, in which the resonant frequency and quality factor of the microwave resonator depend on the dielectric properties of the resonator. A microstrip split-ring resonator with two gaps is adopted for the design of the sensors (i.e., a double split-ring resonator). This resonator is both compact and planar, making it suitable for a lab-on-a-chip approach. Several types of solvents are tested with two types of capillaries to verify sensor performance. At 3 GHz, very good agreement is demonstrated between simulated and measured results.

We present a method of making low-loss split-ring resonators (SRRs) for microfluidic sensing at microwave frequencies using silver-coated copper wire. We show that a simple geometric modification and the use of square cross-section wire give greater electric field confinement in the capacitive region of the resonant sensor. We use a combination of theoretical analysis, finite-element simulations, and empirical measurements to demonstrate the subsequent increases in the sensitivity of these SRRs for complex permittivity measurements of some common solvents.

Herein, we demonstrate a method for simultaneously quantifying the electric and magnetic properties of liquid systems confined within a capillary. This is based upon an optimized perturbation of a microwave-frequency coaxial resonator, chosen to maximize the spatial separation of the two fields and to minimize the depolarization of the liquid. A capillary is passed through the center of the resonator so the sample occupies either maximum electric field (zero magnetic field) or maximum magnetic field (zero electric field) depending on whether an odd or even TEM mode is interrogated. This allows electric and magnetic effects to be distinguished at multiple discrete frequencies. We demonstrate this capability through the quantification of varying ionic content of saline solutions, which interact with both the electric and magnetic fields via several polarization mechanisms. The distinction of different cations and anions is also demonstrated.

A novel microfluidic biosensing platform based on Bipolar-Complementary Oxide Semiconductor (BiCMOS) technology is presented. The device relies on a quadruple electrode system and a microfluidic channel that are directly integrated into the back-end-of-line (BEOL) of the BiCMOS stack. For proof of concept repeatable electrical trapping of single SW620 (colon cancer) cells in the quadruple electrode system is initially demonstrated. Additionally, for the first time a microwave intermodulation technique is used for high sensitivity dielectric spectroscopy, which could pave the way to label-free monitoring of intracellular processes and manipulation such as electroporation.

Purpose Multifactorial etiological factors contribute to denture stomatitis (DS), a type of oral candidiasis; however, unlike other oral candidiasis, DS can occur in a healthy person wearing a denture. In this study, we therefore attempt to explore the association between candida, denture, and mucosal tissue using 1) exfoliative cytology, 2) the candidal levels present in saliva, on mucosal tissues and on denture surfaces, and 3) the salivary flow rate and xerostomic symptoms.

Herein we present a technique for performing complex permittivity measurements with an overmoded, evanescently perturbed coaxial resonator at microwave frequencies. The design of a noninvasive electromagnetic coupling structure, which allows transmission measurements to be taken from one end of a resonant section of coaxial cable, is discussed in detail. Quasi-spectral information was obtained through the exploitation of higher order resonances, and complex permittivity measurements of a number of common industrial solvents were taken at multiple discrete frequencies between 1 and 8 GHz. A combination of experimental and simulated results was used also to characterise the device behavior. The high stability of temporal measurements, coupled with the robustness of the design, make this device ideal for analytical chemistry and industrial process control.

Delivering apoptosis inducing peptides to cells is an emerging area in cancer and molecular therapeutics. Here, we have identified an alternative mechanism of action for the proapoptotic chimeric peptide D-NuBCP-9-r8. Integral to D-NuBCP-9-r8 is the Nur-77-derived D-isoform sequence fsrslhsll that targets Bcl-2, and the cell-penetrating peptide (CPP) octaarginine (r8) that is required for intracellular delivery. We find that the N-terminal phenylalanine of fsrslhsll acts in synergy with the cell-penetrating moiety to enhance peptide uptake at low nontoxic levels and cause rapid membrane blebbing and cell necrosis at higher (IC(50)) concentrations. These effects were not observed when a single phenylalanine-alanine mutation was introduced at the N-terminus of D-NuBCP-9-r8. Using primary samples from chronic lymphocytic leukemia (CLL) patients and cancer cell lines, we show that NuBCP-9-r8 induced toxicity, via membrane disruption, is independent of Bcl-2 expression. Overall, this study demonstrates a new mechanism of action for this peptide and cautions its use as a highly specific entity for targeting Bcl-2. For delivery of therapeutic peptides the work emphasizes that key amino acids in cargo, located several residues away from the cell-penetrating sequence, can significantly influence their cellular uptake and mode of action.

The application of polymers as the drug delivery systems for treating oral infections is a relatively new area of research. The present study was to test the release of the antibacterial drug chlorhexidine diacetate (CHDA), the antifungal drug Nystatin (NYS) and the antiviral drug acyclovir (ACY) from polymer blends of poly(ethyl methacrylate) and poly(n-hexyl methacrylate) of different compositions. The effects of polymer blend composition, drug loading and solubilizing surfactants on the release of the drugs have been studied. Measurements of the in vitro rate of drug release showed a sustained release of drug over extended periods of time. Drug release rates decreased with increasing PEMA content in polymer blends. CHDA release rates increased steadily with increasing drug load. The drug release rates increased with the addition of surfactants. This study demonstrates that the three therapeutic agents show a sustained rate of drug release from polymer blends of PEMA and PHMA over extended periods of time. By varying polymer blend compositions as well as the drug concentration (loading), it is possible to control the drug release rates to a desired value. The drug release rate is enhanced by addition of surfactants that solubilize drugs in the polymer blends.

Pregnancy increases plasma cystatin C, but levels are much higher in preeclampsia. Previous studies have not quantified preeclampsia risk with varying cystatin C concentrations or adjusted for confounders. We performed a case-control study of 100 preeclampsia cases and 100 random pregnancies uncomplicated by hypertension (controls). All women were free of pre-existing hypertension, diabetes, and renal disease, and gave birth to singletons. Plasma cystatin C was measured at delivery. Adjusted odds ratios (OR) and 95% confidence intervals (CI) of preeclampsia by quartiles (based on control distribution) of maternal plasma cystatin C were estimated using multivariable logistic regression models. Mean cystatin C levels were elevated in preeclampsia cases compared with controls (1.38 +/- 0.04 vs. 1.22 +/- 0.03 mg/L, p0.01). Compared to the first quartile, the estimated risk of preeclampsia was increased by approximately 12-fold for the fourth quartile, after adjusting for maternal age, body mass index, physical inactivity, smoking, and gestational age. Increased plasma levels of cystatin C were independently associated with preeclampsia. Further studies are required to assess the role of cystatin C levels in preeclampsia severity and maternal and fetal outcomes.

Dissolving microneedles are especially attractive for transdermal drug delivery as they are associated with improved patient compliance and safety. Furthermore, microneedles made of sugars offer the added benefit of biomolecule stabilisation making them ideal candidates for delivering biological agents such as proteins, peptides and nucleic acids. In this study, we performed experimental and finite element analyses to study the mechanical properties of sugar microneedles and evaluate the effect of sugar composition on microneedle ability to penetrate and deliver drug to the skin. Results showed that microneedles made of carboxymethylcellulose / maltose are superior to those made of carboxymethylcellulose / trehalose and carboxymethylcellulose / sucrose in terms of mechanical strength and the ability to deliver drug. Buckling was predicted to be the main mode of microneedle failure and the order of buckling was positively correlated to the Young’s modulus values of the sugar constituents of each microneedle.

Molecularly imprinted polymers (MIPs) represent a class of artificial receptors that promise an environmentally robust alternative to naturally occurring biorecognition elements of biosensing devices and systems. However, in general, the performance of conventional MIPs in aqueous environments is poor. In the study reported here, this limitation has been addressed by the novel application of MIPs as a solvent extraction solid phase in a biphasic solvent system. This paper describes a previously unreported use of MIPs as solvent extraction reagents, their successful application to aqueous sample media and the opportunities for utilisation of this unique system in novel biosensing and separation procedures. This study demonstrates the development of a novel biphasic solvent system utilising MIP in the extracting phase to enhance both efficiency and selectivity of a simple two phase liquid extraction. Monodisperse propranolol imprinted polymer microspheres [p(divinylbenzene-co-methacrylic acid)] were prepared by precipitation polymerisation. Initially, the affinity of the polymers for (R,S)-propranolol was assessed by established techniques whereby the MIP demonstrated greater affinity for the template than did the non-imprinted control polymer (NIP). Importantly, MIP performance was also assessed using the novel dual solvent system. The depletion of (R,S)-propranolol from the aqueous phase into the polymer containing organic phase was determined. When compared to control extractions containing no polymer the presence of MIP in the extracting solvent phase resulted in an increased extraction of (R,S)-propranolol from the aqueous phase. Importantly, this extraction was significantly greater in the presence of MIP when compared to NIP. This unique principle generates opportunities for MIP based extractions and chemical enrichments in industrial applications, offering commercial, ecological and practical advantages to traditional solvent extraction techniques. The technique is readily transferable to analytical microsystems utilising MIP recognition elements generating promising opportunities for MIP based sensing of aqueous sample media.

Crossflow membrane emulsification is a promising method to achieve very small and uniform emulsions. The droplet size produced is controlled mainly by the choice of membrane. Using microengineering technology it is currently possible to produce membranes with precision defined parameters (uniform pore size, shape and inter-pore distance). In the work presented here, individual pore behaviour was studied using micromachined membranes with wider inter-pore distances (100 ?m). It was found that the diameter of droplets increased during an initial period of operation. Also, interaction between droplets formed at adjacent pores was observed to enhance the reduction of mean droplet size and negatively correlated with inter-pore distance. A ‘push-to-detach’ mechanism was proposed to explain the behaviour observed. It was demonstrated that a micromachined membrane with pore diameter of 2 ?m and inter-pore distance of 20 ?m produced smaller droplets than for membranes with larger inter-pore distances. To facilitate the droplet detachment from the membrane and provide additional control over droplet detachment, the effects of membrane vibration were investigated. Preliminary results showed that smaller droplets could be produced by introducing low frequency (0–100 Hz) membrane vibrations without increasing their size distribution.

A numerical model for segmented flow in a microreactor has been developed. The model is based on computational fluid dynamics (CFD) which means that the flow field and mass transfer are described by a set of partial differential equations. A general purpose CFD code was extended in order to predict the internal flow patterns of fluid segments and the transfer of dissolved chemical species within segments and across fluid segment interfaces. The model has been validated by comparing predicted data with experimental microreactor titrations.

George Ian Barrow qualified as a senior dermatologist and gained his PhD-MD with a thesis on impetigo from the University of Glasgow in 1962. He became a world expert in bacteriology, specialising in the study of marine Vibrio species. He held two World Health Organization fellowships to support further …

The development focus at this international oil producer rests on a framework for sharing knowledge that starts with a business objective and ends with business results. OVERVIEW: Long-recognized for its capability in knowledge management, BP has used principles established prior to the merger with Amoco in 1998 to accelerate the integration of assets from BP, Amoco, Arco, and Burmah/Castrol. The new organization is furthering their capabilities for transferring know-how and innovation through applied technology and a focus on core processes. Improved capability in these areas is a corporate imperative, linked to improving productivity by more than 4 percent per year. Like many corporations, BP Amoco's business units are responsible for delivering results; also, like many corporations, BP aspires to the vision of a lean corporate center. By way of illustration, Group Technology in BP consists of about 30 people working as staff within a corporately supported unit. Their mission is to provide central coordination and guidance to the technology activities of BP business units. Consequently, knowledge management, or Sharing Know-how as the program is known within BP, must, out of necessity, be integrated into the activities of the corporation's businesses. A distinctive aspect of BP's organization, which is critical to the culture that supports Sharing Know-how, is the organization of business units into peer groups (Figure 1). A key reason for the peer group structure, which affects culture and behavior throughout the corporation, is a reliance on the peer group as the fundamental unit for managing capital. For example, four or five business units around the world engaged in on-shore oil production might be formed into an On-shore Oil Production Peer Group. Similarly, two or three business units focused on retail, marketing and convenience store operations may form a peer group. Relying on peer groups for managing capital forces the leaders of these business units to get together regularly to manage that capital program, including reviews of performance, informal sharing about new ideas, people, what's working, and what's not. Obviously what goes on is not just the management of capital; in a more or less direct way, business-unit leaders share knowledge. And they end up learning from one another. The peer group structure thus sets the tone and the example for the rest of the organization about Sharing Know-how (1). Generating and Sharing Knowledge BP's framework for sharing knowledge starts with the business objective and ends with business results (Figure 2). This may sound like corporate pablum, but the idea is that learning and knowledge transfer must not be an end in itself. BP thus portrays learning as a cyclical process that takes place around the execution of business plans, with generally separate activities to be taken up before, during and after a project. Underlying the framework is the idea that business units draw on shared knowledge assets which comprise explicit knowhow, and that they rely on human networks (or communities of practice) to do that. BP takes the view that networks are the building blocks of the knowledge process, borrowing from John Seely Brown's story about the repair technicians at Xerox as the exemplar for how and why networks should operate (2). BP views network members as having a dual citizenship; that is, they are part of the business units but also have a role in supporting the federal welfare by participating in the network (Figure 3). The implication of this is that rather than relying on a corporate functional department, the network becomes the means for sharing know-how among businesses. This approach is seen as a potentially cheaper, more cost-effective way to go about sharing know-how between businesses, one that allows the corporate center to focus on policy rather than the transaction cost for Sharing Know-how. In considering this organizational form, it is important to keep in perspective that BP is a complex, mature industrial enterprise with global reach. …

Omega-3 and n-6 fatty acids are biosynthetic precursors to lipid mediators with antinociceptive and pronociceptive properties. We conducted a randomized, single-blinded, parallel-group clinical trial to assess clinical and biochemical effects of targeted alteration in dietary n-3 and n-6 fatty acids for treatment of chronic headaches. After a 4-week preintervention phase, ambulatory patients with chronic daily headache undergoing usual care were randomized to 1 of 2 intensive, food-based 12-week dietary interventions: a high n-3 plus low n-6 (H3-L6) intervention, or a low n-6 (L6) intervention. Clinical outcomes included the Headache Impact Test (HIT-6, primary clinical outcome), Headache Days per month, and Headache Hours per day. Biochemical outcomes included the erythrocyte n-6 in highly unsaturated fatty acids (HUFA) score (primary biochemical outcome) and bioactive n-3 and n-6 derivatives. Fifty-six of 67 patients completed the intervention. Both groups achieved targeted intakes of n-3 and n-6 fatty acids. In intention-to-treat analysis, the H3-L6 intervention produced significantly greater improvement in the HIT-6 score (-7.5 vs -2.1; P0.001) and the number of Headache Days per month (-8.8 vs -4.0; P=0.02), compared to the L6 group. The H3-L6 intervention also produced significantly greater reductions in Headache Hours per day (-4.6 vs -1.2; P=0.01) and the n-6 in HUFA score (-21.0 vs -4.0%; P0.001), and greater increases in antinociceptive n-3 pathway markers 18-hydroxy-eicosapentaenoic acid (+118.4 vs +61.1%; P0.001) and 17-hydroxy-docosahexaenoic acid (+170.2 vs +27.2; P0.001). A dietary intervention increasing n-3 and reducing n-6 fatty acids reduced headache pain, altered antinociceptive lipid mediators, and improved quality-of-life in this population.

Accumulating evidence suggests that bacteria associated with periodontal disease may exert systemic immunomodulatory effects. Although the improvement in oral hygiene practices in recent decades correlates with the increased incidence of asthma in developed nations, it is not known whether diseases of the respiratory system might be influenced by the presence of oral pathogens. The present study sought to determine whether subcutaneous infection with the anaerobic oral pathogen Porphyromonas gingivalis exerts a regulatory effect on allergic airway inflammation. BALB/c mice sensitized and subsequently challenged with ovalbumin exhibited airway hyperresponsiveness to methacholine aerosol and increased airway inflammatory cell influx and Th2 cytokine (interleukin-4 [IL-4], IL-5, and IL-13) content relative to those in nonallergic controls. Airway inflammatory cell and cytokine contents were significantly reduced by establishment of a subcutaneous infection with P. gingivalis prior to allergen sensitization, whereas serum levels of ovalbumin-specific IgE and airway responsiveness were not altered. Conversely, subcutaneous infection initiated after allergen sensitization did not alter inflammatory end points but did reduce airway responsiveness in spite of increased serum IgE levels. These data provide the first direct evidence of a regulatory effect of an oral pathogen on allergic airway inflammation and responsiveness. Furthermore, a temporal importance of the establishment of infection relative to allergen sensitization is demonstrated for allergic outcomes.

Background- In the Periodontitis and Vascular Events (PAVE) pilot study periodontal therapy was provided as an intervention in a secondary cardiac event prevention model through five coordinated cardiac-dental centers. Methods- Subjects were randomized to either community care or protocol provided scaling and root planing to evaluate effects on periodontal status and systemic levels of high-sensitivity Creactive protein (hs-CRP). Results- After 6 months there was a significant reduction in mean probing depth and extent of 4- or 5-mm pockets. However there were no significant differences in attachment levels bleeding upon probing or extent of subgingival calculus comparing subjects assigned to protocol therapy (n = 151) to those assigned to community care (n = 152). Using intent-to-treat analyses there was no significant effect on serum hs-CRP levels at 6 months. However 48% of the subjects randomized to community care received preventive or periodontal treatments. Secondary analyses demonstrated that consideration of any preventive or periodontal care (i.e. any treatment) compared to no treatment showed a significant reduction in the percentage of people with elevated hs-CRP (values >3 mg/l)at 6 months. However obesity nullified the periodontal treatment effects on hs-CRP reduction. The adjusted odds ratio for hs-CRP levels >3 mg/l at 6 months for any treatment versus no treatment among non-obese individuals was 0.26 (95%confidence interval: 0.09 to 0.72) adjusting for smoking marital status and gender. Conclusion- This pilot study demonstrated the critical role of considering obesity as well as rigorous preventive and periodontal care in trials designed to reduce cardiovascular risk. Originally published Journal of Periodontology Vol. 80 No. 2 Feb 2009

Introduction: S-CKD602, pegylated liposomal formulation of CKD-602, a camptothecin analog, is cleared by the mononuclear phagocyte system (MPS). A phase I study of S-CKD602 reported high interpatient variability in the PK of encapsulated and released CKD-602. In addition, there was a bi-directional interaction between S-CKD602 and monocytes (MO), primary cells of MPS. The exact mechanisms underlying these interactions are unknown. Chemokine ligands play essential roles in migration and activation of MO. These factors may have important effects on nanoparticle PK and PD but have not been evaluated. Thus, we assessed the relationship of chemokines on the PK and PD of S-CKD602 in patients with refractory solid tumor. Methods: S-CKD602 was given IV over 1 h q 3 weeks. The doses ranged from 0.10 to 2.5 mg/m2. PK studies of encapsulated and released CKD-602 in plasma were performed on cycle 1. Blood was collected prior to dose, at the end of the infusion, and from 3 h to 336 h post infusion. The % decrease in MO at their nadir was calculated. The concentrations of CCL2, CCL3, CCL4, and CCL5 in plasma at baseline, 48 h and 96 h post infusion were determined using the Bio-Plex system and analyzed using Bio-Plex software. Quartile distribution was assessed and used for Spearman's correlation coefficient to determine the association between chemokine baseline level and area under the concentration versus time curve (AUC) of chemokines with S-CKD602 PK and PD. The Kruskal-Wallis test was used for comparison among chemokines and cancer types. Results: The CCL5 baseline concentration [CCL5: 10,457 ± 11,549; CCL2: 182.44 ± 104.70; CCL3: 53.00 ± 19.60; CCL4: 42.88 ± 18.64 pg/ml (P Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 754. doi:1538-7445.AM2012-754

Abstract 2122 Vitamin D is important in multiple aspects of health, including the cardiovascular, immune and skeletal systems and its effects are mediated through the vitamin D receptor (VDR). The systems affected by vitamin D are also perturbed by sickle cell disease (SCD). Vitamin D deficiency is common in SCD, but its contribution to disease manifestations is not yet known. In normal populations, vitamin D has been shown to be associated with hypertension and vascular pathology. That association may be particularly relevant to the inflammatory / endothelial damage seen in sickle cell disease. We have used clinical and laboratory data to create separate inflammatory and vaso-occlusive severity scores. Our hypothesis is that specific VDR polymorphisms are associated with disease severity in sickle cell disease. DNA specimens from 1141 study participants in the NIH-funded Silent Infarct Transfusion (SIT) trial were used. In this multi-center international trial, the participants were children ages 4 to 13 years of age with SCD who were screened for the presence of silent cerebral infarction and had demographic and clinical data collected, as well as samples for a biologic repository for a self-renewing source of DNA. An initial 570 samples served as the discovery cohort. The subsequently enrolled 530 individuals formed our validation cohort. We evaluated 79 single nucleotide polymorphisms (SNP) in the VDR gene and three associated genes, CYP27B1, VD binding protein, retinoid X receptor, and tagging SNPs from the African American population from Hapmap. The discovery cohort individuals had VDR haplotype information from a prior genome-wide association study (GWAS), and analysis for additional VDR-related SNPs was performed using a specifically designed Sequenom assay. The validation cohort was analyzed for SNPs that were significant in the discovery cohort. Phenotype data was obtained from the demographic and clinical information of the participants, and was used to create the severity scores. The vaso-occlusive score includes: number of hospitalizations for pain, number of hospitalizations for acute chest, and avascular necrosis. The inflammatory severity score includes: priapism, transient ischemic attacks (TIA), silent cerebral infarct, systolic and diastolic blood pressure, transcranial doppler velocity, white count and baseline hemoglobin. The overall severity score includes all of the inflammatory and vaso-occlusive variables. To derive the scores, the variables were transformed into quartiles. Each individual subject was assigned values of 1, 2, 3, or 4 for each variable with 1 representing lowest severity and 4, the highest. In addition, in concert with prior analyses of the SIT data, the variable for number of hospitalizations for pain was used alone as a severity measure. The severity scores were not normally distributed and were not totally continuous distributions, so the Kruskal-Wallis test was used in association analysis. To look for complex genetic models including potential gene-gene interactions for prediction of disease severity, the Multifactor Dimensionality Reduction (MDR) method was utilized, with repeat analyses performed for each severity score. By univariate analysis, no associations were found between any of the VDR associated SNPs and the 3 severity scores. Using MDR in the discovery cohort, one SNP, rs7965281, was found to be associated with the inflammatory severity score. It remained significant after correcting for multiple comparisons with permutation analysis. In the validation cohort, rs7965281 was tested for association with each of the severity scores. There was no association with the inflammatory or the vaso-occlusive severity score but a trend towards association with the overall severity score (p= 0.08). All the SNPs were tested for association with the variable, number of hospitalizations for pain using regression analysis. Two additional SNPs, rs7855881 and rs34312136 were found to be nominally significant (p=0.01 and p=0.04 respectively). Rs7965281 shows a trend as well with p=0.06. In the literature, rs7965281 is associated with reduced risk for cutaneous melanoma in a large population based study as well as with blood pressure in a British population. Further work in our validation cohort, including MDR analysis for gene-gene interaction using the 3 significant SNPs remains to be done and this may provide further direction in future research. Disclosures: No relevant conflicts of interest to declare.

Herein we present a device for performing non-contact dielectric spectroscopy upon liquids in a microfluidic environment. The device is comprised of a compression-sealed, micromilled polytetrafluoroethylene (PTFE) chip with an embedded GHz-frequency coaxial resonator. The resonator is overmoded, allowing dielectric measurements at six discrete frequencies between 1 and 8 GHz. A novel electromagnetic coupling structure allows transmission measurements to be taken from one end of the resonator, which yields a large dynamic range; provides coupling to all modes, and allows easy integration with the fluidic circuitAn optimised microchannel design maximises sensitivity and repeatability. A simple ‘fingerprint’ method for identifying solvents is demonstrated, whereby a sample is characterised by air-referenced changes in centre frequency and bandwidth of the first six modes of the device. Complex permittivity values are also obtained from these measurements according to a perturbation theory-based inversion, and are quantified for a variety of common solvents. A combination of experimental and simulated results is used to characterise the device behaviour, limits of operation and measurement uncertainty. The error of the fingerprint method is five orders of magnitude lower than the measured changes in frequency, and the uncertainty of the complex permittivity values is < 2%. The high stability of temporal measurements, coupled with the robustness of the design, make this device ideal for analytical chemistry and industrial process control.

Let μ 1 , … , μ k {\mu _1}, \ldots ,{\mu _k} be odd positive integers and n = Σ i = 1 k ( μ i + 1 ) n = \Sigma _{i = 1}^k({\mu _i} + 1) . Let { μ i } i = 1 n \{ {\mu _i}\} _{i = 1}^n be an extended Tchebycheff system on [ a , b ] [a,b] . Let L be a positive linear functional on U ≡ span ( { μ i } ) U \equiv {\operatorname {span}}(\{ {\mu _i}\} ) . We prove that L has a unique representation in the form \[ L ( p ) = ∑ i = 1 k ∑ j = 0 μ i − 1 a i j p ( j ) ( t i ) , a > t 1 > ⋯ > t k > b , L(p) = \sum \limits _{i = 1}^k {\sum \limits _{j = 0}^{{\mu _i} - 1} {{a_{ij}}{p^{(j)}}({t_i}),\quad a > {t_1} > \cdots > {t_k} > b,} } \] for all p ∈ U p \in U . The proof uses the topological degree of a mapping F : D ¯ ⊂ R k → R k F:\overline D \subset {R^k} \to {R^k} . The result is proved by showing that the equation F ( t _ ) = 0 F(\underline {t}) = 0 has a unique solution, which in turn is proved by showing that F has degree 1 and that for any solution t _ \underline {t} to the equation F ( t _ ) = 0 F(\underline {t}) = 0 , det F ′ ( t _ ) > 0 \det F\prime (\underline {t}) > 0 . We also give extensions to the cases when the { u i } \{ {u_i}\} are a periodic extended Tchebycheff system and when L is a nonnegative linear functional.

The n-dimensional Poisson problem is to solve $\Delta _n u = - f$ in a region $R_n $ with $u = g$ on $\partial R_n $. For a given ${\bf x}_ * $ in $R_n $ approximations \[ u\left( {{\bf x}_ * } \right) \simeq \sum _{j = 1}^M {A_j g\left( {{\bf x}_j } \right) + \sum _{k = 1}^N {B_k f\left( {{\bf \xi} _k } \right)} } \] are discussed. Given that the ${\bf x}_j $, $A_j $ are a harmonic interpolation formula of degree d for the Dirichlet problem for $R_n $ one wishes to find the ${\bf \xi} _k $, $B_k $ so that this approximation is exact for all polynomials of degree $ \leqq d$. Existence of the ${\bf \xi} _k $, $B_k $ is related to the question of whether or not $E[u] \equiv u({\bf x}_ * ) - \sum\nolimits_{j = 1}^M {A_j g({\bf x}_j )} $ is a positive linear functional of f of degree $d - 2$. This is established in certain cases. Some specific formulas are given as examples.

This paper simplifies and generalizes an earlier result of the author’s on Gauss interpolation formulas for the one-dimensional heat equation. Such formulas approximate a function at a point ( x ∗ , t ∗ ) ({x^\ast },{t^\ast }) in terms of a linear combination of its values on an initial-boundary curve in the (x, t) plane. The formulas are characterized by the requirement that they be exact for as many basis functions as possible. The basis functions are generated from a Tchebycheff system on the line t = 0 t = 0 by an integral kernel K ( x , y , t ) K(x,y,t) , in analogy with the way heat polynomials are generated from the monomials x i {x^i} by the fundamental solution to the heat equation. The total positivity properties of K ( x , y , t ) K(x,y,t) together with the theory of topological degree are used to establish the existence of the formulas.