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The accumulation of amyloid fibrils is characteristic of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease. Detecting these fibrils with fluorescent or radiolabelled ligands is one strategy for diagnosing and better understanding these diseases. A vast number of amyloid-binding ligands have been reported in the literature as a result. To obtain a better understanding of how amyloid ligands bind, we have compiled a database of 3457 experimental dissociation constants for 2076 unique amyloid-binding ligands. These ligands target Aβ, tau, or αSyn fibrils, as well as relevant biological samples including AD brain homogenates. From this database significant variation in the reported dissociation constants of ligands was found, possibly due to differences in the morphology of the fibrils being studied. Ligands were also found to bind to Aβ(1–40) and Aβ(1–42) fibrils with similar affinities, whereas a greater difference was found for binding to Aβ and tau or αSyn fibrils. Next, the binding of ligands to fibrils was shown to be largely limited by the hydrophobic effect. Some Aβ ligands do not fit into this hydrophobicity-limited model, suggesting that polar interactions can play an important role when binding to this target. Finally several binding site models were outlined for amyloid fibrils that describe what ligands target what binding sites. These models provide a foundation for interpreting and designing site-specific binding assays. [ABSTRACT FROM AUTHOR]

The U.S. Nuclear Regulatory Commission (NRC) and the nuclear power industry have evaluated and discussed various assumptions and methods for the treatment of potential common-cause failures (CCFs) in event and condition assessments (ECAs), specifically risk assessments performed as part of the NRC's Significance Determination Process (SDP) in recent years. The basis for how a potential CCF is treated in SDP risk assessments is provided in NUREG-2225, "Basis for the Treatment of Potential Common-Cause Failure in the Significance Determination Process." In light of new information and advancements in probabilistic risk assessment technology, the NRC and Idaho National Laboratory (INL) have continued the development of the causal alpha factor method (CAFM) for potential use in ECAs. The NRC and INL evaluated the suitability of using CAFM in SDP evaluations and reviewed the methodology to identify any potential data gaps. Furthermore, an investigation was performed on the practice of common-cause component groups to determine if changes are needed to ensure that CCF is appropriately accounted for in the Standardized Plant Analysis Risk models. In addition, a focused review of the existing method that estimates CCF parameters was performed to determine if the assumptions used in the existing process result in CCF parameters that are representative of current industry performance. It was also desired to gather a better understanding of the aspects of the alpha factor method and data calculation process that either have significant effects on the CCF parameters and/or increase the uncertainties associated with these parameters. This paper provides a summary of recently completed work, including insights, conclusions, and recommendations from this effort. [ABSTRACT FROM AUTHOR]

Infectious diarrhea is a major cause of morbidity and mortality, particularly for children in low- and middle-income countries. Cryptosporidium is a diarrheal pathogen for which there is no vaccine and current therapies are only partially effective. In this issue of the JCI, Gilchrist, Campo, and colleagues surveyed a large cohort of Bangladeshi children to profile antibody responses against an array of Cryptosporidium proteins. They discovered 233 proteins to which children developed antibodies, identified seven as being associated with protection from reinfection, and provided insights regarding the longevity of Cryptosporidium antibodies and the development of antibody breadth. In this commentary, we discuss the burden of disease caused by Cryptosporidium and how these studies highlight the strategies to better manage this parasite. [ABSTRACT FROM AUTHOR]

The functional properties of molecular systems are generally determined by the sum of many weak non-covalent interactions, and therefore methods for predicting the relative magnitudes of these interactions is fundamental to understanding the relationship between function and structure in chemistry, biology and materials science. This review focuses on the Surface Site Interaction Point (SSIP) approach which describes molecules as a set of points that capture the properties of all possible non-covalent interactions that the molecule might make with another molecule. The first half of the review focuses on the empirical non-covalent interaction parameters, α and β, and provides simple rules of thumb to estimate free energy changes for interactions between different types of functional group. These parameters have been used to have been used to establish a quantitative understanding of the role of solvent in solution phase equilibria, and to describe non-covalent interactions at the interface between macroscopic surfaces as well as in the solid state. The second half of the review focuses on a computational approach for obtaining SSIPs and applications in multi-component systems where many different interactions compete. Ab initio calculation of the Molecular Electrostatic Potential (MEP) surface is used to derive an SSIP description of a molecule, where each SSIP is assigned a value equivalent to the corresponding empirical parameter, α or β. By considering the free energies of all possible pairing interactions between all SSIPs in a molecular ensemble, it is possible to calculate the speciation of all intermolecular interactions and hence predict thermodynamic properties using the SSIMPLE algorithm. SSIPs have been used to describe both the solution phase and the solid state and provide accurate predictions of partition coefficients, solvent effects on association constants for formation of intermolecular complexes, and the probability of cocrystal formation. SSIPs represent a simple and intuitive tool for describing the relationship between chemical structure and non-covalent interactions with sufficient accuracy to understand and predict the properties of complex molecular ensembles without the need for computationally expensive simulations. [ABSTRACT FROM AUTHOR]

Salt bridges were used to attach polymerisable amidine monomers to an oligomeric benzoic acid template. CuAAC oligomerisation reactions in the presence of a benzoic acid 3-mer template gave the amidine 3-mer copy as the major product. Cleavage of ester linkers was used to hydrolyse off the amidine recognition units and convert the product into a benzoic acid 3-mer copy of the original template. [ABSTRACT FROM AUTHOR]

The institution of the black church in America is centered around two things: the people and their events. Very little scholarship has been documented about the physical buildings that became homes for the people and host to their events. These early church houses became the first evidence of a constructed material culture for formerly enslaved persons in America. The design and construction of black church houses provided enslaved as well as free persons of color the opportunity to physically create buildings that would become the center of African American life, beginning as early as the late 18th century and reaching to the present. Coupled with this exercise of the creation of architectural placemaking is the defining and application of the term "sacred space". [ABSTRACT FROM AUTHOR]

SUMMARY: In this Perspective article, we describe the visions of the PhotoRedesign consortium funded by the European Research Council of how to enhance photosynthesis. The light reactions of photosynthesis in individual phototrophic species use only a fraction of the solar spectrum, and high light intensities can impair and even damage the process. In consequence, expanding the solar spectrum and enhancing the overall energy capacity of the process, while developing resilience to stresses imposed by high light intensities, could have a strong positive impact on food and energy production. So far, the complexity of the photosynthetic machinery has largely prevented improvements by conventional approaches. Therefore, there is an urgent need to develop concepts to redesign the light‐harvesting and photochemical capacity of photosynthesis, as well as to establish new model systems and toolkits for the next generation of photosynthesis researchers. The overall objective of PhotoRedesign is to reconfigure the photosynthetic light reactions so they can harvest and safely convert energy from an expanded solar spectrum. To this end, a variety of synthetic biology approaches, including de novo design, will combine the attributes of photosystems from different photoautotrophic model organisms, namely the purple bacterium Rhodobacter sphaeroides, the cyanobacterium Synechocystis sp. PCC 6803 and the plant Arabidopsis thaliana. In parallel, adaptive laboratory evolution will be applied to improve the capacity of reimagined organisms to cope with enhanced input of solar energy, particularly in high and fluctuating light. [ABSTRACT FROM AUTHOR]

Burst wave lithotripsy (BWL) is a technology under clinical investigation for non-invasive fragmentation of urinary stones. Under certain ranges of ultrasound exposure parameters, this technology can cause cavitation in tissue leading to renal injury. This study sought to measure the focal pressure amplitude needed to cause cavitation in vivo and determine its consistency in native tissue, in an implanted stone model and under different exposure parameters. The kidneys of eight pigs were exposed to transcutaneous BWL ultrasound pulses. In each kidney, two locations were targeted: the renal sinus and the kidney parenchyma. Each was exposed for 5 min at a set pressure level and parameters, and cavitation was detected using an active cavitation imaging method based on power Doppler ultrasound. The threshold was determined by incrementing the pressure amplitude up or down after each 5-min interval until cavitation occurred/subsided. The pressure thresholds were remeasured postsurgery, targeting an implanted stone or collecting space (in sham). The presence of a stone or sham surgery did not significantly impact the threshold for tissue cavitation. Targeting parenchyma instead of kidney collecting space and lowering the ultrasound pulse repetition frequency both resulted in an increased pressure threshold for cavitation. [ABSTRACT FROM AUTHOR]

The self‐assembly of a unique molecular container is reported: a hybrid hydrogen‐bonded/metal‐coordinated cage where both hydrogen‐bonding and metal‐coordination form the crucial part of the topology. The hybrid cage was prepared combining hydrogen‐bonded rosette motif and palladium(II)/platinum(II) coordination to a pyridine ligand. It was also shown that the hybrid cage could be prepared by integrative self‐sorting from simple components. For the first time the genuine dual character of the hybrid cage was manifested as both self‐assembling parts responded selectively to different stimuli (such as phosphine and cyanurate), which resulted in the disassembly of the cage. [ABSTRACT FROM AUTHOR]

Aberrations induced by soft tissue inhomogeneities often complicate high-intensity focused ultrasound (HIFU) therapies. In this work, a bilayer phantom made from polyvinyl alcohol hydrogel and ballistic gel was built to mimic alternating layers of water-based and lipid tissues characteristic of an abdominal body wall and to reproducibly distort HIFU fields. The density, sound speed, and attenuation coefficient of each material were measured using a homogeneous gel layer. A surface with random topographical features was designed as an interface between gel layers using a 2D Fourier spectrum approach and replicating different spatial scales of tissue inhomogeneities. Distortion of the field of a 256-element 1.5 MHz HIFU array by the phantom was characterized through hydrophone measurements for linear and nonlinear beam focusing and compared to the corresponding distortion induced by an ex vivo porcine body wall of the same thickness. Both spatial shift and widening of the focal lobe were observed, as well as dramatic reduction in focal pressures caused by aberrations. The results suggest that the phantom produced levels of aberration that are similar to a real body wall and can serve as a research tool for studying HIFU effects as well as for developing algorithms for aberration correction. [ABSTRACT FROM AUTHOR]

The elevated circulating levels of cytokines associated with a variety of infectious and immune-mediated conditions are frequently termed a cytokine storm. Here, we explain the protective functions of cytokines in "ideal" responses; the multi-factorial origins that can drive these responses to become pathological; and how this ultimately leads to vascular damage, immunopathology, and worsening clinical outcomes. [ABSTRACT FROM AUTHOR]

The ability of Toxoplasma gondii to cause clinical disease in immune‐competent and immune‐deficient hosts coupled with its ease of use in vitro and availability of murine models has led to its use as a model organism to study how the immune system controls an intracellular infection. This article reviews the studies that established the role of the cytokine IFN‐γ in the activation of macrophages to control T gondii and the events that lead to the mobilization and expansion of macrophage populations and their ability to limit parasite replication. Macrophages also have pro‐inflammatory functions that promote protective NK and T‐cell activities as well as regulatory properties that facilitate the resolution of inflammation. Nevertheless, while macrophages are important in determining the outcome of infection, T gondii has evolved mechanisms to subvert macrophage activation and can utilize their migratory activities to promote dissemination and these two properties underlie the ability of this parasite to persist and cause disease. [ABSTRACT FROM AUTHOR]

The energetics of halogen bond formation in solution have been investigated for a series of nickel fluoride halogen bond acceptors; trans‐[NiF(2‐C5NF4)(PEt3)2] (A1), trans‐[NiF{2‐C5NF3(4‐H)}(PEt3)2] (A2), trans‐[NiF{2‐C5NF3(4‐NMe2)}(PEt3)2] (A3) and trans‐[NiF{2‐C5NF2H(4‐CF3)}(PCy3)2] (A4) with neutral organic halogen bond donors, iodopentafluorobenzene (D1), 1‐iodononafluorobutane (D2) and bromopentafluorobenzene (D3), in order to establish the significance of changes from perfluoroaryl to perfluoroalkyl donors and from iodine to bromine donors. 19F NMR titration experiments have been employed to obtain the association constants, enthalpy, and entropy for the halogen bond formed between these donor‐acceptor partners in protiotoluene. For A2–A4, association constants of the halogen bonds formed with iodoperfluoroalkane (D2) are consistently larger than those obtained for analogous complexes with the iodoperfluoroarene (D1). For complexes formed with A2–A4, the strength of the halogen bond is significantly lowered upon modification of the halogen donor atom from I (in D1) to Br (in D3) (for D1: 5≤K285≤12 m−1, for D3: 1.0≤K193≤1.6 m−1). The presence of the electron donating NMe2 substituent on the pyridyl ring of acceptor A3 led to an increase in −ΔH, and the association constants of the halogen bond complexes formed with D1–D3, compared to those formed by A1, A2 and A4 with the same donors. [ABSTRACT FROM AUTHOR]

The discovery of interleukin (IL)-6 and its receptor subunits provided a foundation to understand the biology of a group of related cytokines: IL-12, IL-23, and IL-27. These family members utilize shared receptors and cytokine subunits and influence the outcome of cancer, infection, and inflammatory diseases. Consequently, many facets of their biology are being therapeutically targeted. Here, we review the landmark discoveries in this field, the combinatorial biology inherent to this family, and how patient datasets have underscored the critical role of these pathways in human disease. We present significant knowledge gaps, including how similar signals from these cytokines can mediate distinct outcomes, and discuss how a better understanding of the biology of the IL-12 family provides new therapeutic opportunities. The IL-12 family of cytokines influences the outcome of cancer, infection, and inflammatory diseases. Stumhofer, Hunter, and Tait review the combinatorial biology inherent to this family and the recent clinical insights that underscore the critical role of these pathways in human disease. [ABSTRACT FROM AUTHOR]

The theoretical calculation of Surface Site Interaction Points (SSIP) has been used successfully in some applications in the solid and liquid phase. In this work we propose a new set of optimizations for the search of SSIP using the Molecular Electrostatic Potential Surfaces (MEPS) calculated with Density Functional Theory and B3LYP/6‐31*G basis set. The measures that have been implemented are based on the search for the best agreement between experimental H‐bond donor and acceptor parameters (α and β) and the MEPS extremes exploring a range of electron density levels. Additionally, a parameterization as a function of atom types has been performed. The results show that the MEPS calculated at 0.01 au electron density level slightly improves the correlation with experimental data in comparison with the calculation over other density values. This fact is related to the bigger contribution of local electrostatics at higher density levels. The refinement has provided significant improvements to the correlation between theoretical and experimental data. Moreover, the proposed calculation over 0.01 au is six times faster on average than the computation at 0.002 au. The proposed methodology has been developed with the purpose to obtain high precision SSIP in a fast way and to improve their applications in virtual cocrystal screening, calculation of free energies in solution and molecular docking. © 2018 Wiley Periodicals, Inc. A method for fast and precise calculation of surface site interaction points (SSIP) has been proposed in this work. The basis of this method is the application of the footprint algorithm over high density molecular electrostatic potential surfaces (MEPS) calculated using DFT theory. Additionally, a parameterization of the MEPS as a function of atomic types has been performed. The methodology implies a better correlation of experimental data with ab‐initio calculations. This leads to better estimation of the intensity of H‐bond donor and acceptors and could produce significant improvements on SSIP applications. [ABSTRACT FROM AUTHOR]

The Primary Care Behavioral Health (PCBH) model of service delivery is being used increasingly as an effective way to integrate behavioral health services into primary care. Despite its growing popularity, scientifically robust research on the model is lacking. In this article, we provide a qualitative review of published PCBH model research on patient and implementation outcomes. We review common barriers and potential solutions for improving the quantity and quality of PCBH model research, the vital data that need to be collected over the next 10 years, and how to collect those data. [ABSTRACT FROM AUTHOR]

Introduction: Early identification of sepsis significantly improves outcomes, suggesting a role for prehospital screening. An end-tidal carbon dioxide (ETCO2) value ≤ 25 mmHg predicts mortality and severe sepsis when used as part of a prehospital screening tool. Recently, the Quick Sequential Organ Failure Assessment (qSOFA) score was also derived as a tool for predicting poor outcomes in potentially septic patients. Methods: We conducted a retrospective cohort study among patients transported by emergency medical services to compare the use of ETCO2 ≤ 25 mmHg with qSOFA score of ≥ 2 as a predictor of mortality or diagnosis of severe sepsis in prehospital patients with suspected sepsis. Results: By comparison of receiver operator characteristic curves, ETCO2 had a higher discriminatory power to predict mortality, sepsis, and severe sepsis than qSOFA. Conclusion: Both non-invasive measures were easily obtainable by prehospital personnel, with ETCO2 performing slightly better as an outcome predictor. [ABSTRACT FROM AUTHOR]

Short chain fatty acids (SCFAs) are major gut metabolites that are involved in the regulation of dysfunction in immune responses, such as autoimmunity and cytokine storm. Numerous studies have reported a protective action of SCFAs against infectious diseases. This study investigated whether SCFAs have protective effect for immunity during fowl adenovirus-4 (FAdV-4) infection. We examined whether SCFA mixture (acetate, propionate, and butyrate) administration could protect against intramuscular challenge of a virulent viral strain. SCFA treatment promoted MHCII-expressing monocytes, the active form of T cells, and effector molecules in both peripheral and lymphoid tissues. It also boosted the production of immune molecules involved in pathogen elimination by intraepithelial lymphocytes and changed the intestinal microbial composition. We suggest that gut metabolites influence the gut microbial environment, and these changes stimulate macrophages and T cells to fight against the intramuscular challenge of FAdV-4. [ABSTRACT FROM AUTHOR]

Short chain fatty acids (SCFAs) are major gut metabolites that are involved in the regulation of dysfunction in immune responses, such as autoimmunity and cytokine storm. Numerous studies have reported a protective action of SCFAs against infectious diseases. This study investigated whether SCFAs have protective effect for immunity during fowl adenovirus-4 (FAdV-4) infection. We examined whether SCFA mixture (acetate, propionate, and butyrate) administration could protect against intramuscular challenge of a virulent viral strain. SCFA treatment promoted MHCII-expressing monocytes, the active form of T cells, and effector molecules in both peripheral and lymphoid tissues. It also boosted the production of immune molecules involved in pathogen elimination by intraepithelial lymphocytes and changed the intestinal microbial composition. We suggest that gut metabolites influence the gut microbial environment, and these changes stimulate macrophages and T cells to fight against the intramuscular challenge of FAdV-4. [ABSTRACT FROM AUTHOR]

The article explores the political and social views of Anglican Reverend William Smith on republican resistance to American independence from Great Britain during the Revolutionary War. The author reflects on the literary influence on Smith of the play "Cato" by Joseph Addison and the essay series "Cato's Letters." Emphasis is also given to topics such as the role of slavery in Smith's ideology, Smith's use of the pseudonym Cato in published letters, and the rhetorical tactic of attribution.

The concept of immune privilege of the central nervous system (CNS) has dominated the study of inflammatory processes in the brain. However, clinically relevant models have highlighted that innate pathways limit pathogen invasion of the CNS and adaptive immunity mediates control of many neural infections. As protective responses can result in bystander damage, there are regulatory mechanisms that balance protective and pathological inflammation, but these mechanisms might also allow microbial persistence. The focus of this review is to consider the host-pathogen interactions that influence neurotropic infections and to highlight advances in our understanding of innate and adaptive mechanisms of resistance as key determinants of the outcome of CNS infection. Advances in these areas have broadened our comprehension of how the immune system functions in the brain and can readily overcome immune privilege. [ABSTRACT FROM AUTHOR]

Determining the position and magnitude of Surface Site Interaction Points (SSIP) is a useful technique for understanding intermolecular interactions. SSIPs have been used for the prediction of solvation properties and for virtual co-crystal screening. To determine the SSIPs for a molecule, the Molecular Electrostatic Potential Surface (MEPS) is first calculated using ab initio methods such as Density Functional Theory. This leads to a high cost in terms of computation time and is not compatible with the analysis of huge molecular databases. Herein, we present a method for the fast estimation of SSIPs, which is based on the MEPS calculated from MMFF94 atomic partial charges. The results show that this method can be used to calculate SSIPs for large molecular databases with a much higher speed than the original ab initio methodology. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Factors that determine the solubility of polymorphs and cocrystals are analysed using experimental data to show that the change in the solubility of a compound produced by the formation of a multicomponent crystal can be estimated in a straightforward manner, if the solubilities of the pure compound and the coformer are known. [ABSTRACT FROM AUTHOR]

Lodygin and colleagues recently identified a candidate grey matter target antigen in a rat model of multiple sclerosis, a disease classically associated with the white matter antigen, myelin. Imaging of brain tissue in recipients revealed that while myelin-specific T cells were directed to the white matter, the -synuclein-specific T cells were localized to the grey matter of the cerebral cortex associated with additional inflammatory cells (Figure). One T-cell vaccine product tested in a phase IIb clinical trial, imilecleucel-T, contained irradiated autologous myelin-reactive T cells with the goal that this might lead to the immune-mediated deletion of disease-causing myelin-reactive T cells. [Extracted from the article]

The ability of T cells to operate in the central nervous system (CNS) is required for resistance to multiple pathogens that affect this tissue. The intracellular parasite Toxoplasma gondii has evolved to persist in the CNS and poses unique challenges to the immune system with the need to control parasite replication while balancing the adverse pathology associated with local inflammation. This article reviews the models used to study the response to T. gondii during toxoplasmic encephalitis and highlights some of the broader lessons that are relevant to understanding how T cells function in the CNS. [ABSTRACT FROM AUTHOR]

The expansion of integrated, collaborative, behavioral health services in primary care requires a trained behavioral health workforce with specific competencies to deliver effective, evidence-informed, team-based care. Most behavioral health providers do not have training or experience working as primary care behavioral health consultants (BHCs), and require structured training to function effectively in this role. This article discusses one such training program developed to meet the needs of a large healthcare system initiating widespread implementation of the primary care behavioral health model of service delivery. It details the Department of Defense's experience in developing its extensive BHC training program, including challenges of addressing personnel selection and hiring issues, selecting a model for training, developing and implementing a phased training curriculum, and improving the training over time to address identified gaps. Future directions for training improvements and lessons learned in a large healthcare system are discussed. [ABSTRACT FROM AUTHOR]

Interleukin 6 (IL-6) has a broad effect on cells of the immune system and those not of the immune system and often displays hormone-like characteristics that affect homeostatic processes. IL-6 has context-dependent pro- and anti-inflammatory properties and is now regarded as a prominent target for clinical intervention. However, the signaling cassette that controls the activity of IL-6 is complicated, and distinct intervention strategies can inhibit this pathway. Clinical experience with antagonists of IL-6 has raised new questions about how and when to block this cytokine to improve disease outcome and patient wellbeing. Here we discuss the effect of IL-6 on innate and adaptive immunity and the possible advantages of various antagonists of IL-6 and consider how the immunobiology of IL-6 may inform clinical decisions. [ABSTRACT FROM AUTHOR]

The self-assembly between a water-soluble bis-bidentate ligand L18w and Co(II) salts in water affords three high-spin Co(II) products: a dinuclear meso-helicate [Co2(L18w)3]X4; a tetrahedral cage [Co4(L18w)6]X8; and a dodecanuclear truncated-tetrahedral cage [Co12(L18w)18]X24 (X = BF4 or ClO4). All three products were crystallized under different conditions and structurally characterized. In [Co2(L18w)3]X4 all three bridging ligands span a pair of metal ions; in the two larger products, there is a metal ion at each vertex of the Co4 or Co12 polyhedral cage array with a bridging ligand spanning a pair of metal ions along every edge. All three structural types are known: what is unusual here is the presence of all three from the same reaction. The assemblies Co2, Co4, and Co12 are in slow equilibrium (hours/days) in aqueous solution, and this can be conveniently monitored by ¹H NMR spectroscopy because (i) the paramagnetism of Co(II) disperses the signals over a range of ca. 200 ppm and (ii) the different symmetries of the three species give characteristically different numbers of independent ¹H NMR signals, which makes identification easy. From temperature- and concentration-dependent ¹H NMR studies it is clear that increasing temperature and increasing dilution favors fragmentation to give a larger proportion of the smaller assemblies for entropic reasons. High concentrations and low temperature favor the larger assembly despite the unfavorable entropic and electrostatic factors associated with its formation. We suggest that this arises from the hydrophobic effect: reorganization of several smaller complexes into one larger one results in a smaller proportion of the hydrophobic ligand surface being exposed to water, with a larger proportion of the ligand surface protected in the interior of the assembly. In agreement with this, ¹H NMR spectra in a nonaqueous solvent (MeNO2) show formation of only [Co2(L18w)3]X4 because the driving force for reorganization into larger assemblies is now absent. Thus, we can identify the contributions of temperature, concentration, and solvent on the result of the metal/ligand self-assembly process and have determined the speciation behavior of the Co2/Co4/Co12 system in aqueous solution. [ABSTRACT FROM AUTHOR]

Interleukin-27 (IL-27) is a cytokine with strikingly diverse influences on the immune response. Although it was initially linked with the development of Th1 responses, it is now recognized as a potent antagonist of different classes of inflammation through its ability to directly modify CD4+ and CD8+ T cell effector functions, to induce IL-10, and to promote specialized T regulatory cell responses. Although this aspect of IL-27 biology has provided insights into how the immune system prevents hyperactivity in the setting of infectious and autoimmune inflammation, in vaccination and cancer models the stimulatory effects of IL-27 on CD8+ T cell function appear prominent. Additionally, associations between IL-27 and antibody-mediated disease have led to an interest in defining the impact of IL-27 on innate immunity and humoral responses in different disease states. The maturation of this literature has been accompanied by attempts to translate these findings from experimental models into human diseases and by efforts to define where IL-27 might represent a viable therapeutic target. [ABSTRACT FROM AUTHOR]

Psychologists played a crucial role in the successful implementation of integrated behavioral health care services in Department of Defense (DoD) primary care clinics. On the front lines of policy development, training programs, clinical care, and program evaluations, psychologists successfully promoted integrated care as a core component of the DoD patient-centered medical home. We review the development of integrated care and discuss the roles of psychologists in the DoD to provide an exemplar of the impact psychologists can have on the implementation and sustainment of integrated care. [ABSTRACT FROM AUTHOR]

A virtual cocrystal screening methodbased on calculated gas phasemolecular electrostatic potential surfaces (MEPS) of the individualcomponents has been validated using experimental cocrystal screensreported in the literature. The noncovalent interactions of a moleculewith its environment are described by a discrete set of independentsurface site interaction points (SSIPs), whose properties can be calculatedfrom the ab initioMEPS. The stability of a crystalis estimated based on pairing SSIPs such that the sum of the pairwiseinteraction energies is optimized. This provides a means of calculatingthe relative stability of a cocrystal compared with the pure componentswithout knowing anything about the three-dimensional structures ofthe crystalline states. For a set of potential crystal coformers (CCF),the difference between interaction site pairing energies of differentsolid forms (ΔE) provides a method for rankingCCFs based on the calculated probability of cocrystal formation. Themethod was applied to cocrystal screens of 18 compounds that reportedboth hits and misses, and in most cases, the virtual cocrystal screenreproduces experimental results well. In lists of CCFs ranked by ΔE, the experimentally observed hits were significantly enrichedat the top, and this indicates that virtual screening is a promisingtool for focusing experimental efforts on the most promising CCF candidates. [ABSTRACT FROM AUTHOR]

Physical-layer (PHY) cooperation is a technique for achieving multiple-input–multiple-output (MIMO)-like performance improvements on small devices that cannot support antenna arrays. Devices in a network transmit on behalf of their neighbors to act as “virtual MIMO” antennas. Since small devices are typically battery constrained, PHY cooperation immediately leads to the following question related to the energy efficiency (bits per joule) of devices: Is the performance improvement worth the extra energy costs of transmitting for others? Through an in-depth hardware test-bed study, we find that PHY cooperation can improve energy efficiency by as much as 320%, or it can reduce energy efficiency by as much as 25%, depending upon topology. With this performance gap in mind, we propose the distributed energy-conserving cooperation (DECC) protocol. DECC tunes the amount of effort that each device dedicates to providing cooperative assistance for others so that the energy that each device spends on cooperation is commensurate with the personal benefits that are received by that device. With DECC, users can tune their level of cooperation with completely node-localized decision-making. Thus, DECC allows nodes to tap into a large energy-efficiency benefit, suffering only a bounded preset loss when this benefit is not available. [ABSTRACT FROM PUBLISHER]

The goals of this study were to identify characteristics of both behavioral health providers (BHPs) and the patients seen in a primary care behavioral health (PCBH) model of service delivery using prospective data obtained from BHPs. A secondary objective was to explore similarities and differences between these variables within the Veterans Health Administration (VHA) and United States Air Force (USAF) primary care clinics. A total of 159 VHA and 23 USAF BHPs, representing almost every state in the United States, completed the study, yielding data from 403 patient appointments. BHPs completed a web-based questionnaire that assessed BHP and setting characteristics, and a separate questionnaire after each patient seen on one day of clinical service. Data demonstrated that there are many similarities between the VHA and USAF BHPs and practices. Both systems tend to use well-trained psychologists as BHPs, had systems that support the BHP being in close proximity to the primary care providers, and have seamless operational elements (i.e., shared record, one waiting room, same-day appointments, and administrative support for BHPs). Comorbid anxiety and depression was the most common presenting problem in both systems, but overall rates were higher in VHA clinics, and patients were significantly more likely to meet diagnostic criteria for mental health conditions. This study provides the first systematic, prospective examination of BHPs and practices within a PCBH model of service delivery in two large health systems with well over 5 years of experience with behavioral health integration. Many elements of the PCBH model were implemented in a manner consistent with the model, although some variability exists within both settings. These data can help guide future implementation and training efforts. [ABSTRACT FROM AUTHOR]

Effective molarity (EM) is a key parameter that determines the efficiency of a range of supramolecular phenomena from the folding of macromolecules to multivalent ligand binding. Coordination complexes formed between zinc porphyrins equipped H-bond donor sites and pyridine ligands equipped with H-bond acceptor sites have allowed systematic quantification of EM values for the formation of intramolecular H-bonds in 240 different systems. The results provide insights into the relationship of EM to supramolecular architecture, H-bond strength, and solvent. Previous studies on ligands equipped with phosphonate diester and ether H-bond acceptors were inconclusive, but the experiments described here on ligands equipped with phosphine oxide, amide, and ester H-bond acceptors resolve these ambiguities. Chemical double-mutant cycles were used to dissect the thermodynamic contributions of individual H-bond interactions to the overall stabilities of the complexes and hence determine the values of EM, which fall in the range 1-1000 mM. Solvent has little effect on EM, and the values measured in toluene and 1,1,2,2-tetrachloroethane are similar. For H-bond acceptors that have similar geometries but different H-bond strengths (amide and ester), the values of EM are very similar. For H-bond acceptors that have different geometries but similar H-bond strengths (amide and phosphonate diester), there is little correlation between the values of EM. These results imply that supramolecular EMs are independent of solvent and intrinsic H-bond strength but depend on supramolecular architecture and geometric complementarity. [ABSTRACT FROM AUTHOR]

Measurements have been made of the adhesion and frictionforcesbetween organic monolayers in heptane/acetone mixtures using an atomicforce microscope (AFM). It has been found that the contact mechanicsare best modeled by treating the friction force as the sum of a load-dependentterm (attributed to “molecular plowing”) and an area-dependentterm attributed to shearing (adhesion). The relative contributionsof plowing and shearing are determined by the coefficient of friction,μ, and the surface shear strength τ. The transition fromadhesion- to load-determined friction is controlled by the solvationstate of the surface: solvated surfaces represent a limiting casein which the shear term approaches zero, and the friction-load relationshipis linear, while in other circumstances, the friction-load relationshipis nonlinear and consistent with Derjaguin–Muller–Toporovmechanics. A striking correlation has been observed between the concentration-dependenceof the association constant (Ka) for theformation of 1:1 hydrogen-bonded complexes and the pull-off force Faand surface shear strength τ for thesame molecules when one partner is immobilized by attachment to anAFM probe and the other is adsorbed to a surface. Analysis of theconcentration-dependence of Faand τenables the prediction of KSwith remarkablyhigh precision, indicating that for these hydrogen bonding systems,the tip–sample adhesion is dominated by the H-bond thermodynamics.For mixed monolayers, H-bond thermodynamics dominate the interactioneven at very low concentrations of the H-bond acceptor. Even for weaklyadhering systems, a nonlinear friction-load relationship results.The variation in τ with the film composition is correlated veryclosely with the variation in Fa. However,the coefficient of friction varies little with the film compositionand is invariant with the strength of tip–sample adhesion,being dominated by molecular plowing and, for sufficiently large concentrationsof hydroxyl terminated adsorbates, the disruption of intramonolayerhydrogen bonding interactions. [ABSTRACT FROM AUTHOR]

It has been more than 15 years since the identification of individual interleukin-27 (IL-27) and IL-27 receptor components. The last decade has seen the description of the signaling pathways engaged by IL-27, and an appreciation has emerged that this cytokine can modulate the intensity and duration of many classes of T cell responses. Here we provide an overview of the immunobiology of IL-27 and review advances in understanding the functions of individual IL-27 and IL-27 receptor subunits and the role of IL-27 in dictating the balance between protective and pathological immunity. Additionally, this cytokine has been proposed as a therapy to modify inflammatory conditions or to promote antitumor responses, and situations where experimental and clinical data sets implicate IL-27 in the outcome of disease are highlighted. [ABSTRACT FROM AUTHOR]

Toxoplasma gondii is a common parasite of animals and humans and can cause serious opportunistic infections. However, the majority of infections are asymptomatic, possibly because the organism has co-evolved with its many vertebrate hosts and has developed multiple strategies to persist asymptomatically for the lifetime of the host. Over the past two decades, infection studies in the mouse, combined with forward-genetics approaches aimed at unravelling the molecular basis of infection, have revealed that T. gondii virulence is mediated, in part, by secretion of effector proteins into the host cell during invasion. Here, we review recent advances that illustrate how these virulence factors disarm innate immunity and promote survival of the parasite. [ABSTRACT FROM AUTHOR]

The ability of neurons to modulate synaptic strength underpins synaptic plasticity, learning and memory, and adaptation to sensory experience. Despite the importance of synaptic adaptation in directing, reinforcing, and revising the behavioral response to environmen-tal influences, the cellular and molecular mechanisms underlying synaptic adaptation are far from clear. Brain-derived neurotrophic factor (BDNF) is a prime initiator of structural and functional synaptic adaptation. However, the signaling cascade activated by BDNF to initiate these adaptive changes has not been elucidated. We have previously shown that BDNF activates mitogen- and stress-activated kinase 1 (MSK1 ), which regulates gene transcription via the phosphorylation of both CREB and histone H3. Using mice with a kinase-dead knock-in mutation of MSK 1, we now show that MSK 1 is necessary for the upregulation of synaptic strength in response to environmental enrichment in vivo. Furthermore, neurons from MSK1 kinase-dead mice failed to show scaling of synaptic transmission in response to activity deprivation in vitro, a deficit that could be rescued by reintroduction of wild-type MSK1. We also show that MSK1 forms part of a BDNF- and MAPK-dependent signaling cascade required for homeostatic synaptic scaling, which likely resides in the ability of MSK1 to regulate cell surface GluAl expression via the induction of Arc/Arg3.1. These results demonstrate that MSK1 is an integral part of a signaling pathway that underlies the adaptive response to synaptic and environmental experience. MSK 1 may thus act as a key homeostat in the activity- and experience-dependent regulation of synaptic strength. [ABSTRACT FROM AUTHOR]

Abstract: The substrate for the proteins that express genetic information in the cell is not naked DNA but an assembly of nucleosomes, where the DNA is wrapped around histone proteins. The organization of these nucleosomes on genomic DNA is influenced by the DNA sequence. Here, we present a structure-based computational approach that translates sequence information into the energy required to bend DNA into a nucleosome-bound conformation. The calculations establish the relationship between DNA sequence and histone octamer binding affinity. In silico selection using this model identified several new DNA sequences, which were experimentally found to have histone octamer affinities comparable to the highest-affinity sequences known. The results provide insights into the molecular mechanism through which DNA sequence information encodes its organization. A quantitative appreciation of the thermodynamics of nucleosome positioning and rearrangement will be one of the key factors in understanding the regulation of transcription and in the design of new promoter architectures for the purposes of tuning gene expression dynamics. [Copyright &y& Elsevier]

Interleukin (IL)-27 is a member of the IL-6 and IL-12 family composed of the IL-27p28 and Epstein–Barr virus-induced gene 3 (EBI3) subunits. Although IL-27 was originally identified as a proinflammatory factor, subsequent studies have revealed the pleiotropic nature of this cytokine. This review discusses recent work that has explored the effect of IL-27 on CD4+ T cell subsets, including T regulatory type 1 (Tr-1) cells, T follicular helper cells (Tfhs), and forkhead box P3 (Foxp3)+ T regulatory cells (Tregs). Additionally, we highlight studies that have identified a role for the IL-27p28 subunit as a cytokine receptor antagonist. Much of the recent work on IL-27 has been relevant to human disease states characterized by inappropriate or excessive inflammation, and this review discusses potential opportunities to use IL-27 as a therapeutic agent. [ABSTRACT FROM AUTHOR]

Intermolecular complexes formed between metalloporphyrins and pyridine ligands equipped with multiple H-bond donors and acceptors have been used to measure the free energy contributions due to intramolecular ether-phenol H-bonding in the 24 different supramolecular architectures using chemical double mutant cycles in toluene. The ether-phenol interactions are relatively weak, and there are significant populations of partially bound states where between zero and four intramolecular H-bonds are made in addition to the porphyrin-ligand coordination interaction. The complexes were analyzed as ensembles of partially bound states to determine the effective molarities for the intramolecular interactions by comparison with the corresponding intermolecular ether-phenol H-bonds. The properties of the ether-phenol interactions were compared with phosphonate diester-phenol interactions in a closely related ligand system, which has more powerful H-bond acceptor oxygens positioned at the same location on the ligand framework. This provides a comparison of the properties of weak and strong H-bonds embedded in the same 24 supramolecular architectures. When the product of the intermolecular association constant and the effective molarity KEM > 1, there is a linear increase in the free energy contribution due to H-bonding with log EM, because the intramolecular interactions contribute fully to the stability of the complex. When KEM < 1, the H-bonded state is not significantly populated, and there is no impact on the overall stability of the complex. Intermolecular phosphonate diester-phenol H-bonds are 2 orders of magnitude stronger than ether-phenol H-bonds in toluene, so for the phosphonate diester ligand system, 23 of the 24 supramolecular architectures make intramolecular H-bonds. However, only 8 of these architectures lead to detectable H-bonding in the ether ligand system. The other 15 complexes have a suitable geometry for formation of H-bonds, but the ether-phenol interaction is not strong enough to overcome the reorganization costs associated with making intramolecular contacts, i.e., KEM < 1 for the ether ligands, and KEM > 1 for the phosphonate diester ligands. The values of EM measured for two different types of H-bond acceptor are linearly correlated, which suggests that EM is a property of the supramolecular acrchitecture. However, the absolute value of EM for an intramolecular phosphonate diester H-bond is about 4 times lower than the corresponding value for an intramolecular ether-phenol interaction embedded in the same supramolecular framework, which suggests that there may be some interplay of K and EM. [ABSTRACT FROM AUTHOR]

Information about several topics discussed at the conference sponsored by Canada-United States Law Institute held on April 8-10, 2010 on the intellectual property rights in the Canada and the U.S. partnership is presented. Topics include the concept of intellectual property, enforcement and protection of the intellectual property rights, and the methods of achieve convergence. The conference featured several speakers, including Christopher Hunter, William Manson, and Margaret Ann Wilkinson.

Secondary electrostatic interactions between adjacent hydrogen bonds can have a significant effect on the stability of a supramolecular complex. In theory, the binding strength should be maximized if all the hydrogen-bond donors (D) are on one component and all the hydrogen-bond acceptors (A) are on the other. Here, we describe a readily accessible AAAA-DDDD quadruple hydrogen-bonding array that exhibits exceptionally strong binding for a small-molecule hydrogen-bonded complex in a range of different solvents (Ka > 3 × 1012 M-1 in CH2Cl2, 1.5 × 106 M-1 in CH3CN and 3.4 × 105 M-1 in 10% v/v DMSO/CHCl3). The association constant in CH2Cl2 corresponds to a binding free energy (?G) in excess of -71 kJ mol-1 (more than 20% of the thermodynamic stability of a carbon-carbon covalent bond), which is remarkable for a supramolecular complex held together by just four intercomponent hydrogen bonds. [ABSTRACT FROM AUTHOR]

The synthesis of a family of zinc porphyrins and pyridine ligands equipped with peripheral H-bonding functionality has provided access to a wide range of closely related supramolecular complexes featuring between zero and four intramolecular H-bonds. An automated UV/vis titration system was used to characterize 120 different complexes, and these data were used to construct a large of number of different chemical double mutant cycles to quantify the intramolecular H-bonding interactions. The results probe the quantitative structure-activity relationship that governs cooperativity in the assembly of complex molecular recognition interfaces. Specifically, variations in the chemical structures of the complexes have allowed us to change the supramolecular architecture, conformational flexibility, geometric complementarity, the number and nature of the H-bond interactions, and the overall stability of the complex. The free energy contributions from individual H-bonds are additive, and there is remarkably little variation with architecture in the effective molarity for the formation of intramolecular interactions. Intramolecular H-bonds are not observed in complexes where they are geometrically impossible, but there are no cases where excellent geometric complementarity leads to very high affinities. Similarly, changes in conformational flexibility seem to have limited impact on the values of effective molarity (EM). The major variation that was found for all of the 48 intramolecular interactions that were examined using double mutant cycles is that the values of EM for intramolecular carboxylate ester-phenol H-bonds (200 mM) are an order of magnitude larger than those found for phosphonate diester-phenol H-bonds (30 mM). The corresponding intermolecular phosphonate diester-phenol H-bonds are 2 orders of magnitude more stable than carboxylate ester-phenol H-bonds, and the large differences in EM may be due to some kind of compensation effect, where the stronger H-bond is harder to make, because it imposes tighter constraints on the geometry of the complex. [ABSTRACT FROM AUTHOR]

Behavioral healthcare will be an essential piece of meeting the patient-centered medical home (PCMH) principles of easy access and whole person, coordinated, and integrated care as primary care clinics transform themselves into PCMHs. As this transformation occurs, PCMH clinic staff and behavioral health providers must carefully consider how to adapt their operations to include the provision of integrated-collaborative behavioral health services within the PCMH. Without this careful consideration, integrated-collaborative behavioral healthcare will likely fail to reach its full potential. We discuss the operational and clinical components that appear to be important for success when integrating behavioral healthcare into the PCMH. [ABSTRACT FROM AUTHOR]

Abstract: There are over 10,000 species of parasitic protozoa, a subset of which can cause considerable disease in humans. Here we examine in detail the complex immune response generated during infection with a subset of these parasites: Trypanosoma cruzi, Leishmania sp., Toxoplasma gondii, and Plasmodium sp. While these particular species perhaps represent the most studied parasites in terms of understanding how T cells function during infection, it is clear that the lessons learned from this body of work are also relevant to the other protozoa known to induce a CD8+ T cell response. This review will highlight some of the key studies that established that CD8+ T cells play a major role in protective immunity to protozoa, the factors that promote the generation as well as maintenance of the CD8+ T cell response during these infections, and draw attention to some of the gaps in our knowledge. Moreover, the development of new tools, including MHC-Class I tetramer reagents and the use of TCR transgenic mice or genetically modified parasites, has provided a better appreciation of how parasite specific CD8+ T cell responses are initiated and new insights into their phenotypic plasticity [Copyright &y& Elsevier]

Abstract: The previously reported complex [Ru(ttpy)(CN)3]− [ttpy=4′(p-tolyl)-2,2′:6′,2″-terpyridine] is conveniently synthesised by reaction of ttpy with Ru(dmso)4Cl2 to give [Ru(ttpy)(dmso)Cl2], which reacts in turn with KCN in aqueous ethanol to afford [Ru(ttpy)(CN)3]− which was isolated and crystallographically characterised as both its (PPN)+ and K+ salts. The K+ salt contains clusters containing three complex anions and three K+ cations connected by end-on and side-on cyanide ligation to the K+ ions. The solution speciation behaviour of [Ru(ttpy)(CN)3]− was investigated with both Zn2+ and K+ salts in MeCN, a solvent sufficiently non-competitive to allow the added metal cations to associate with the complex anion via the externally-directed cyanide lone pairs. UV–Vis spectroscopic titration of (PPN)[Ru(ttpy)(CN)3] with Zn(ClO4)2 showed a blue shift of 2900cm−1 in the 1MLCT absorption manifold due to the ‘metallochromism’ effect; a series of distinct binding events could be discerned corresponding to formation of 4:1, 1:1 and then 1:3 anion:cation adducts, all with high formation constants, as the titration proceeded. In contrast titration of (PPN)[Ru(ttpy)(CN)3] with the more weakly Lewis-acidic KPF6 resulted in a much smaller blue-shift of the 1MLCT absorptions, and the titration data corresponded to formation of 1:1 and then 2:1 cation:anion adducts with weaker stepwise association constants of the order of 104 and then 103 M−1. Although association of [Ru(ttpy)(CN)3]− resulted in a blue-shift of the 1MLCT absorptions, the luminescence was steadily quenched, as raising the 3MLCT level makes radiationless decay via a low-lying 3MC state possible. [Copyright &y& Elsevier]

1H NMR dilution experiments were used to monitor self-association of acridine in solution in four different solvents. The pattern of complexation-induced changes in chemical shift is similar in chloroform, methanol, and carbon tetrachloride, which implies that the aggregate has a similar structure in these three solvents. However, the chemical shift pattern is different in acetone, implying a different aggregate structure. Crystallization by evaporation and by crash cooling from these solvents gave the stable polymorph III in all cases, except for the crash cooling experiment in acetone, which gave the metastable polymorph VII. This result suggests that the supramolecular aggregate structure, which is formed in solution, influences the solid state structure obtained on crystallization. Complexation-induced changes in 1H NMR chemical shift indicate solvent-dependent differences in the supramolecular solution structures of prenucleation aggregates of acridine. These differences correlate with differences in the polymorphic form of the solid obtained on crash cooling. [ABSTRACT FROM AUTHOR]

Abstract: Experimental X-ray crystal structures and a database of calculated structural parameters of DNA octamers were used in combination to analyse the mechanics of DNA bending in the nucleosome core complex. The 1kx5 X-ray crystal structure of the nucleosome core complex was used to determine the relationship between local structure at the base-step level and the global superhelical conformation observed for nucleosome-bound DNA. The superhelix is characterised by a large curvature (597°) in one plane and very little curvature (10°) in the orthogonal plane. Analysis of the curvature at the level of 10-step segments shows that there is a uniform curvature of 30° per helical turn throughout most of the structure but that there are two sharper kinks of 50° at ±2 helical turns from the central dyad base pair. The curvature is due almost entirely to the base-step parameter roll. There are large periodic variations in roll, which are in phase with the helical twist and account for 500° of the total curvature. Although variations in the other base-step parameters perturb the local path of the DNA, they make minimal contributions to the total curvature. This implies that DNA bending in the nucleosome is achieved using the roll–slide–twist degree of freedom previously identified as the major degree of freedom in naked DNA oligomers. The energetics of bending into a nucleosome-bound conformation were therefore analysed using a database of structural parameters that we have previously developed for naked DNA oligomers. The minimum energy roll, the roll flexibility force constant and the maximum and minimum accessible roll values were obtained for each base step in the relevant octanucleotide context to account for the effects of conformational coupling that vary with sequence context. The distribution of base-step roll values and corresponding strain energy required to bend DNA into the nucleosome-bound conformation defined by the 1kx5 structure were obtained by applying a constant bending moment. When a single bending moment was applied to the entire sequence, the local details of the calculated structure did not match the experiment. However, when local 10-step bending moments were applied separately, the calculated structure showed excellent agreement with experiment. This implies that the protein applies variable bending forces along the DNA to maintain the superhelical path required for nucleosome wrapping. In particular, the 50° kinks are constraints imposed by the protein rather than a feature of the 1kx5 DNA sequence. The kinks coincide with a relatively flexible region of the sequence, and this is probably a prerequisite for high-affinity nucleosome binding, but the bending strain energy is significantly higher at these points than for the rest of the sequence. In the most rigid regions of the sequence, a higher strain energy is also required to achieve the standard 30° curvature per helical turn. We conclude that matching of the DNA sequence to the local roll periodicity required to achieve bending, together with the increased flexibility required at the kinks, determines the sequence selectivity of DNA wrapping in the nucleosome. [Copyright &y& Elsevier]