Role of Tim4 in the regulation of ABCA1+ adipose tissue macrophages and post-prandial cholesterol levels.

Dyslipidemia is a main driver of cardiovascular diseases. The ability of macrophages to scavenge excess lipids implicate them as mediators in this process and understanding the mechanisms underlying macrophage lipid metabolism is key to the development of new treatments. Here, we investigated how adipose tissue macrophages regulate post-prandial cholesterol transport. Single-cell RNA sequencing and protected bone marrow chimeras demonstrated that ingestion of lipids led to specific transcriptional activation of a population of resident macrophages expressing Lyve1, Tim4, and ABCA1. Blocking the phosphatidylserine receptor Tim4 inhibited lysosomal activation and the release of post-prandial high density lipoprotein cholesterol following a high fat meal. Both effects were recapitulated by chloroquine, an inhibitor of lysosomal function. Moreover, clodronate-mediated cell-depletion implicated Tim4+ resident adipose tissue macrophages in this process. Thus, these data indicate that Tim4 is a key regulator of post-prandial cholesterol transport and adipose tissue macrophage function and may represent a novel pathway to treat dyslipidemia.

Recruited macrophages that colonize the post-inflammatory peritoneal niche convert into functionally divergent resident cells.

Inflammation generally leads to recruitment of monocyte-derived macrophages. What regulates the fate of these cells and to what extent they can assume the identity and function of resident macrophages is unclear. Here, we show that macrophages elicited into the peritoneal cavity during mild inflammation persist long-term but are retained in an immature transitory state of differentiation due to the presence of enduring resident macrophages. By contrast, severe inflammation results in ablation of resident macrophages and a protracted phase wherein the cavity is incapable of sustaining a resident phenotype, yet ultimately elicited cells acquire a mature resident identity. These macrophages also have transcriptionally and functionally divergent features that result from inflammation-driven alterations to the peritoneal cavity micro-environment and, to a lesser extent, effects of origin and time-of-residency. Hence, rather than being predetermined, the fate of inflammation-elicited peritoneal macrophages seems to be regulated by the environment.

Rate of replenishment and microenvironment contribute to the sexually dimorphic phenotype and function of peritoneal macrophages.

Macrophages reside in the body cavities where they maintain serosal homeostasis and provide immune surveillance. Peritoneal macrophages are implicated in the etiology of pathologies including peritonitis, endometriosis, and metastatic cancer; thus, understanding the factors that govern their behavior is vital. Using a combination of fate mapping techniques, we have investigated the impact of sex and age on murine peritoneal macrophage differentiation, turnover, and function. We demonstrate that the sexually dimorphic replenishment of peritoneal macrophages from the bone marrow, which is high in males and very low in females, is driven by changes in the local microenvironment that arise upon sexual maturation. Population and single-cell RNA sequencing revealed marked dimorphisms in gene expression between male and female peritoneal macrophages that was, in part, explained by differences in composition of these populations. By estimating the time of residency of different subsets within the cavity and assessing development of dimorphisms with age and in monocytopenic Ccr2 -/- mice, we demonstrate that key sex-dependent features of peritoneal macrophages are a function of the differential rate of replenishment from the bone marrow, whereas others are reliant on local microenvironment signals. We demonstrate that the dimorphic turnover of peritoneal macrophages contributes to differences in the ability to protect against pneumococcal peritonitis between the sexes. These data highlight the importance of considering both sex and age in susceptibility to inflammatory and infectious diseases.

Tissue-specific differentiation of colonic macrophages requires TGFß receptor-mediated signaling.

Intestinal macrophages (mφ) form one of the largest populations of mφ in the body and are vital for the maintenance of gut homeostasis. They have several unique properties and are derived from local differentiation of classical Ly6Chi monocytes, but the factors driving this tissue-specific process are not understood. Here we have used global transcriptomic analysis to identify a unique homeostatic signature of mature colonic mφ that is acquired as they differentiate in the mucosa. By comparing the analogous monocyte differentiation process found in the dermis, we identify TGFß as an indispensable part of monocyte differentiation in the intestine and show that it enables mφ to adapt precisely to the requirements of their environment. Importantly, TGFßR signaling on mφ has a crucial role in regulating the accumulation of monocytes in the mucosa, via mechanisms that are distinct from those used by IL10.

Epitaxial growth of few-layer MoS2(0001) on FeS2{100}.

Physical vapour deposition of Mo on an FeS2{100} surface was performed at 170 K. Near-epitaxial growth of MoS2(0001) overlayers of the order of 1 nm thickness was observed when the Mo-covered substrate was subsequently heated to 600 K.

Structure and stress of Re(1121); chiral terraces at a racemic surface.

The surface structure and morphology of the clean Re(1121) surface has been investigated through combined low energy electron diffraction intensity analysis of data taken at multiple angles of incidence, scanning tunneling microscopy, and first-principles density functional calculations. The results show how this globally racemic surface terminates in two chirally distinct terraces, which show large-scale out-of-plane atomic relaxations and in-plane lateral movement of the uppermost atoms. We further identify and discuss the initial stages of step bunching upon adsorption of oxygen that leads ultimately to the large-scale faceting of the surface. Finally, we present calculations of surface stress and the response to applied surface strain, which suggest routes to the exertion of control over the expression of chirality at the surface.

Weak intermolecular interactions in an ionically bound molecular adsorbate: cyclopentadienyl/Cu(111).

The dissociative adsorption of cyclopentadiene (C(5)H(6)) on Cu(111) yields a cyclopentadienyl (Cp) species with strongly anionic characteristics. The Cp potential energy surface and frictional coupling to the substrate are determined from measurements of dynamics of the molecule together with density functional calculations. The molecule is shown to occupy degenerate threefold adsorption sites and molecular motion is characterized by a low diffusional energy barrier of 40±3 meV with strong frictional dissipation. Repulsive dipole-dipole interactions are not detected despite charge transfer from substrate to adsorbate.

Effects of weaning and syndyphalin-33 on expression of melanocortinergic appetite-regulating genes in swine.

Syndyphalin-33 (SD-33) increases feed intake in sheep and recently weaned pigs. To assess the effects of SD-33 on hypothalamic gene expression, hypothalami were collected from unweaned pigs (n=19; 21±3 d of age) on day 0. Remaining pigs received an intramuscular injection of 0.5 µmole/kg SD-33 (SD) or saline (VEH) and weaned into individual pens. On days 1, 4, and 7 after weaning, hypothalami were collected from subsets of pigs (n=8 or 9) within each treatment group. Expression of µ-opioid receptor (MOR) was less in SD pigs than in VEH pigs on day 1 and day 4, suggesting down-regulation of the receptor by SD-33. Expression of hypothalamic melanocortin 4 receptor (MC4R) at 1 d after weaning was increased in VEH pigs (but not SD pigs) relative to levels before weaning. Expression of AGRP was not significantly altered by weaning or treatment at 1 d after weaning. At 4 d after weaning, expression of AGRP was greater in SD pigs than in VEH pigs, but at day 7 expression was less in SD pigs than in VEH pigs. A strong positive correlation was noted between expression levels of MOR and MC4R across treatment and time. Treatment with SD-33 appeared to partially abrogate the effects of weaning on expression of two key appetite-regulating genes within 24 h. Effects of SD-33 appear to be mediated at least in part by the µ-opioid receptor and include actions on the melanocortinergic pathway.

Surface stress in d-band metal surfaces.

Using calculations within the density functional approach, we make a survey of the surface stresses of relevant d-band metal surfaces. Unlike the case for surface energies, where volcano-shaped dependences have been found across the d period, the surface stress values show a non-trivial dependence on the metal species and surface termination, which cannot be anticipated from homogeneous electron gas models. A qualitative interpretation as regards the origin of this dependence can be given on the basis of the decomposition of the surface stress into repulsive and attractive electronic components.

Effects of syndyphalin-33 on feed intake and circulating measures of growth hormone, cortisol, and immune cell populations in the recently weaned pig.

The synthetic met-enkephalin syndyphalin-33 (SD-33) increases feed intake in sheep and transiently increases circulating GH concentrations in sheep, rats, and pigs. Two experiments were performed to evaluate the effects of SD-33 on recently weaned pigs. In a preliminary experiment, pigs were administered SD-33 (0.5 micromol/kg, given intramuscularly) or saline immediately before a 3-h transport and subsequent placement into group pens. Treatment with SD-33 increased (P = 0.01) daily feed intake; cumulatively, pen intake over 7 d postweaning tended (P = 0.06) to be greater than in control pens. In Exp. 2, pigs were weaned and fitted with jugular catheters. The following day, pigs were treated with SD-33 or saline as described above. Transient increases (P < 0.05) in circulating concentrations of GH (at 1 and 1.5 h postinjection) and cortisol (at 3.5 and 4 h postinjection) were observed in pigs treated with SD-33 relative to controls. No difference in feed intake was observed between treatments over 4 d postinjection. Increased (P < 0.05) numbers of circulating neutrophils, lymphocytes, and monocytes were observed in both treatment groups over 4 d postinjection, and treatment with SD-33 tended (P = 0.07) to selectively increase monocyte numbers. Although SD-33 has potential to be used to increase feed intake and decrease the negative effects of stress during weaning in pigs, further investigation is needed to better understand the timing of effect and to rule out possible immunosuppressive effects.

Surface stress of stepped chiral metal surfaces.

The use of surface stress as a physical probe for examining chiral effects in surfaces is proposed. First-principles calculations of the surface stress in stepped achiral and chiral bcc metal surfaces (Fe, Mo, and W) are presented. When no mirror symmetry is present, principal stress orientations are unconstrained; nevertheless, we find that the stress is smoothly varying along a suitably chosen stereographic zone of surfaces. Stress ellipses for Fe differ qualitatively from those of Mo and W, suggesting that its surface stress has a distinct origin.

Methane dissociation and methyl diffusion on PdO{100}.

The CH(4)-->CH(3)+H dissociation on the defect-free Pd-2O terminated PdO{100} surface is investigated by first principles calculations. CH(3) chemisorbs preferentially at O sites, where the adsorption is 0.68 eV more stable than at Pd sites. Analysis of the electronic structure of adsorption geometries reveals that the enhanced stability is due to the strongly covalent character of the bonding between surface O and CH(3). However, transition state searches suggest that the Pd atom is the most likely active site for CH(4) dissociation. An alternative route toward the most stable chemisorbed state is proposed that involves diffusion of CH(3) on the surface.

Quality of prescription and fabrication of single-unit crowns by general dental practitioners in Wales.

The aim of this investigation was to describe the quality of prescription and fabrication of single-unit crowns by general dental practitioners in Wales. One hundred pre-piloted questionnaires were distributed to commercial laboratories in Wales with large catchment areas, and 20 pre-piloted questionnaires were distributed to the production laboratory at the Cardiff Dental Hospital. Information was collected relating to the quality of prescription and master impressions for single-unit crowns. One hundred and seven completed questionnaires were returned (response rate = 89%). Sixty per cent (n = 64) of questionnaires related to single-unit crowns being made in general practice under private funding arrangements, 30% (n = 32) were being made in general dental practice under National Health Service (public) funding arrangements and 10% (n = 11) were collected from the Dental Hospital. Polyvinylsiloxane impression material was used to record the master impression in all cases (n = 107). Plastic stock trays were used to make the master impression in 79% of cases (n = 85), metal stock trays were used in 19% of cases (n = 20) and special trays were used in 2% of cases (n = 2). Eighty-five per cent (n = 91) of master casts were considered to be adequate for crown fabrication. Less than 50% of written instructions (n = 52) were considered 'clear' and of sufficient detail to adequately specify the planned crown. In 21% of cases (n = 22), the technician had to contact the dentist for clarification of the design prior to making the crown. While the quality of impression making for single-unit crowns was of a reasonable standard, the quality of the accompanying written communication was poor and more than one-half of written instructions examined failed to meet the requirements of the European Union Medical Devices Directive.

Theory of C2Hx species on Pt{110} (1x2): reaction pathways for dehydrogenation.

A complete reaction sequence for molecular dissociation at a surface has been characterized using density functional theory. The barriers for sequential ethane dehydrogenation on Pt{110} are found to fall into distinct energy sets: very low barriers, with values in the range of 0.29-0.42 eV, for the initial ethane dissociation to ethene and ethylidene at the surface; medium barriers, in the range of 0.72-1.10 eV, for dehydrogenation of C(2)H(4) fragments to vinylidene and ethyne; and high barriers, requiring more than 1.45 eV, for further dehydrogenation. For dissociation processes where more than one pathway has been found, the lowest energetic route links the most stable reactant adsorbed state at the surface to a product state involving the hydrocarbon moiety adsorbed in its most stable configuration at the surface. Hence there is a clear link between surface stability and kinetics for these species.

Ridge-bridge adsorption of molecular oxygen on Pt[110](1 x 2) from first principles.

The chemisorption of molecular oxygen on the missing-row reconstructed Pt[110](1 x 2) surface has been investigated using ab initio calculations based on spin-density functional theory. The calculated energetic, structural, vibrational, and electronic properties of the chemisorbed O2 species are discussed in terms of the available experimental data. We find that adsorption in the ridge-bridge site is strongly preferred on energetic grounds, relative to adsorption on the [111] microfacets or in the valley sites of the reconstructed surface. We argue in favor of initial adsorption in the ridge-bridge sites, followed by adsorption in the valley long-bridge sites at higher coverages, without excluding the possibility of bridge-site adsorption on the [111] microfacets.

Modulation of the host's immune response by schistosome larvae.

Schistosomes appear to have evolved several strategies to down-regulate the host's immune response in order to promote their own survival. For the host, down-regulation is also beneficial as it can limit the extent of pathology. It is widely accepted that schistosomes modulate the immune response during the chronic phase of infection after egg deposition has started. However, there is increasing evidence that modulation of the immune response can occur much earlier at the time infective cercariae penetrate the host skin. In this review, we explore the various lines of evidence that excretory/secretory (ES) molecules from cercariae down-regulate the host's immune response. We highlight the immunological factors that are produced and may be involved in regulating the immune system (e.g. IL-10, and eicosanoids), as well as speculating on possible mechanisms of immune modulation (e.g. mast-cell activation, T-cell apoptosis, and/or the skewed activation of antigen-presenting cells [APCs]). Finally, we draw attention to several molecules of schistosome origin that have the potential to stimulate the regulatory response (e.g. glycans) and link these to potential host receptors (e.g. TLRs and C-type lectins).

The structure of the chiral Pt531 surface: a combined LEED and DFT study.

The structure of the chiral kinked Pt531 surface has been determined by low-energy electron diffraction intensity-versus-energy (LEED-IV) analysis and density functional theory (DFT). Large contractions and expansions of the vertical interlayer distances with respect to the bulk-terminated surface geometry were found for the first six layers (LEED: d12 = 0.44 A, d23 = 0.69 A, d34 = 0.49 A, d45 = 0.95 A, d56 = 0.56 A; DFT: d12 = 0.51 A, d23 = 0.55 A, d34 = 0.74 A, d45 = 0.78 A, d56 = 0.63 A; dbulk = 0.66 A). Energy-dependent cancellations of LEED spots over unusually large energy ranges, up to 100 eV, can be explained by surface roughness and reproduced by applying a model involving 0.25 ML of vacancies and adatoms in the scattering calculations. The agreement between the results from LEED and DFT is not as good as in other cases, which could be due to this roughness of the real surface.

Stabilizing CO on Au with NO2: electronegative species as promoters on coinage metals?

CO adsorption on NO(2)-predosed Au[111] reveals an unexpected attractive coadsorbate interaction, associated with an unprecedented blueshift of the CO stretch frequency, a sizeable attenuation of the infrared NO(2) symmetric stretch band, and a (sq.rt(7) x sq.rt(7))R19 degrees structure characterized by scanning tunneling microscopy and low energy electron diffraction. Density functional calculations allow us to rationalize these observations, and point towards a general pattern of behavior for electronegative coadsorbates on coinage metals, with important implications for catalytic promotion.

Driving forces for self-organized coadsorption: C6H6/2O and C6H6/2CO on Ni[111].

The self-organized (2log3 x 2log3) coadsorbed phases of C(6)H(6) with O and with CO are investigated within first-principles density functional theory. The main driving force for formation of the C(6)H(6)/2O phase is found to be the reduction of O adatom repulsive interactions, while for the C(6)H(6)/2CO phase it is the interspecies attractive interactions and benzene-benzene repulsive interactions which are most important.