Cxcr4-ccr7 heterodimerization is a driver of breast cancer progression

Metastatic breast cancer has one of the highest mortality rates among women in western society. Chemokine receptors CXCR4 and CCR7 have been shown to be linked to the metastatic spread of breast cancer, however, their precise function and underlying molecular pathways leading to the acquisition of the pro-metastatic properties remain poorly understood. We demonstrate here that the CXCR4 and CCR7 receptor ligands, CXCL12 and CCL19, cooperatively bind and selectively elicit synergistic signalling responses in invasive breast cancer cell lines as well as primary mammary human tumour cells. Furthermore, for the first time, we have documented the presence of CXCR4-CCR7 heterodimers in advanced primary mammary mouse and human tumours where number of CXCR4-CCR7 complexes directly correlate with the severity of the disease. The functional significance of the CXCR4-CCR7 association was also demonstrated when their forced heterodimerization led to the acquisition of invasive phenotype in non-metastatic breast cancer cells. Taken together, our data establish the CXCR4-CCR7 receptor complex as a new functional unit, which is responsible for the acquisition of breast cancer cell metastatic phenotype and which may serve as a novel biomarker for invasive mammary tumours.Valentina Poltavets, Jessica W. Faulkner, Deepak Dhatrak, Robert J. Whitfield, Shaun R. McColl and Marina Kochetkov

In vivo dual RNA-seq reveals that neutrophil recruitment underlies differential tissue tropism of Streptococcus pneumoniae.

Streptococcus pneumoniae is a genetically diverse human-adapted pathogen commonly carried asymptomatically in the nasopharynx. We have recently shown that a single nucleotide polymorphism (SNP) in the raffinose pathway regulatory gene rafR accounts for a difference in the capacity of clonally-related strains to cause localised versus systemic infection. Using dual RNA-seq, we show that this SNP affects expression of bacterial genes encoding multiple sugar transporters, and fine-tunes carbohydrate metabolism, along with extensive rewiring of host transcriptional responses to infection, particularly expression of genes encoding cytokine and chemokine ligands and receptors. The data predict a crucial role for differential neutrophil recruitment (confirmed by in vivo neutrophil depletion and IL-17 neutralization) indicating that early detection of bacteria by the host in the lung environment is crucial for effective clearance. Thus, dual RNA-seq provides a powerful tool for understanding complex host-pathogen interactions and reveals how a single bacterial SNP can drive differential disease outcomes

The influence of surface hardness on the fretting wear of steel pairs: its role in debris retention in the contact

The influence of specimen hardness (between 275 kgf mm−2 and 835 kgf mm−2) in an AISI Type O1 steel-on-steel fretting contact was examined. In equal-hardness pairs, a variation in the wear volume of around 20% across the range of hardnesses examined was observed. However, in pairs where the two specimens in the couple had different hardnesses, a critical hardness differential threshold existed, above which the wear was predominantly associated with the harder specimen (with debris embedment on the softer specimen surface). This retention of debris provides protection of that surface from further wear and also results in accelerated wear of the harder counterface due to abrasion by the oxide debris bed which has built up on the opposing specimen

Regulatory T cells are paramount effectors in progesterone regulation of embryo implantation and fetal growth

Published: June 8, 2023Progesterone (P4) is essential for embryo implantation, but the extent to which the pro-gestational effects of P4 depend on the maternal immune compartment is unknown. Here, we investigate whether regulatory T cells (Treg cells) act to mediate luteal phase P4 effects on uterine receptivity in mice. P4 antagonist RU486 administered to mice on days 0.5 and 2.5 post coitum (dpc) to model luteal phase P4 deficiency caused fewer CD4+Foxp3+ Treg cells and impaired Treg functional competence, along with dysfunctional uterine vascular remodeling and perturbed placental development in mid-gestation. These effects were linked with fetal loss and fetal growth restriction, accompanied by a Th1/CD8-skewed T cell profile. Adoptive transfer at implantation of Treg cells - but not T conventional (Tconv) cells - alleviated fetal loss and fetal growth restriction by mitigating adverse effects of reduced P4 signaling on uterine blood vessel remodeling and placental structure, and restoring maternal T cell imbalance. These findings demonstrate an essential role for Treg cells in mediating P4 effects at implantation, and indicate that Treg cells are a sensitive and critical effector mechanism through which P4 drives uterine receptivity to support robust placental development and fetal growth.Ella S. Green, Lachlan M. Moldenhauer, Holly M. Groome, David J. Sharkey, Peck Y. Chin, Alison S. Care, Rebecca L. Robker, Shaun R. McColl, and Sarah A., Robertso

Is the wear coefficient dependent upon slip amplitude in fretting?: Vingsbo and Söderberg revisited

More than 25 years ago, Vingsbo and Söderberg published a seminal paper regarding the mapping of behaviour in fretting contacts (O. Vingsbo, S. Söderberg, On fretting maps, Wear, 126 (1988) 131–147). In this paper, it was proposed that in the gross-slip fretting regime, the wear coefficient increased by between one and two orders of magnitude as the fretting displacement amplitude increased from around 20 µm to 300 µm (defined as the limits of the gross-slip regime). Since the publication of this paper, there have been many papers published in the literature regarding fretting in the gross-sliding regime where such a strong dependence of wear coefficient upon fretting displacement has not been observed, with instead, the wear coefficient being shown to be almost independent of fretting amplitude. Indeed, many researchers have demonstrated that there is a good correlation between wear volume and frictional energy dissipated in the contact for many material combinations, with the additional insight that a threshold in energy dissipated in the contact exists, below which no wear is observed (experimental data relating to fretting of a high strength steel is presented in the current paper which supports this concept). It is argued that in deriving a wear coefficient in fretting, there are two key considerations which have not always been addressed: (i) the far-field displacement amplitude is not an adequate substitute for the slip amplitude (the former is the sum of the latter together with any elastic deformation in the system between the contact and the point at which the displacement is measured); and (ii) there is a threshold in the fretting duration, below which no wear occurs and above which the rate of increase in wear volume with increasing duration is constant (this constant may be termed the wear coefficient, ktrue). Not addressing these two issues results in the derivation of a nominal wear coefficient (knominal) which is always less than ktrue. A simple analysis is presented which indicates that knominal / ktrue = 1 - A - B where A is associated with erroneously utilising the far field displacement amplitude in place of the contact slip amplitude in the calculation of the wear coefficient and B is associated with the failure to recognise that there is a threshold in fretting duration below which no wear occurs. A and B are shown to depend upon the tractional force required to initiate sliding (itself dependent upon the applied load and coefficient of friction), the system stiffness, the applied displacement amplitude, the threshold fretting duration below which no wear occurs and the number of fretting cycles in the test. Using typical values of these parameters, the ratio of knominal to ktrue has been shown to be strongly dependent upon the applied displacement amplitude over the range addressed by Vingsbo and Söderberg (with the ratio rapidly decreasing by an order of magnitude over this range). As such, it is argued that ktrue shows no strong dependence on slip amplitude in fretting, and that the strong dependence of knominal upon displacement amplitude presented by Vingsbo and Söderberg does not imply a change in ktrue as is often inferred. The routine recording of force–displacement loops in fretting is a major experimental advancement which has taken place since the publication of the paper by Vingsbo and Söderberg. It is argued that this technique must be routinely used to allow the correct interpretation of wear data in terms of the actual slip amplitude (or energy dissipated); moreover, a range of conditions should be experimentally examined to allow the threshold fretting duration below which no wear has occurred to be evaluated and its significance assessed

CXCR5(+)CD8(+) T cells shape antibody responses In Vivo following protein immunisation and peripheral viral infection

Crosstalk between T and B cells is crucial for generating high-affinity, class-switched antibody responses. The roles of CD4+ T cells in this process have been wellcharacterised. In contrast, regulation of antibody responses by CD8+ T cells is significantly less defined. CD8+ T cells are principally recognised for eliciting cytotoxic responses in peripheral tissues and forming protective memory. However, recent findings have identified a novel population of effector CD8+ T cells that co-opt a differentiation program characteristic of CD4+ T follicular helper (Tfh) cells, upregulate the chemokine receptor CXCR5 and localise to B cell follicles. While it has been shown that CXCR5+CD8+ T cells mediate the removal of viral reservoirs in the context of follicular-trophic viral infections and maintain the response to chronic insults by virtue of progenitor/stem-like properties, it is not known if CXCR5+CD8+ T cells arise during acute peripheral challenges in the absence of follicular infection and whether they influence B cell responses in vivo in these settings. Using the ovalbumin-specific T cell receptor transgenic (OT-I) system in an adoptive transfer-immunisation/infection model, this study demonstrates that CXCR5+CD8+ T cells arise in response to protein immunisation and peripheral viral infection, displaying a follicular-homing phenotype, expression of cell surface molecules associated with Tfh cells and limited cytotoxic potential. Furthermore, studies assessing the B cell response in the presence of OT-I or Cxcr5-/- OT-I cells revealed that CXCR5+CD8+ T cells shape the antibody response to protein immunisation and peripheral viral infection, promoting class switching to IgG2c in responding B cells. Overall, the results highlight a novel contribution of CD8+ T cells to antibody responses, expanding the functionality of the adaptive immune system.Timona S. Tyllis, Kevin A. Fenix, Todd S. Norton, Ervin E. Kara, Duncan R. McKenzie, Shannon C. Davi

Review and assessment of latent and sensible heat flux accuracy over the global oceans

For over a decade, several research groups have been developing air-sea heat flux information over the global ocean, including latent (LHF) and sensible (SHF) heat fluxes over the global ocean. This paper aims to provide new insight into the quality and error characteristics of turbulent heat flux estimates at various spatial and temporal scales (from daily upwards). The study is performed within the European Space Agency (ESA) Ocean Heat Flux (OHF) project. One of the main objectives of the OHF project is to meet the recommendations and requirements expressed by various international programs such as the World Research Climate Program (WCRP) and Climate and Ocean Variability, Predictability, and Change (CLIVAR), recognizing the need for better characterization of existing flux errors with respect to the input bulk variables (e.g. surface wind, air and sea surface temperatures, air and surface specific humidities), and to the atmospheric and oceanic conditions (e.g. wind conditions and sea state). The analysis is based on the use of daily averaged LHF and SHF and the asso- ciated bulk variables derived from major satellite-based and atmospheric reanalysis products. Inter-comparisons of heat flux products indicate that all of them exhibit similar space and time patterns. However, they also reveal significant differences in magnitude in some specific regions such as the western ocean boundaries during the Northern Hemisphere winter season, and the high southern latitudes. The differences tend to be closely related to large differences in surface wind speed and/or specific air humidity (for LHF) and to air and sea temperature differences (for SHF). Further quality investigations are performed through comprehensive comparisons with daily-averaged LHF and SHF estimated from moorings. The resulting statistics are used to assess the error of each OHF product. Consideration of error correlation between products and observations (e.g., by their assimilation) is also given. This reveals generally high noise variance in all products and a weak signal in common with in situ observations, with some products only slightly better than others. The OHF LHF and SHF products, and their associated error characteristics, are used to compute daily OHF multiproduct-ensemble (OHF/MPE) estimates of LHF and SHF over the ice-free global ocean on a 0.25° × 0.25° grid. The accuracy of this heat multiproduct, determined from comparisons with mooring data, is greater than for any individual product. It is used as a reference for the anomaly characterization of each individual OHF product

CCL18 aggravates atherosclerosis by inducing CCR6-dependent T-cell influx and polarization

Biopharmaceutic

Search for a W' boson decaying to a bottom quark and a top quark in pp collisions at sqrt(s) = 7 TeV

Results are presented from a search for a W' boson using a dataset corresponding to 5.0 inverse femtobarns of integrated luminosity collected during 2011 by the CMS experiment at the LHC in pp collisions at sqrt(s)=7 TeV. The W' boson is modeled as a heavy W boson, but different scenarios for the couplings to fermions are considered, involving both left-handed and right-handed chiral projections of the fermions, as well as an arbitrary mixture of the two. The search is performed in the decay channel W' to t b, leading to a final state signature with a single lepton (e, mu), missing transverse energy, and jets, at least one of which is tagged as a b-jet. A W' boson that couples to fermions with the same coupling constant as the W, but to the right-handed rather than left-handed chiral projections, is excluded for masses below 1.85 TeV at the 95% confidence level. For the first time using LHC data, constraints on the W' gauge coupling for a set of left- and right-handed coupling combinations have been placed. These results represent a significant improvement over previously published limits.Comment: Submitted to Physics Letters B. Replaced with version publishe

Search for the standard model Higgs boson decaying into two photons in pp collisions at sqrt(s)=7 TeV

A search for a Higgs boson decaying into two photons is described. The analysis is performed using a dataset recorded by the CMS experiment at the LHC from pp collisions at a centre-of-mass energy of 7 TeV, which corresponds to an integrated luminosity of 4.8 inverse femtobarns. Limits are set on the cross section of the standard model Higgs boson decaying to two photons. The expected exclusion limit at 95% confidence level is between 1.4 and 2.4 times the standard model cross section in the mass range between 110 and 150 GeV. The analysis of the data excludes, at 95% confidence level, the standard model Higgs boson decaying into two photons in the mass range 128 to 132 GeV. The largest excess of events above the expected standard model background is observed for a Higgs boson mass hypothesis of 124 GeV with a local significance of 3.1 sigma. The global significance of observing an excess with a local significance greater than 3.1 sigma anywhere in the search range 110-150 GeV is estimated to be 1.8 sigma. More data are required to ascertain the origin of this excess.Comment: Submitted to Physics Letters