Matched sizes of activating and inhibitory receptor/ligand pairs are required for optimal signal integration by human Natural Killer cells

It has been suggested that receptor-ligand complexes segregate or co-localise within immune synapses according to their size, and this is important for receptor signaling. Here, we set out to test the importance of receptor-ligand complex dimensions for immune surveillance of target cells by human Natural Killer (NK) cells. NK cell activation is regulated by integrating signals from activating receptors, such as NKG2D, and inhibitory receptors, such as KIR2DL1. Elongating the NKG2D ligand MICA reduced its ability to trigger NK cell activation. Conversely, elongation of KIR2DL1 ligand HLA-C reduced its ability to inhibit NK cells. Whereas normal-sized HLA-C was most effective at inhibiting activation by normal-length MICA, only elongated HLA-C could inhibit activation by elongated MICA. Moreover, HLA-C and MICA that were matched in size co-localised, whereas HLA-C and MICA that were different in size were segregated. These results demonstrate that receptor-ligand dimensions are important in NK cell recognition, and suggest that optimal integration of activating and inhibitory receptor signals requires the receptor-ligand complexes to have similar dimensions

Coevolution of activating and inhibitory receptors within mammalian carcinoembryonic antigen families

<p>Abstract</p> <p>Background</p> <p>Most rapidly evolving gene families are involved in immune responses and reproduction, two biological functions which have been assigned to the carcinoembryonic antigen (CEA) gene family. To gain insights into evolutionary forces shaping the CEA gene family we have analysed this gene family in 27 mammalian species including monotreme and marsupial lineages.</p> <p>Results</p> <p>Phylogenetic analysis provided convincing evidence that the primordial CEA gene family in mammals consisted of five genes, including the immune inhibitory receptor-encoding <it>CEACAM1 </it>(CEA-related cell adhesion molecule) ancestor. Our analysis of the substitution rates within the nucleotide sequence which codes for the ligand binding domain of CEACAM1 indicates that the selection for diversification is, perhaps, a consequence of the exploitation of CEACAM1 by a variety of viral and bacterial pathogens as their cellular receptor. Depending on the extent of the amplification of an ancestral <it>CEACAM1</it>, the number of <it>CEACAM1</it>-related genes varies considerably between mammalian species from less than five in lagomorphs to more than 100 in bats. In most analysed species, ITAM (immunoreceptor tyrosine-based activation motifs) or ITAM-like motif-containing proteins exist which contain Ig-V-like, ligand binding domains closely related to that of CEACAM1. Human CEACAM3 is one such protein which can function as a CEACAM1 decoy receptor in granulocytes by mediating the uptake and destruction of specific bacterial pathogens via its ITAM-like motif. The close relationship between <it>CEACAM1 </it>and its ITAM-encoding relatives appears to be maintained by gene conversion and reciprocal recombination. Surprisingly, secreted CEACAMs resembling immunomodulatory CEACAM1-related trophoblast-specific pregnancy-specific glycoproteins (PSGs) found in humans and rodents evolved only in a limited set of mammals. The appearance of <it>PSG</it>-like genes correlates with invasive trophoblast growth in these species.</p> <p>Conclusions</p> <p>These phylogenetic studies provide evidence that pathogen/host coevolution and a possible participation in fetal-maternal conflict processes led to a highly species-specific diversity of mammalian CEA gene families.</p

Radiofrequency-based treatment in therapy-related clinical practice – a narrative review. Part I : acute conditions

This is an Accepted Manuscript of an article published by Taylor & Francis Group in Physical Therapy Reviews on 24 June 2015, available online at: https://www.tandfonline.com/doi/full/10.1179/1743288X15Y.0000000016Background: Radiofrequency electromagnetic field (RFEMF or simply RF)-based electrophysical agents (EPAs) have been employed in therapy-related clinical practice for several decades. They are used to reduce pain and inflammation and enhance tissue healing. Although these agents have generally become less popular in contemporary therapy practice, surveys have shown that some of these modalities are still reasonably widely used. Objective: To review the evidence for the use of non-invasive low frequency RFs (30 kHz–30 MHz) in therapy-related clinical practice. Major findings: All peer reviewed therapy-related clinical studies published in English and concerning low frequency RF were sought. Identified literature was divided into acute and chronic segments based on their clinical area and analysed to assess the volume and scope of current evidence. The studies on acute conditions were reviewed in detail for this paper. One hundred twenty clinical studies were identified, of which 30 related to acute conditions. The majority of studies employed Pulsed Shortwave Therapy (PSWT). Twenty-two studies out of 30 were related to conditions of pain and inflammation, seven to tissue healing and one to acute pneumothorax. No studies were identified on frequencies other than shortwave. Conclusions: Evidence for and against RF-based therapy is available. There is reasonable evidence in support of PSWT to alleviate postoperative pain and promote postoperative wound healing. Evidence for other acute conditions is sparse and conflicting. A general lack of research emphasis in the non-shortwave RF band is evident, with studies on acute conditions almost non-existent. Further and wider research in this area is warranted.Peer reviewe

Biofeedback for training balance and mobility tasks in older populations: a systematic review

<p>Abstract</p> <p>Context</p> <p>An effective application of biofeedback for interventions in older adults with balance and mobility disorders may be compromised due to co-morbidity.</p> <p>Objective</p> <p>To evaluate the feasibility and the effectiveness of biofeedback-based training of balance and/or mobility in older adults.</p> <p>Data Sources</p> <p>PubMed (1950-2009), EMBASE (1988-2009), Web of Science (1945-2009), the Cochrane Controlled Trials Register (1960-2009), CINAHL (1982-2009) and PsycINFO (1840-2009). The search strategy was composed of terms referring to biofeedback, balance or mobility, and older adults. Additional studies were identified by scanning reference lists.</p> <p>Study Selection</p> <p>For evaluating effectiveness, 2 reviewers independently screened papers and included controlled studies in older adults (i.e. mean age equal to or greater than 60 years) if they applied biofeedback during repeated practice sessions, and if they used at least one objective outcome measure of a balance or mobility task.</p> <p>Data Extraction</p> <p>Rating of study quality, with use of the Physiotherapy Evidence Database rating scale (PEDro scale), was performed independently by the 2 reviewers. Indications for (non)effectiveness were identified if 2 or more similar studies reported a (non)significant effect for the same type of outcome. Effect sizes were calculated.</p> <p>Results and Conclusions</p> <p>Although most available studies did not systematically evaluate feasibility aspects, reports of high participation rates, low drop-out rates, absence of adverse events and positive training experiences suggest that biofeedback methods can be applied in older adults. Effectiveness was evaluated based on 21 studies, mostly of moderate quality. An indication for effectiveness of visual feedback-based training of balance in (frail) older adults was identified for postural sway, weight-shifting and reaction time in standing, and for the Berg Balance Scale. Indications for added effectiveness of applying biofeedback during training of balance, gait, or sit-to-stand transfers in older patients post-stroke were identified for training-specific aspects. The same applies for auditory feedback-based training of gait in older patients with lower-limb surgery.</p> <p>Implications</p> <p>Further appropriate studies are needed in different populations of older adults to be able to make definitive statements regarding the (long-term) added effectiveness, particularly on measures of functioning.</p

Caenorhabditis elegans SMA-10/LRIG Is a Conserved Transmembrane Protein that Enhances Bone Morphogenetic Protein Signaling

Bone morphogenetic protein (BMP) pathways control an array of developmental and homeostatic events, and must themselves be exquisitely controlled. Here, we identify Caenorhabditis elegans SMA-10 as a positive extracellular regulator of BMP–like receptor signaling. SMA-10 acts genetically in a BMP–like (Sma/Mab) pathway between the ligand DBL-1 and its receptors SMA-6 and DAF-4. We cloned sma-10 and show that it has fifteen leucine-rich repeats and three immunoglobulin-like domains, hallmarks of an LRIG subfamily of transmembrane proteins. SMA-10 is required in the hypodermis, where the core Sma/Mab signaling components function. We demonstrate functional conservation of LRIGs by rescuing sma-10(lf) animals with the Drosophila ortholog lambik, showing that SMA-10 physically binds the DBL-1 receptors SMA-6 and DAF-4 and enhances signaling in vitro. This interaction is evolutionarily conserved, evidenced by LRIG1 binding to vertebrate receptors. We propose a new role for LRIG family members: the positive regulation of BMP signaling by binding both Type I and Type II receptors

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field