Amplitude shading and phase weighting of a vertical linear array in the SOFAR channel by the linear minimum variance estimation technique

A single linear vertical passive array is used in the 'SOFAR' channel to determine the depth of a single underwater source at a constant range. The phase and amplitude weights applied to the array are determined by the linear minimum variance estimation technique. The resulting beam pattern is compared to the conventional time domain beamformer. It was found that the linear minimum variance estimation technique of amplitude shading and phase weighting was significantly superior to the conventional beamformer.http://archive.org/details/amplitudeshading00mcviCaptain, Canadian Armed ForcesApproved for public release; distribution is unlimited

Diversity and environmental adaptation of phagocytic cell metabolism

Phagocytes are cells of the immune system that play important roles in phagocytosis, respiratory burst and degranulation-key components of innate immunity and response to infection. This diverse group of cells includes monocytes, macrophages, dendritic cells, neutrophils, eosinophils, and basophils-heterogeneous cell populations possessing cell and tissue-specific functions of which cellular metabolism comprises a critical underpinning. Core functions of phagocytic cells are diverse and sensitive to alterations in environmental- and tissue-specific nutrients and growth factors. As phagocytic cells adapt to these extracellular cues, cellular processes are altered and may contribute to pathogenesis. The considerable degree of functional heterogeneity among monocyte, neutrophil, and other phagocytic cell populations necessitates diverse metabolism. As we review our current understanding of metabolism in phagocytic cells, gaps are focused on to highlight the need for additional studies that hopefully enable improved cell-based strategies for counteracting cancer and other diseases

Leveraging repetition for improved automatic lyric transcription in popular music

Transcribing lyrics from musical audio is a challenging research prob-lem which has not benefited from many advances made in the related field of automatic speech recognition, owing to the prevalent musical accompaniment and differences between the spoken and sung voice. However, one aspect of this problem which has yet to be exploited by researchers is that significant portions of the lyrics will be repeated throughout the song. In this paper we investigate how this information can be leveraged to form a consensus transcription with improved consistency and accuracy. Our results show that improvements can be gained using a variety of techniques, and that relative gains are largest under the most challenging and realistic experimental conditions

Editorial: Metabolism Meets Function: Untangling the Cross-Talk Between Signaling and Metabolism

Tumor metabolism is a long established field in cancer biology, as the seminal findings of Otto Warburg date back to the 1920s. Since then, the discovery that oncogenes, besides promoting the Warburg effect, modulate anabolic pathways, has prompted scientists to re-evaluate the role that tumor metabolism plays in the neoplastic process. Today, metabolic reprogramming of neoplastic cells is considered a hallmark of cancer, with the discovery that flexibility in the acquisition of various cellular characteristics is supported by specific metabolic pathways. Clinical and pharmacological advances, for example the application of FDG-PET in the clinical setting (1) and the development of novel pharmacological strategies based on antimetabolites (2), provide further support and validation of the role of metabolism in cancer. Here, we present a collection of works with the aim of bringing together work from a variety of scientists across the field of tumor metabolism toward an understanding of how different metabolic pathways are activated in neoplastic and surrounding cells, the mechanisms linking altered metabolism to tumorigenesis and the potential for pharmacological applications

Analysis of Binding of KIR3DS1*014 to HLA Suggests Distinct Evolutionary History of KIR3DS1

NK cell activity is regulated by the integration of positive and negative signals. One important source of these signals for human NK cells is the killer Ig-like receptor (KIR) family, which includes both members that transduce positive and those that generate negative signals. KIR3DL1 inhibits NK cell activity upon engagement by its ligand HLA-Bw4. The highly homologous KIR3DS1 is an activating receptor, which is implicated in the outcome of a variety of pathological situations. However, unlike KIR3DL1, direct binding of KIR3DS1+ cells to HLA has not been demonstrated. We analyzed four key amino acid differences between KIR3DL1*01502 and KIR3DS1*013 to determine their role in KIR binding to HLA. Single substitutions of these residues dramatically reduced binding by KIR3DL1. In the reciprocal experiment, we found that the rare KIR3DS1 allotype KIR3DS1*014 binds HLA-Bw4 even though it differs from KIR3DS1*013 at only one of these positions (position 138). This reactivity was unexpectedly dependent on residues at other variable positions, as HLA-Bw4 binding was lost in receptors with KIR3DL1-like residues at both positions 199 and 138. These data provide the first evidence, to our knowledge, for the direct binding of KIR3DS1+ cells to HLA-Bw4 and highlight the key role for position 138 in determining ligand specificity of KIR3DS1. They also reveal that KIR3DS1 reactivity and specificity is dictated by complex interactions between the residues in this region, suggesting a unique functional evolution of KIR3DS1 within the activating KIR family

Peritoneal tissue-resident macrophages are metabolically poised to engage microbes using tissue-niche fuels

The importance of metabolism in macrophage function has been reported, but the in vivo relevance of the in vitro observations is still unclear. Here we show that macrophage metabolites are defined in a specific tissue context, and these metabolites are crucially linked to tissue-resident macrophage functions. We find the peritoneum to be rich in glutamate, a glutaminolysis-fuel that is exploited by peritoneal-resident macrophages to maintain respiratory burst during phagocytosis via enhancing mitochondrial complex-II metabolism. This niche-supported, inducible mitochondrial function is dependent on protein kinase C activity, and is required to fine-tune the cytokine responses that control inflammation. In addition, we find that peritoneal-resident macrophage mitochondria are recruited to phagosomes and produce mitochondrially derived reactive oxygen species, which are necessary for microbial killing. We propose that tissue-resident macrophages are metabolically poised in situ to protect and exploit their tissue-niche by utilising locally available fuels to implement specific metabolic programmes upon microbial sensing

Pharmacologic or Genetic Targeting of Glutamine Synthetase Skews Macrophages toward an M1-like Phenotype and Inhibits Tumor Metastasis.

Glutamine-synthetase (GS), the glutamine-synthesizing enzyme from glutamate, controls important events, including the release of inflammatory mediators, mammalian target of rapamycin (mTOR) activation, and autophagy. However, its role in macrophages remains elusive. We report that pharmacologic inhibition of GS skews M2-polarized macrophages toward the M1-like phenotype, characterized by reduced intracellular glutamine and increased succinate with enhanced glucose flux through glycolysis, which could be partly related to HIF1α activation. As a result of these metabolic changes and HIF1α accumulation, GS-inhibited macrophages display an increased capacity to induce T cell recruitment, reduced T cell suppressive potential, and an impaired ability to foster endothelial cell branching or cancer cell motility. Genetic deletion of macrophagic GS in tumor-bearing mice promotes tumor vessel pruning, vascular normalization, accumulation of cytotoxic T cells, and metastasis inhibition. These data identify GS activity as mediator of the proangiogenic, immunosuppressive, and pro-metastatic function of M2-like macrophages and highlight the possibility of targeting this enzyme in the treatment of cancer metastasis

Mutational and Structural Analysis of KIR3DL1 Reveals a Lineage-Defining Allotypic Dimorphism That Impacts Both HLA and Peptide Sensitivity

Killer Ig-like receptors (KIRs) control the activation of human NK cells via interactions with peptide-laden HLAs. KIR3DL1 is a highly polymorphic inhibitory receptor that recognizes a diverse array of HLA molecules expressing the Bw4 epitope, a group with multiple polymorphisms incorporating variants within the Bw4 motif. Genetic studies suggest that KIR3DL1 variation has functional significance in several disease states, including HIV infection. However, owing to differences across KIR3DL1 allotypes, HLA-Bw4, and associated peptides, the mechanistic link with biological outcome remains unclear. In this study, we elucidated the impact of KIR3DL1 polymorphism on peptide-laden HLA recognition. Mutational analysis revealed that KIR residues involved in water-mediated contacts with the HLA-presented peptide influence peptide binding specificity. In particular, residue 282 (glutamate) in the D2 domain underpins the lack of tolerance of negatively charged C-terminal peptide residues. Allotypic KIR3DL1 variants, defined by neighboring residue 283, displayed differential sensitivities to HLA-bound peptide, including the variable HLA-B*57:01-restricted HIV-1 Gag-derived epitope TW10. Residue 283, which has undergone positive selection during the evolution of human KIRs, also played a central role in Bw4 subtype recognition by KIR3DL1. Collectively, our findings uncover a common molecular regulator that controls HLA and peptide discrimination without participating directly in peptide-laden HLA interactions. Furthermore, they provide insight into the mechanics of interaction and generate simple, easily assessed criteria for the definition of KIR3DL1 functional groupings that will be relevant in many clinical applications, including bone marrow transplantation

Positive regulation of plasmacytoid dendritic cell function via Ly49Q recognition of class I MHC

Plasmacytoid dendritic cells (pDCs) are an important source of type I interferon (IFN) during initial immune responses to viral infections. In mice, pDCs are uniquely characterized by high-level expression of Ly49Q, a C-type lectin-like receptor specific for class I major histocompatibility complex (MHC) molecules. Despite having a cytoplasmic immunoreceptor tyrosine-based inhibitory motif, Ly49Q was found to enhance pDC function in vitro, as pDC cytokine production in response to the Toll-like receptor (TLR) 9 agonist CpG-oligonucleotide (ODN) could be blocked using soluble monoclonal antibody (mAb) to Ly49Q or H-2Kb. Conversely, CpG-ODN–dependent IFN-α production by pDCs was greatly augmented upon receptor cross-linking using immobilized anti-Ly49Q mAb or recombinant H-2Kb ligand. Accordingly, Ly49Q-deficient pDCs displayed a severely reduced capacity to produce cytokines in response to TLR7 and TLR9 stimulation both in vitro and in vivo. Finally, TLR9-dependent antiviral responses were compromised in Ly49Q-null mice infected with mouse cytomegalovirus. Thus, class I MHC recognition by Ly49Q on pDCs is necessary for optimal activation of innate immune responses in vivo