Explore the vast range of titles available.

Natural killer (NK) cells are important mediators of anti-tumor immunity and are active against several hematologic malignancies, including multiple myeloma (MM). Umbilical cord blood (CB) is a promising source of allogeneic NK cells but large scale ex vivo expansion is required for generation of clinically relevant CB-derived NK (CB-NK) cell doses. Here we describe a novel strategy for expanding NK cells from cryopreserved CB units using artificial antigen presenting feeder cells (aAPC) in a gas permeable culture system. After 14 days, mean fold expansion of CB-NK cells was 1848-fold from fresh and 2389-fold from cryopreserved CB with >95% purity for NK cells (CD56(+)/CD3(-)) and less than 1% CD3(+) cells. Though surface expression of some cytotoxicity receptors was decreased, aAPC-expanded CB-NK cells exhibited a phenotype similar to CB-NK cells expanded with IL-2 alone with respect to various inhibitory receptors, NKG2C and CD94 and maintained strong expression of transcription factors Eomesodermin and T-bet. Furthermore, CB-NK cells formed functional immune synapses with and demonstrated cytotoxicity against various MM targets. Finally, aAPC-expanded CB-NK cells showed significant in vivo activity against MM in a xenogenic mouse model. Our findings introduce a clinically applicable strategy for the generation of highly functional CB-NK cells which can be used to eradicate MM.

An investigation was carried out into the charging rate dependence of local structural changes in a layered 0.5Li 2 MnO 3 –0.5LiMn 1/3 Ni 1/3 Co 1/3 O 2 solid solution during the initial charging cycle. To clarify the mechanism involved in local atomic rearrangement, a pair distribution function (PDF) analysis was performed using the results of powder neutron diffraction and synchrotron X-ray total scattering measurements. First-principles calculations (VASP code) were used to determine the initial structure when performing the PDF analysis. The bond-length strain ( λ ) and the bond-angle strain ( σ 2 ) for the optimized model were calculated following the PDF analysis in order to clarify the effect of the charging rate on the crystal structure distortion. Before charging, the distortion was small for MnO 6 octahedra compared to that for NiO 6 and CoO 6 octahedra. During charging at a rate of 1C, the MnO 6 octahedra experienced increasing distortion, whereas at 3C the CoO 6 octahedra became more distorted. In addition, when charging at 3C, the values of λ and σ 2 increased for NiO 6 octahedra that had entered the Li layer as a result of cation mixing. This appeared to be related to whether the localized atom was Mn or Co within the average structure during charge process. It is thought that distortion occurs in MO 6 octahedra containing whichever element becomes localized, and this depends on the charging rate. This leads to the possibility that decreasing the fractional composition of the element that becomes localized may lead to reduced distortion and improved the cyclability.

Pulmonary aspergillosis is an opportunistic fungal infection affecting immunocompromised individuals. Increasing understanding of natural killer (NK) cell immunobiology has aroused considerable interest around the role of NK cells in pulmonary aspergillosis in the immunocompromised host. Murine studies indicate that NK cells play a critical role in pulmonary clearance of . We show that the interaction between NK cells and induces partial activation of NK cell immune response, characterised by low-level production of IFN-γ, TNF-α, MIP-1α, MIP-1β, and RANTES, polarisation of lytic granules and release of fungal DNA. We observed a contact-dependent down-regulation of activatory receptors NKG2D and NKp46 on the NK cell surface, and a failure of full granule release. Furthermore, the NK cell cytokine-mediated response to leukaemic cells was impaired in the presence of . These observations suggest that -mediated NK cell immunoparesis may represent an important mechanism of immune evasion during pulmonary aspergillosis.

Peptides that have high affinity for target molecules on the surface of cancer cells are crucial for the development of targeted cancer therapies. However, unstructured peptides often fail to bind their target molecules with high affinity. To efficiently identify high-affinity target-binding peptides, we have constructed a fluorescent protein scaffold, designated gFPS, in which structurally constrained peptides are integrated at residues K131-L137 of superfolder green fluorescent protein. Molecular dynamics simulation supported the suitability of this site for presentation of exogenous peptides with a constrained structure. gFPS can present 4 to 12 exogenous amino acids without a loss of fluorescence. When gFPSs presenting human epidermal growth factor receptor type 2 (HER2)-targeting peptides were added to the culture medium of HER2-expressing cells, we could easily identify the peptides with high HER2-affinity and -specificity based on gFPS fluorescence. In addition, gFPS could be expressed on the yeast cell surface and applied for a high-throughput screening. These results demonstrate that gFPS has the potential to serve as a powerful tool to improve screening of structurally constrained peptides that have a high target affinity, and suggest that it could expedite the one-step identification of clinically applicable cancer cell-binding peptides.

To the Editor, X-linked lymphoproliferative disease (XLP) is a rare disorder characterized by an extreme vulnerability to Epstein- Barr virus (EBV) infection, frequently resulting in hemophagocytic lymphohistiocytosis (HLH) [1]. XLP-1, its more common subtype, is caused by defects in the SH2D1A gene that encodes the signaling lymphocyte activation molecule-associated protein (SAP), which regulates the activation of T lymphocytes [2], whereas XLP-2 is caused by mutations in the XIAP gene, also known as BIRC4 [3].

An attempt was made to verify the observation that Streptomyces griseus was prevalent in soil based on isolation work. A genus-specific PCR was developed for Streptomyces based on the housekeeping gene atpD and used to investigate species diversity within selected soils. The presence of S. griseus was investigated to determine coexistence of resistance-only streptomycin phosphotransferase (strA) in the same soil as streptomycin producers. Two additional PCR-based assays were developed; one specific for strA in association with production, the other for more diverse strA and other related phosphotranferases. Both the S. griseus atpD and strA genes were below the PCR detection limit in all soils examined. A number of more diverse phosphotransferase genes were amplified, a minority of which may be associated with streptomycin production. We conclude that neither streptomycin producers nor S. griseus are prevalent in the fresh or chitin and starch-amended soils examined (less than 0.1% of soil actinobacteria). One of the soil sites had received plantomycin (active ingredient: streptomycin) and diversity studies suggested that this altered the streptomycete populations present in the soil.

To date, single-cell studies of human white adipose tissue (WAT) have been based on small cohort sizes and no cellular consensus nomenclature exists. Herein, we performed a comprehensive meta-analysis of publicly available and newly generated single-cell, single-nucleus, and spatial transcriptomic results from human subcutaneous, omental, and perivascular WAT. Our high-resolution map is built on data from ten studies and allowed us to robustly identify >60 subpopulations of adipocytes, fibroblast and adipogenic progenitors, vascular, and immune cells. Using these results, we deconvolved spatial and bulk transcriptomic data from nine additional cohorts to provide spatial and clinical dimensions to the map. This identified cell-cell interactions as well as relationships between specific cell subtypes and insulin resistance, dyslipidemia, adipocyte volume, and lipolysis upon long-term weight changes. Altogether, our meta-map provides a rich resource defining the cellular and microarchitectural landscape of human WAT and describes the associations between specific cell types and metabolic states. Single-cell studies of human white adipose tissue (WAT) provide insights into the specialized cell types in the tissue. Here the authors combine publicly available and newly generated high-resolution and bulk transcriptomic results from multiple human datasets to provide a comprehensive cellular map of white adipose tissue.

Most candidate drugs currently fail later-stage clinical trials, largely due to poor prediction of efficacy on early target selection 1 . Drug targets with genetic support are more likely to be therapeutically valid 2 , 3 , but the translational use of genome-scale data such as from genome-wide association studies for drug target discovery in complex diseases remains challenging 4 – 6 . Here, we show that integration of functional genomic and immune-related annotations, together with knowledge of network connectivity, maximizes the informativeness of genetics for target validation, defining the target prioritization landscape for 30 immune traits at the gene and pathway level. We demonstrate how our genetics-led drug target prioritization approach (the priority index) successfully identifies current therapeutics, predicts activity in high-throughput cellular screens (including L1000, CRISPR, mutagenesis and patient-derived cell assays), enables prioritization of under-explored targets and allows for determination of target-level trait relationships. The priority index is an open-access, scalable system accelerating early-stage drug target selection for immune-mediated disease. A genetics-led translational approach integrating functional genomic predictors, knowledge of network connectivity and immune ontologies defines the drug target prioritization landscape for 30 immune traits at the gene and pathway level.

Natural killer (NK) cells are key components of the innate immune system, providing potent antitumor immunity. Here, we show that the tumor growth factor-β (TGF-β)/SMAD signaling pathway is an important mechanism for NK cell immune evasion in childhood B-acute lymphoblastic leukemia (ALL). We characterized NK cells in 50 consecutive children with B-ALL at diagnosis, end induction and during maintenance therapy compared with age-matched controls. ALL-NK cells at diagnosis had an inhibitory phenotype associated with impaired function, most notably interferon-γ production and cytotoxicity. By maintenance therapy, these phenotypic and functional abnormalities partially normalized; however, cytotoxicity against autologous blasts remained impaired. We identified ALL-derived TGF-β1 to be an important mediator of leukemia-induced NK cell dysfunction. The TGF-β/SMAD signaling pathway was constitutively activated in ALL-NK cells at diagnosis and end induction when compared with healthy controls and patients during maintenance therapy. Culture of ALL blasts with healthy NK cells induced NK dysfunction and an inhibitory phenotype, mediated by activation of the TGF-β/SMAD signaling pathway, and abrogated by blocking TGF-β. These data indicate that by regulating the TGF-β/SMAD pathway, ALL blasts induce changes in NK cells to evade innate immune surveillance, thus highlighting the importance of developing novel therapies to target this inhibitory pathway and restore antileukemic cytotoxicity.

An investigation was carried out into the charging rate dependence of local structural changes in a layered 0.5Li.sub.2MnO.sub.3-0.5LiMn.sub.1/3Ni.sub.1/3Co.sub.1/3O.sub.2 solid solution during the initial charging cycle. To clarify the mechanism involved in local atomic rearrangement, a pair distribution function (PDF) analysis was performed using the results of powder neutron diffraction and synchrotron X-ray total scattering measurements. First-principles calculations (VASP code) were used to determine the initial structure when performing the PDF analysis. The bond-length strain ([lambda]) and the bond-angle strain ([sigma].sup.2) for the optimized model were calculated following the PDF analysis in order to clarify the effect of the charging rate on the crystal structure distortion. Before charging, the distortion was small for MnO.sub.6 octahedra compared to that for NiO.sub.6 and CoO.sub.6 octahedra. During charging at a rate of 1C, the MnO.sub.6 octahedra experienced increasing distortion, whereas at 3C the CoO.sub.6 octahedra became more distorted. In addition, when charging at 3C, the values of [lambda] and [sigma].sup.2 increased for NiO.sub.6 octahedra that had entered the Li layer as a result of cation mixing. This appeared to be related to whether the localized atom was Mn or Co within the average structure during charge process. It is thought that distortion occurs in MO.sub.6 octahedra containing whichever element becomes localized, and this depends on the charging rate. This leads to the possibility that decreasing the fractional composition of the element that becomes localized may lead to reduced distortion and improved the cyclability.