To exploit autologous NK cells for cancer immunotherapy, it is highly relevant to circumvent killer cell immunoglobulin‐like receptor (KIR)‐mediated self‐inhibition of human NK cells by ...HLA‐I–expressing tumor cells. Here, we show that stimulation of NK cells with IL‐12/15/18 for two days led to downregulation of surface expression of the inhibitory KIR2DL2/L3, KIR2DL1 and KIR3DL1 receptors on peripheral blood NK cells. Downregulation of KIR expression was attributed to decreased KIR mRNA levels which could be re‐induced already 3 days after re‐culture in IL‐2. Reduced KIR2DL2/L3 expression on IL‐12/15/18–activated NK cells resulted in less inhibition upon antibody‐mediated KIR engagement and increased CD16‐dependent cytotoxicity in redirected lysis assays. Most importantly, downregulated KIR2DL2/L3 expression enabled enhanced cytotoxicity of IL‐12/15/18–stimulated NK cells against tumor cells expressing cognate HLA‐I molecules. NK cells pre‐activated with IL‐12/15/18 were previously shown to exert potent anti‐tumor activity and memory‐like long‐lived functionality, mediating remission in a subset of acute myeloid leukemia (AML) patients in a clinical trial. Our study reveals a novel mechanism of IL‐12/15/18 in improving the cytotoxicity of NK cells by reducing their sensitivity to inhibition by self–HLA‐I due to decreased KIR expression, highlighting the potency of IL‐12/15/18–activated NK cells for anti‐tumor immunotherapy protocols.
Stimulation of human NK cells with IL‐12/15/18 induced transient downregulation of surface expression and mRNA levels of inhibitory killer immunoglobulin‐like receptors (KIRs). Reduced KIR expression translated into enhanced NK cytotoxicity against cognate HLA‐I–expressing tumor cells, highlighting the potency of IL‐12/15/18–activated NK cells for anti‐tumor immunotherapy protocols.
Saturn's ionosphere is produced when the otherwise neutral atmosphere is exposed to a flow of energetic charged particles or solar radiation. At low latitudes the solar radiation should result in a ...weak planet-wide glow in the infrared, corresponding to the planet's uniform illumination by the Sun. The observed electron density of the low-latitude ionosphere, however, is lower and its temperature higher than predicted by models. A planet-to-ring magnetic connection has been previously suggested, in which an influx of water from the rings could explain the lower-than-expected electron densities in Saturn's atmosphere. Here we report the detection of a pattern of features, extending across a broad latitude band from 25 to 60 degrees, that is superposed on the lower-latitude background glow, with peaks in emission that map along the planet's magnetic field lines to gaps in Saturn's rings. This pattern implies the transfer of charged species derived from water from the ring-plane to the ionosphere, an influx on a global scale, flooding between 30 to 43 per cent of the surface of Saturn's upper atmosphere. This ring 'rain' is important in modulating ionospheric emissions and suppressing electron densities.
Signaling between the endoplasmic reticulum (ER) and mitochondria regulates a number of key neuronal functions, many of which are perturbed in Alzheimer's disease. Moreover, damage to ER-mitochondria ...signaling is seen in cell and transgenic models of Alzheimer's disease. However, as yet there is little evidence that ER-mitochondria signaling is altered in human Alzheimer's disease brains. ER-mitochondria signaling is mediated by interactions between the integral ER protein VAPB and the outer mitochondrial membrane protein PTPIP51 which act to recruit and “tether” regions of ER to the mitochondrial surface. The VAPB-PTPIP51 tethers are now known to regulate a number of ER-mitochondria signaling functions including delivery of Ca2+from ER stores to mitochondria, mitochondrial ATP production, autophagy and synaptic activity. Here we investigate the VAPB-PTPIP51 tethers in post-mortem control and Alzheimer's disease brains. Quantification of ER-mitochondria signaling proteins by immunoblotting revealed loss of VAPB and PTPIP51 in cortex but not cerebellum at end-stage Alzheimer's disease. Proximity ligation assays were used to quantify the VAPB-PTPIP51 interaction in temporal cortex pyramidal neurons and cerebellar Purkinje cell neurons in control, Braak stage III-IV (early/mid-dementia) and Braak stage VI (severe dementia) cases. Pyramidal neurons degenerate in Alzheimer's disease whereas Purkinje cells are less affected. These studies revealed that the VAPB-PTPIP51 tethers are disrupted in Braak stage III-IV pyramidal but not Purkinje cell neurons. Thus, we identify a new pathogenic event in post-mortem Alzheimer's disease brains. The implications of our findings for Alzheimer's disease mechanisms are discussed.
•VAPB, PTPIP51 and IP3R1 levels are reduced in temporal cortex in late-stage Alzheimer's disease•Proximity ligation assays reveal that the VAPB-PTPIP51 interaction is disrupted in temporal cortex pyramidal neurons in early (Braak stage III-IV) Alzheimer's disease•We identify damage to the VAPB-PTPIP51 ER-mitochondria tethers as a new pathogenic event in Alzheimer’s disease.•Disruption of the VAPB-PTPIP51 tethers may contribute to the neurodegenerative process in Alzheimer’s disease
We report results of a search for oscillations involving a light sterile neutrino over distances of 1.04 and 735 km in a ν_{μ}-dominated beam with a peak energy of 3 GeV. The data, from an exposure ...of 10.56×10^{20} protons on target, are analyzed using a phenomenological model with one sterile neutrino. We constrain the mixing parameters θ_{24} and Δm_{41}^{2} and set limits on parameters of the four-dimensional Pontecorvo-Maki-Nakagawa-Sakata matrix, |U_{μ4}|^{2} and |U_{τ4}|^{2}, under the assumption that mixing between ν_{e} and ν_{s} is negligible (|U_{e4}|^{2}=0). No evidence for ν_{μ}→ν_{s} transitions is found and we set a world-leading limit on θ_{24} for values of Δm_{41}^{2}≲1 eV^{2}.
Mastitis is a common and costly production disease on dairy farms. In Canada, the incidence rate of clinical mastitis (IRCM) has been determined for conventionally managed dairy farms; however, no ...studies to date have assessed rates in organically managed systems. The objectives of this observational study were (1) to determine the producer-reported IRCM and predominant pathogen types on conventional and organic dairy farms in Southern Ontario, Canada, and (2) to evaluate the association of both mean overall IRCM and pathogen-specific IRCM with management system, housing type, and pasture access. Data from 59 dairy farms in Southern Ontario, Canada, distributed across conventional (n=41) and organic management (n=18) systems, were collected from April 2011 to May 2012. In addition to management system, farms were categorized by housing method (loose or tie-stall) and pasture access for lactating cows. Participating producers identified and collected samples from 936 cases of clinical mastitis. The most frequently isolated mastitis pathogens were coagulase-negative staphylococci, Bacillus spp., Streptococcus spp., Staphylococcus aureus, and Escherichia coli. The IRCM was higher on conventional farms than organic (23.7 vs. 13.2 cases per 100 cow-years) and was not associated with housing type (loose or tie-stall), pasture access, or herd-average milk yield. Bulk tank somatic cell count tended to be lower on conventional farms than organic (222,000 vs. 272,000cells/mL). Pathogen-specific IRCM attributed to Staph. aureus, Bacillus spp., and E. coli was greater on conventional than organic farms, but was not associated with housing or any other factors. In conclusion, organic management was associated with reduced overall and pathogen-specific IRCM.
We report the final measurement of the neutrino oscillation parameters Δm322 and sin2 θ23 using all data from the MINOS and MINOS+ experiments. These data were collected using a total exposure of ...23.76 × 1020 protons on target producing νμ and νμ beams and 60.75 kt yr exposure to atmospheric neutrinos. The measurement of the disappearance of νμ and the appearance of νe events between the Near and Far detectors yields ... and ... at 68% C.L. for normal (inverted) hierarchy. (ProQuest: ... denotes formulae omited.).
Epigenetics, the modification of chromatin without changing the DNA sequence itself, determines whether a gene is expressed, and how much of a gene is expressed. Methylation of lysine 27 on histone 3 ...(H3K27me), a modification usually associated with gene repression, has established roles in regulating the expression of genes involved in lineage commitment and differentiation. Not surprisingly, alterations in the homeostasis of this critical mark have emerged as a recurrent theme in the pathogenesis of many cancers. Perturbations in the distribution or levels of H3K27me occur due to deregulation at all levels of the process, either by mutation in the histone itself, or changes in the activity of the writers, erasers, or readers of this mark. Additionally, as no single histone mark alone determines the overall transcriptional readiness of a chromatin region, deregulation of other chromatin marks can also have dramatic consequences. Finally, the significance of mutations altering H3K27me is highlighted by the poor clinical outcome of patients whose tumors harbor such lesions. Current therapeutic approaches targeting aberrant H3K27 methylation remain to be proven useful in the clinic. Understanding the biological consequences and gene expression pathways affected by aberrant H3K27 methylation may lead to identification of new therapeutic targets and strategies.
Abstract
Summary
Antimicrobial peptides (AMPs) are the key components of the innate immune system that protect against pathogens, regulate the microbiome and are promising targets for pharmaceutical ...research. Computational tools based on machine learning have the potential to aid discovery of genes encoding novel AMPs but existing approaches are not designed for genome-wide scans. To facilitate such genome-wide discovery of AMPs we developed a fast and accurate AMP classification framework, ampir. ampir is designed for high throughput, integrates well with existing bioinformatics pipelines, and has much higher classification accuracy than existing methods when applied to whole genome data.
Availability and implementation
ampir is implemented primarily in R with core feature calculation methods written in C++. Release versions are available via CRAN and work on all major operating systems. The development version is maintained at https://github.com/legana/ampir.
Supplementary information
Supplementary data are available at Bioinformatics online.
Segmental duplications at breakpoints (BP4-BP5) of chromosome 15q13.2q13.3 mediate a recurrent genomic imbalance syndrome associated with mental retardation, epilepsy, and/or electroencephalogram ...(EEG) abnormalities.
DNA samples from 1445 unrelated patients submitted consecutively for clinical array comparative genomic hybridisation (CGH) testing at Children's Hospital Boston and DNA samples from 1441 individuals with autism from 751 families in the Autism Genetic Resource Exchange (AGRE) repository.
We report the clinical features of five patients with a BP4-BP5 deletion, three with a BP4-BP5 duplication, and two with an overlapping but smaller duplication identified by whole genome high resolution oligonucleotide array CGH. These BP4-BP5 deletion cases exhibit minor dysmorphic features, significant expressive language deficits, and a spectrum of neuropsychiatric impairments that include autism spectrum disorder, attention deficit hyperactivity disorder, anxiety disorder, and mood disorder. Cognitive impairment varied from moderate mental retardation to normal IQ with learning disability. BP4-BP5 covers approximately 1.5 Mb (chr15:28.719-30.298 Mb) and includes six reference genes and 1 miRNA gene, while the smaller duplications cover approximately 500 kb (chr15:28.902-29.404 Mb) and contain three reference genes and one miRNA gene. The BP4-BP5 deletion and duplication events span CHRNA7, a candidate gene for seizures. However, none of these individuals reported here have epilepsy, although two have an abnormal EEG.
The phenotype of chromosome 15q13.2q13.3 BP4-BP5 microdeletion/duplication syndrome may include features of autism spectrum disorder, a variety of neuropsychiatric disorders, and cognitive impairment. Recognition of this broader phenotype has implications for clinical diagnostic testing and efforts to understand the underlying aetiology of this syndrome.
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