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Inflammatory response heterogeneity has impeded high-resolution dissection of diverse immune cell populations during activation. We characterize mouse cutaneous immune cells by single-cell RNA sequencing, after inducing inflammati...
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Inflammatory response heterogeneity has impeded high-resolution dissection of diverse immune cell populations during activation. We characterize mouse cutaneous immune cells by single-cell RNA sequencing, after inducing inflammation using imiquimod and oxazolone dermatitis models. We identify 13 CD45+subpopulations, which broadly represent most functionally characterized immune cell types. Oxazolone pervasively upregulatesJak2/Stat3expression across T?cells and antigen-presenting cells (APCs). Oxazolone also inducesIl4/Il13expression in newly infiltrating basophils, andIl4raandCcl24,most prominently in APCs. In contrast, imiquimod broadly upregulatesIl17/Il22andCcl4/Ccl5. A comparative analysis of single-cell inflammatory transcriptional responses reveals that APC response to oxazolone is tightly restricted by cell identity, whereas imiquimod enforces shared programs on multiple APC populations in parallel. These global molecular patterns not only contrast immune responses on a systems level but also suggest that the mechanisms of new sources of inflammation can eventually be deduced by comparison to known signatures.
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Immunotherapy is among the most rapidly evolving treatment strategies in oncology. The therapeutic potential of immune-checkpoint inhibitors is exemplified by the recent hail of Food and Drug Administration (FDA) approvals for the...
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Immunotherapy is among the most rapidly evolving treatment strategies in oncology. The therapeutic potential of immune-checkpoint inhibitors is exemplified by the recent hail of Food and Drug Administration (FDA) approvals for their use in various malignancies. Continued efforts to enhance outcomes with immunotherapy agents have led to the formulation of advanced treatment strategies. Recent evidence from pre-clinical studies evaluating immune-checkpoint inhibitors in various cancer cell-lines has suggested that combinatorial approaches may have superior survival outcomes compared to single-agent immunotherapy regimens. Preliminary trials assessing combination therapy with anti-PD-1/PD-L1 plus anti-CTLA-4 immune-checkpoint inhibitors have documented considerable advantages in survival indices over single-agent immunotherapy. The therapeutic potential of combinatorial approaches is highlighted by the recent FDA approval of nivolumab plus ipilimumab for patients with advanced melanoma. Presently, dual-immune checkpoint inhibition with anti-programmed death receptor-1/programmed cell death receptor- ligand-1 (anti-PD-1/PD-L1) plus anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-4) monoclonal antibodies (MoAbs) is being evaluated for a wide range of tumor histologies. Furthermore, several ongoing clinical trials are investigating combination checkpoint inhibition in association with traditional treatment modalities such as chemotherapy, surgery, and radiation. In this review, we summarize the current landscape of combination therapy with anti-PD-1/PD-L1 plus anti-CTLA-4 MoAbs for patients with melanoma and non-small cell lung cancer (NSCLC). We present a synopsis of the prospects for expanding the indications of dual immune-checkpoint inhibition therapy to a more diverse set of tumor histologies.
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Inappropriate CD4 T helper (Th) differentiation can compromise host immunity or promote autoimmune disease. To identify disease-relevant regulators of T?cell fate, we examined mutations that modify risk for multiple sclerosis (MS)...
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Inappropriate CD4 T helper (Th) differentiation can compromise host immunity or promote autoimmune disease. To identify disease-relevant regulators of T?cell fate, we examined mutations that modify risk for multiple sclerosis (MS), a canonical organ-specific autoimmune disease. This analysis identified a role for Zinc finger E-box-binding homeobox (ZEB1). Deletion of ZEB1 protects against experimental autoimmune encephalitis (EAE), a mouse model of multiple sclerosis (MS). Mechanistically, ZEB1 in CD4 T?cells is required for pathogenic Th1 and Th17 differentiation. Genomic analyses of paired human and mouse expression data elucidated an unexpected role for ZEB1 in JAK-STAT signaling. ZEB1 inhibits miR-101-3p that represses JAK2 expression, STAT3/STAT4 phosphorylation, and subsequent expression of interleukin-17 (IL-17) and interferon gamma (IFN-γ). Underscoring its clinical relevance, ZEB1 and JAK2 downregulation decreases pathogenic cytokines expression in T?cells from MS patients. Moreover, a Food and Drug Administration (FDA)-approved JAK2 inhibitor is effective in EAE. Collectively, these findings identify a conserved, potentially targetable mechanism regulating disease-relevant inflammation.
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Due to the increasing emergence of drug-resistant pathogenic microorganisms, there is a world-wide quest to develop new-generation antibiotics. Antimicrobial peptides (AMPs) are small peptides with a broad spectrum of antibiotic a...
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Due to the increasing emergence of drug-resistant pathogenic microorganisms, there is a world-wide quest to develop new-generation antibiotics. Antimicrobial peptides (AMPs) are small peptides with a broad spectrum of antibiotic activities against bacteria, fungi, protozoa, viruses and sometimes exhibit cytotoxic activity toward cancer cells. As a part of the native host defense system, most AMPs target the membrane integrity of the microorganism, leading to cell death by lysis. These membrane lytic effects are often toxic to mammalian cells and restrict their systemic application. However, AMPs containing predominantly either tryptophan or proline can kill microorganisms by targeting intracellular pathways and are therefore a promising source of next-generation antibiotics. A minimum length of six amino acids is required for high antimicrobial activity in tryptophan-rich AMPs and the position of these residues also affects their antimicrobial activity. The aromatic side chain of tryptophan is able to rapidly form hydrogen bonds with membrane bilayer components. Proline-rich AMPs interact with the 70S ribosome and disrupt protein synthesis. In addition, they can also target the heat shock protein in target pathogens, and consequently lead to protein misfolding. In this review, we will focus on describing the structures, sources, and mechanisms of action of the aforementioned AMPs.
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Trametes pubescens, white rot fungus, has been used for folk medicine in Asian countries to treat ailments such as cancer and gastrointestinal diseases. This study was initiated to evaluate the in vitro antioxidant, anti-diabetes,...
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Trametes pubescens, white rot fungus, has been used for folk medicine in Asian countries to treat ailments such as cancer and gastrointestinal diseases. This study was initiated to evaluate the in vitro antioxidant, anti-diabetes, anti-dementia, and anti-inflammatory activities of T. pubescens fruiting bodies. The 1,1-diphenyl-2-picryl-hydrazyl (DPPH) free radical scavenging activities of T. pubescens methanol (ME) and hot water (HWE) extracts (2.0 mg/mL) were comparable to butylated hydroxytoluene (BHT), the positive control. However, the chelating effects of ME and HWE were significantly higher than that of BHT. The HWE (6 mg/mL) also showed comparable reducing power to BHT. Eleven phenol compounds were detected by high performance liquid chromatography (HPLC) analysis. The α-amylase and α-glucosidase inhibitory activities of the ME and HWE of the mushroom were lower than Acarbose, the standard reference; however, the inhibitory effects of the mushroom extracts at 2.0 mg/mL were moderate. The acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory effects of ME and HWE were moderate and comparable with galanthamine, the standard drug to treat early stages of Alzheimer’s disease (AD). The ME had a neuroprotective effect against glutamate-induced PC-12 cell cytotoxicity at the concentration range of 2–40 μg/mL. The mushroom extracts also showed inflammation inhibitory activities such as production of nitric oxide (NO) and expression of inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS)-induced murine macrophage-like cell lines (RAW 264.7) and significantly suppressed the carrageenan-induced rat paw-edema. Therefore, fruiting body extracts of T. pubescens demonstrated antioxidant related anti-diabetes, anti-dementia and anti-inflammatory activities. View Full-Text
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The homeostatic mechanisms that fail to restrain chronic tissue inflammation in diseases, such as psoriasis vulgaris, remain incompletely understood. We profiled transcriptomes and epitopes of single psoriatic and normal skin-resi...
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The homeostatic mechanisms that fail to restrain chronic tissue inflammation in diseases, such as psoriasis vulgaris, remain incompletely understood. We profiled transcriptomes and epitopes of single psoriatic and normal skin-resident T cells, revealing a gradated transcriptional program of coordinately regulated inflammation-suppressive genes. This program, which is sharply suppressed in lesional skin, strikingly restricts Th17/Tc17 cytokine and other inflammatory mediators on the single-cell level. CRISPR-based deactivation of two core components of this inflammation-suppressive program, ZFP36L2 and ZFP36, replicates the interleukin-17A (IL-17A), granulocyte macrophage-colony-stimulating factor (GM-CSF), and interferon gamma (IFNγ) elevation in psoriatic memory T cells deficient in these transcripts, functionally validating their influence. Combinatoric expression analysis indicates the suppression of specific inflammatory mediators by individual program members. Finally, we find that therapeutic IL-23 blockade reduces Th17/Tc17 cell frequency in lesional skin but fails to normalize this inflammatory-suppressive program, suggesting how treated lesions may be primed for recurrence after withdrawal of treatment.
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Modern Wi-Fi networks are trending towards using a wider channel bandwidth to achieve high physical layer data rate. The wide channel band experiences fluctuations across the different frequencies, causing diversity in the frequen...
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Modern Wi-Fi networks are trending towards using a wider channel bandwidth to achieve high physical layer data rate. The wide channel band experiences fluctuations across the different frequencies, causing diversity in the frequency domain. Frequency-aware Wi-Fi protocols exploit this frequency diversity and consequently achieve high wireless capacity. However, most of the existing works have not considered quality-of-service (QoS) issues. In this paper, we present a new Wi-Fi protocol called QoS-Fi, that provides QoS for the mobile users in the frequency aware Wi-Fi network. QoS-Fi dynamically assigns orthogonal frequency division multiplexing (OFDM) subchannels for heterogeneous mobile users to meet the QoS demands. To achieve this goal, we apply an OFDM-based variable-length Bloom filter (VBF) that synergistically integrates the channel quality estimation and QoS channel coordination. To the best of our knowledge, this is the first work that employs QoS at the frequency domain for Wi-Fi networks. We study the impact of variable-length signatures in the aspect of throughput maximization and meeting the QoS requirements and further develop a decentralized QoS-aware channel-allocation algorithm that achieves sub-optimal performance. Our USRP/GNURadio-based experiments and trace-driven simulations show that QoS-Fi provides up to 1.39× and 1.29× throughput improvements compared to the legacy EDCA and well-known Knopp and Humblet's and round robin (K&H/RR) scheduling, respectively in the QoS-regimes.
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Modern Wi-Fi networks are trending towards using a wider channel bandwidth to achieve high physical layer data rate. The wide channel band experiences fluctuations across the different frequencies, causing diversity in the frequen...
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Modern Wi-Fi networks are trending towards using a wider channel bandwidth to achieve high physical layer data rate. The wide channel band experiences fluctuations across the different frequencies, causing diversity in the frequency domain. Frequency-aware Wi-Fi protocols exploit this frequency diversity and consequently achieve high wireless capacity. However, most of the existing works have not considered quality-of-service (QoS) issues. In this paper, we present a new Wi-Fi protocol called QoS-Fi, that provides QoS for the mobile users in the frequency aware Wi-Fi network. QoS-Fi dynamically assigns orthogonal frequency division multiplexing (OFDM) subchannels for heterogeneous mobile users to meet the QoS demands. To achieve this goal, we apply an OFDM-based variable-length Bloom filter (VBF) that synergistically integrates the channel quality estimation and QoS channel coordination. To the best of our knowledge, this is the first work that employs QoS at the frequency domain for Wi-Fi networks. We study the impact of variable-length signatures in the aspect of throughput maximization and meeting the QoS requirements and further develop a decentralized QoS-aware channel-allocation algorithm that achieves sub-optimal performance. Our USRP/GNURadio-based experiments and trace-driven simulations show that QoS-Fi provides up to 1.39 × and 1.29 × throughput improvements compared to the legacy EDCA and well-known Knopp and Humblet’s and round robin (K&H/RR) scheduling, respectively in the QoS-regimes.
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Automation software need to be continuously updated by addressing software bugs contained in their repositories. However, bugs have different levels of importance; hence, it is essential to prioritize bug reports based on their se...
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Automation software need to be continuously updated by addressing software bugs contained in their repositories. However, bugs have different levels of importance; hence, it is essential to prioritize bug reports based on their severity and importance. Manually managing the deluge of incoming bug reports faces time and resource constraints from the development team and delays the resolution of critical bugs. Therefore, bug report prioritization is vital. This study proposes a new model for bug prioritization based on average one dependence estimator; it prioritizes bug reports based on severity, which is determined by the number of attributes. The more the number of attributes, the more the severity. The proposed model is evaluated using precision, recall, F1-Score, accuracy, G-Measure, and Matthew’s correlation coefficient. Results of the proposed model are compared with those of the support vector machine (SVM) and Naive Bayes (NB) models. Eclipse and Mozilla datasetswere used as the sources of bug reports. The proposed model improved the bug repository management and outperformed the SVM and NB models. Additionally, the proposed model used a weaker attribute independence supposition than the former models, thereby improving prediction accuracy with minimal computational cost.
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This article presents a 320
$\times $
240 indirect time-of-flight (iToF) CMOS image sensor (CIS) with on-chip motion artifact suppression and background light cancelling (BGLC). The proposed iToF CIS uses a backside-illuminate...
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This article presents a 320
$\times $
240 indirect time-of-flight (iToF) CMOS image sensor (CIS) with on-chip motion artifact suppression and background light cancelling (BGLC). The proposed iToF CIS uses a backside-illuminated trident pinned photodiode (PPD) that assists charge transfer with a built-in lateral electric field for enhanced depth accuracy. To overcome the limitation of the conventional iToF CIS that exhibits motion artifact, we propose a pseudo-four-tap (P4-tap) demodulation method with alternate phase driving using a conventional two-tap pixel structure with a high fill factor of over 43%. In addition, by combining the advantages of both the P4-tap and conventional two-tap demodulation schemes, we propose hybrid depth imaging with reduced motion artifact for moving objects, while providing high-depth precision for the static background. For outdoor mobile applications of the iToF CIS, we integrated on-chip BGLC circuits to eliminate the BGL-induced depth error. A prototype chip is fabricated using a 90-nm backside illumination (BSI) CIS process. The BSI trident PPD enabled a low depth error of under 0.54% over the range of 0.75–4 m, with a modulation frequency of 100 MHz. Motion artifact was suppressed at 60 frames/s of hybrid depth imaging owing to the proposed P4-tap scheme. With the on-chip BGLC circuit, the experimental results demonstrate a 0.55% depth error at a 1-m distance, even under 120-klx BGL illumination.
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