HeMPPCAT: Mixtures of Probabilistic Principal Component Analysers for Data with Heteroscedastic Noise

Mixtures of probabilistic principal component analysis (MPPCA) is a well-known mixture model extension of principal component analysis (PCA). Similar to PCA, MPPCA assumes the data samples in each mixture contain homoscedastic noise. However, datasets with heterogeneous noise across samples are becoming increasingly common, as larger datasets are generated by collecting samples from several sources with varying noise profiles. The performance of MPPCA is suboptimal for data with heteroscedastic noise across samples. This paper proposes a heteroscedastic mixtures of probabilistic PCA technique (HeMPPCAT) that uses a generalized expectation-maximization (GEM) algorithm to jointly estimate the unknown underlying factors, means, and noise variances under a heteroscedastic noise setting. Simulation results illustrate the improved factor estimates and clustering accuracies of HeMPPCAT compared to MPPCA

Laser-written tunable liquid crystal aberration correctors

In this Article, we present a series of novel laser-written liquid crystal (LC) devices for aberration control for applications in beam shaping or aberration correction through adaptive optics. Each transparent LC device can correct for a chosen aberration mode with continuous greyscale tuning up to a total magnitude of more than 2π radians phase difference peak to peak at a wavelength of λ = 660 nm. For the purpose of demonstration, we present five different devices for the correction of five independent Zernike polynomial modes (although the technique could readily be used to manufacture devices based on other modes). Each device is operated by a single electrode pair tuned between 0 and 10 V. These devices have potential as a low-cost alternative to spatial light modulators for applications where a low-order aberration correction is sufficient and transmissive geometries are required

Bifunctional atomically dispersed ruthenium electrocatalysts for efficient bipolar membrane water electrolysis

Atomically dispersed catalysts (ADCs) have recently drawn considerable interest for use in water electrolysis to produce hydrogen, because they allow for maximal utilization of metal species, particularly the expensive and scarce platinum group metals. Herein, we report the electrocatalytic performance of atomically dispersed ruthenium catalysts (Ru ADCs) with ultralow Ru loading (0.2 wt%). The as-obtained Ru ADCs (Ru (0.2)-NC) are active for both hydrogen evolution reaction (HER) and oxygen evolution reaction (OER), which only require a low overpotential (η) of 47.1 and 72.8 mV to deliver 10 mA cm for HER in 0.5 M HSO and 1.0 M KOH, respectively, and of 300 mV for OER in 1.0 M KOH, showing favorable bifunctionality. Density functional theory (DFT) calculations reveal that the Ru-N bonding plays an important role in lowering the energy barrier of the reactions, boosting the HER and OER activities. Furthermore, the bipolar membrane (BPM) water electrolysis using the bifunctional Ru (0.2)-NC as both HER and OER catalysts can afford 10 mA cm under a low cell voltage of only 0.89 V, and does not show any performance decay upon 100 h continuous operation, showing great potential for energy-saving hydrogen production.L. L. acknowledges the financial support from the National Innovation Agency of Portugal through the Mobilizador Programme (Baterias 2030, Grant No. POCI-01-0247-FEDER-046109). B. L. acknowledges the Natural Science Foundation of LiaoNing Province, China (Grant No. 20180510014) for funding. Z. P. Y. is grateful for the scholarship offered by the China Scholarship Council (Grant No. 201806150015). This work was also in part financially supported by: LA/P/0045/2020 (ALiCE), UIDB/50020/2020 and UIDP/50020/2020 (LSRE-LCM) funded by national funds through FCT/MCTES (PIDDAC); project 2DMAT4FUEL (POCI-01-0145-FEDER-029600 - COMPETE2020 – FCT/MCTES - PIDDAC, Portugal). In addition, this work was carried out in part through the use of the INL Advanced Electron Microscopy, Imaging and Spectroscopy (AEMIS) Facility

Reproducible copy number variation patterns among single circulating tumor cells of lung cancer patients

Circulating tumor cells (CTCs) enter peripheral blood from primary tumors and seed metastases. The genome sequencing of CTCs could offer noninvasive prognosis or even diagnosis, but has been hampered by low single-cell genome coverage of scarce CTCs. Here, we report the use of the recently developed multiple annealing and looping-based amplification cycles for whole-genome amplification of single CTCs from lung cancer patients. We observed characteristic cancer-associated single-nucleotide variations and insertions/deletions in exomes of CTCs. These mutations provided information needed for individualized therapy, such as drug resistance and phenotypic transition, but were heterogeneous from cell to cell. In contrast, every CTC from an individual patient, regardless of the cancer subtypes, exhibited reproducible copy number variation (CNV) patterns, similar to those of the metastatic tumor of the same patient. Interestingly, different patients with the same lung cancer adenocarcinoma (ADC) shared similar CNV patterns in their CTCs. Even more interestingly, patients of small-cell lung cancer have CNV patterns distinctly different from those of ADC patients. Our finding suggests that CNVs at certain genomic loci are selected for the metastasis of cancer. The reproducibility of cancer-specific CNVs offers potential for CTC-based cancer diagnostics.Chemistry and Chemical Biolog

RESCUE OF HIPPO CO-ACTIVATOR YAP1 TRIGGERS DNA DAMAGE-INDUCED APOPTOSIS IN HEMATOLOGICAL CANCERS

Oncogene–induced DNA damage elicits genomic instability in epithelial cancer cells, but apoptosis is blocked through inactivation of the tumor suppressor p53. In hematological cancers, the relevance of ongoing DNA damage and mechanisms by which apoptosis is suppressed are largely unknown. We found pervasive DNA damage in hematologic malignancies including multiple myeloma, lymphoma and leukemia, which leads to activation of a p53–independent, pro-apoptotic network centered on nuclear relocalization of ABL1 kinase. Although nuclear ABL1 triggers cell death through its interaction with the Hippo pathway co–activator YAP1 in normal cells, we show that low YAP1 levels prevent nuclear ABL1–induced apoptosis in these hematologic malignancies. YAP1 is under the control of a serine–threonine kinase, STK4. Importantly, genetic inactivation of STK4 restores YAP1 levels, triggering cell death in vitro and in vivo. Our data therefore identify a novel synthetic–lethal strategy to selectively target cancer cells presenting with endogenous DNA damage and low YAP1 levels

Prevention and Mitigation of Acute Radiation Syndrome in Mice by Synthetic Lipopeptide Agonists of Toll-Like Receptor 2 (TLR2)

Bacterial lipoproteins (BLP) induce innate immune responses in mammals by activating heterodimeric receptor complexes containing Toll-like receptor 2 (TLR2). TLR2 signaling results in nuclear factor-kappaB (NF-κB)-dependent upregulation of anti-apoptotic factors, anti-oxidants and cytokines, all of which have been implicated in radiation protection. Here we demonstrate that synthetic lipopeptides (sLP) that mimic the structure of naturally occurring mycoplasmal BLP significantly increase mouse survival following lethal total body irradiation (TBI) when administered between 48 hours before and 24 hours after irradiation. The TBI dose ranges against which sLP are effective indicate that sLP primarily impact the hematopoietic (HP) component of acute radiation syndrome. Indeed, sLP treatment accelerated recovery of bone marrow (BM) and spleen cellularity and ameliorated thrombocytopenia of irradiated mice. sLP did not improve survival of irradiated TLR2-knockout mice, confirming that sLP-mediated radioprotection requires TLR2. However, sLP was radioprotective in chimeric mice containing TLR2-null BM on a wild type background, indicating that radioprotection of the HP system by sLP is, at least in part, indirect and initiated in non-BM cells. sLP injection resulted in strong transient induction of multiple cytokines with known roles in hematopoiesis, including granulocyte colony-stimulating factor (G-CSF), keratinocyte chemoattractant (KC) and interleukin-6 (IL-6). sLP-induced cytokines, particularly G-CSF, are likely mediators of the radioprotective/mitigative activity of sLP. This study illustrates the strong potential of LP-based TLR2 agonists for anti-radiation prophylaxis and therapy in defense and medical scenarios

Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors1,2, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Metabolic and Functional Genomic Studies Identify Deoxythymidylate Kinase as a Target in LKB1-Mutant Lung Cancer

The LKB1/STK11 tumor suppressor encodes a serine/threonine kinase which coordinates cell growth, polarity, motility, and metabolism. In non-small cell lung cancer, LKB1 is somatically inactivated in 25-30% of cases, often concurrently with activating KRAS mutation. Here, we employed an integrative approach to define novel therapeutic targets in KRAS-driven LKB1 mutant lung cancers. High-throughput RNAi screens in lung cancer cell lines from genetically engineered mouse models driven by activated KRAS with or without coincident Lkb1 deletion led to the identification of Dtymk, encoding deoxythymidylate kinase which catalyzes dTTP biosynthesis, as synthetically lethal with Lkb1 deficiency in mouse and human lung cancer lines. Global metabolite profiling demonstrated that Lkb1-null cells had striking decreases in multiple nucleotide metabolites as compared to the Lkb1-wt cells. Thus, LKB1 mutant lung cancers have deficits in nucleotide metabolism conferring hypersensitivity to DTYMK inhibition, suggesting that DTYMK is a potential therapeutic target in this aggressive subset of tumors

Hydrogen Epoch of Reionization Array (HERA) Phase II Deployment and Commissioning

This paper presents the design and deployment of the Hydrogen Epoch of Reionization Array (HERA) phase II system. HERA is designed as a staged experiment targeting 21 cm emission measurements of the Epoch of Reionization. First results from the phase I array are published as of early 2022, and deployment of the phase II system is nearing completion. We describe the design of the phase II system and discuss progress on commissioning and future upgrades. As HERA is a designated Square Kilometre Array pathfinder instrument, we also show a number of “case studies” that investigate systematics seen while commissioning the phase II system, which may be of use in the design and operation of future arrays. Common pathologies are likely to manifest in similar ways across instruments, and many of these sources of contamination can be mitigated once the source is identified