A recently developed matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) method to spatially profile the location and distribution of multiple N-linked glycan species in ...frozen tissues has been extended and improved for the direct analysis of glycans in clinically derived formalin-fixed paraffin-embedded (FFPE) tissues. Formalin-fixed tissues from normal mouse kidney, human pancreatic and prostate cancers, and a human hepatocellular carcinoma tissue microarray were processed by antigen retrieval followed by on-tissue digestion with peptide N-glycosidase F. The released N-glycans were detected by MALDI-IMS analysis, and the structural composition of a subset of glycans could be verified directly by on-tissue collision-induced fragmentation. Other structural assignments were confirmed by off-tissue permethylation analysis combined with multiple database comparisons. Imaging of mouse kidney tissue sections demonstrates specific tissue distributions of major cellular N-linked glycoforms in the cortex and medulla. Differential tissue distribution of N-linked glycoforms was also observed in the other tissue types. The efficacy of using MALDI-IMS glycan profiling to distinguish tumor from non-tumor tissues in a tumor microarray format is also demonstrated. This MALDI-IMS workflow has the potential to be applied to any FFPE tissue block or tissue microarray to enable higher throughput analysis of the global changes in N-glycosylation associated with cancers.
We introduce ProjectQ, an open source software effort for quantum computing. The first release features a compiler framework capable of targeting various types of hardware, a high-performance ...simulator with emulation capabilities, and compiler plug-ins for circuit drawing and resource estimation. We introduce our Python-embedded domain-specific language, present the features, and provide example implementations for quantum algorithms. The framework allows testing of quantum algorithms through simulation and enables running them on actual quantum hardware using a back-end connecting to the IBM Quantum Experience cloud service. Through extension mechanisms, users can provide back-ends to further quantum hardware, and scientists working on quantum compilation can provide plug-ins for additional compilation, optimization, gate synthesis, and layout strategies.
The quantum computation of electronic energies can break the curse of dimensionality that plagues many-particle quantum mechanics. It is for this reason that a universal quantum computer has the ...potential to fundamentally change computational chemistry and materials science, areas in which strong electron correlations present severe hurdles for traditional electronic structure methods. Here we present a state-of-the-art analysis of accurate energy measurements on a quantum computer for computational catalysis, using improved quantum algorithms with more than an order of magnitude improvement over the best previous algorithms. As a prototypical example of local catalytic chemical reactivity we consider the case of a ruthenium catalyst that can bind, activate, and transform carbon dioxide to the high-value chemical methanol. We aim at accurate resource estimates for the quantum computing steps required for assessing the electronic energy of key intermediates and transition states of its catalytic cycle. In particular, we present quantum algorithms for double-factorized representations of the four-index integrals that can significantly reduce the computational cost over previous algorithms, and we discuss the challenges of increasing active space sizes to accurately deal with dynamical correlations. We address the requirements for future quantum hardware in order to make a universal quantum computer a successful and reliable tool for quantum computing enhanced computational materials science and chemistry, and identify open questions for further research.
Purpose An optimal prostate biopsy in clinical practice is based on a balance among adequate detection of clinically significant prostate cancers (sensitivity), assuredness regarding the accuracy of ...negative sampling (negative predictive value), limited detection of clinically insignificant cancers and good concordance with whole gland surgical pathology results to allow accurate risk stratification and disease localization for treatment selection. Inherent within this optimization is variation of the core number, location, labeling and processing for pathological evaluation. To date, there is no consensus in this regard. The purpose of this review is to 1) define the optimal number and location of biopsy cores during primary prostate biopsy among men with suspected prostate cancer, 2) define the optimal method of labeling prostate biopsy cores for pathological processing which will provide relevant and necessary clinical information for all potential clinical scenarios, and 3) determine the maximal number of prostate biopsy cores allowable within a specimen jar which would not preclude accurate histological evaluation of the tissue. Materials and Methods A bibliographic search using PubMed® covering the period up to July 2012 yielded approximately 550 articles. Articles were reviewed and categorized based on which of the 3 objectives of this review was addressed. Data were extracted, analyzed and summarized. Recommendations are provided based on this literature review and our clinical experience. Results The use of 10 to 12-core extended sampling protocols increases cancer detection rates compared to traditional sextant sampling methods and reduces the likelihood of repeat biopsy by increasing negative predictive value, ultimately allowing more accurate risk stratification without increasing the likelihood of detecting insignificant cancers. As the number of cores increases above 12, the increase in diagnostic yield becomes marginal. Only limited evidence supports the use of initial biopsy schemes involving more than 12 cores or saturation. Apical and laterally directed sampling of the peripheral zone increases cancer detection rate, reduces the need for repeat biopsies and predicts pathological features on prostatectomy while transition zone biopsies do not. There are little data to suggest that knowing the exact site of an individual positive biopsy core provides meaningful clinical information. However, determining laterality of cancer on biopsy may be helpful for predicting sites of extracapsular extension and therapeutic planning. Placement of multiple biopsy cores in a single container (greater than 2) appears to compromise pathological evaluation, which can reduce cancer detection rate and increase the likelihood of equivocal diagnoses. Conclusions A 12-core systematic biopsy that incorporates apical and far-lateral cores in the template distribution allows maximal cancer detection, avoids repeat biopsy, and provides information adequate for identifying men who need therapy and planning that therapy while minimizing the detection of occult, indolent prostate cancers. This literature review does not provide compelling evidence that individual site specific labeling of cores benefits clinical decision making regarding the management of prostate cancer. Based on the available literature, we recommend packaging no more than 2 cores in each jar to avoid reduction of the cancer detection rate through inadequate tissue sampling.
In Troyer and Kutas (2018), individual differences in knowledge of the world of Harry Potter (HP) rapidly modulated individuals' average electrical brain potentials to contextually supported words in ...sentence endings. Using advances in single-trial electroencephalogram analysis, we examined whether this relationship is strictly a result of domain knowledge mediating the proportion of facts each participant knew; we find it is not. Participants read sentences ending in a contextually supported word, reporting online whether they had known each fact. Participants' reports correlated with HP domain knowledge and reliably modulated event-related brain potentials to sentence-final words within 250 ms. Critically, domain knowledge had a dissociable influence in the same time window for endings that participants reported not having known and/or were less likely to be known/remembered across participants. We hypothesize that knowledge impacts written word processing primarily by affecting the neural processes of (implicit) retrieval from long-term memory (LTM): Greater knowledge eases otherwise difficult retrieval processes.
The methylotrophic yeast Pichia pastoris is widely used in the manufacture of industrial enzymes and pharmaceuticals. Like most biotechnological production hosts, P. pastoris is heterotrophic and ...grows on organic feedstocks that have competing uses in the production of food and animal feed. In a step toward more sustainable industrial processes, we describe the conversion of P. pastoris into an autotroph that grows on CO2. By addition of eight heterologous genes and deletion of three native genes, we engineer the peroxisomal methanol-assimilation pathway of P. pastoris into a CO2-fixation pathway resembling the Calvin–Benson–Bassham cycle, the predominant natural CO2-fixation pathway. The resulting strain can grow continuously with CO2 as a sole carbon source at a µmax of 0.008 h−1. The specific growth rate was further improved to 0.018 h−1 by adaptive laboratory evolution. This engineered P. pastoris strain may promote sustainability by sequestering the greenhouse gas CO2, and by avoiding consumption of an organic feedstock with alternative uses in food production.A yeast species used to produce proteins and chemicals is engineered to grow solely on the greenhouse gas CO2.
Biomarkers are rapidly gaining importance in personalized medicine. Although numerous molecular signatures have been developed over the past decade, there is a lack of overlap and many biomarkers ...fail to validate in independent patient cohorts and hence are not useful for clinical application. For these reasons, identification of novel and robust biomarkers remains a formidable challenge. We combine targeted proteomics with computational biology to discover robust proteomic signatures for prostate cancer. Quantitative proteomics conducted in expressed prostatic secretions from men with extraprostatic and organ-confined prostate cancers identified 133 differentially expressed proteins. Using synthetic peptides, we evaluate them by targeted proteomics in a 74-patient cohort of expressed prostatic secretions in urine. We quantify a panel of 34 candidates in an independent 207-patient cohort. We apply machine-learning approaches to develop clinical predictive models for prostate cancer diagnosis and prognosis. Our results demonstrate that computationally guided proteomics can discover highly accurate non-invasive biomarkers.
Reducing the incidence and mortality rates for clear cell renal cell carcinoma (ccRCC) remains a significant clinical challenge with poor 5‐year survival rates. A unique tissue cohort was assembled ...of matched ccRCC and distal nontumor tissues (n = 20) associated with moderate risk of disease progression, half of these from individuals who progressed to metastatic disease and the other half who remained disease free. These tissues were used for MALDI imaging MS profiling of proteins in the 2–20 kDa range, resulting in a panel of 108 proteins that had potential disease‐specific expression patterns. Protein lysates from the same tissues were analyzed by MS/MS, resulting in identification of 56 proteins of less than 20 kDa molecular weight. The same tissues were also used for global lipid profiling analysis by MALDI‐FT‐ICR MS. From the cumulative protein and lipid expression profile data, a refined panel of 26 proteins and 39 lipid species was identified that could either distinguish tumor from nontumor tissues, or tissues from recurrent disease progressors from nonrecurrent disease individuals. This approach has the potential to not only improve prognostic assessment and enhance postoperative surveillance, but also to inform on the underlying biology of ccRCC progression.
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