This book addresses a question fundamental to any discussion of grammatical theory and grammatical variation: to what extent can principles of grammar be explained through language use? The book ...argues that there is a profound correspondence between performance data and the fixed conventions of grammars. Preferences and patterns found in the one, the book shows, are reflected in constraints and variation patterns in the other. The theoretical consequences of the proposed ‘performance-grammar correspondence hypothesis’ are far-reaching — for current grammatical formalisms, for the innateness hypothesis, and for psycholinguistic models of performance and learning. Drawing on empirical generalizations and insights from language typology, generative grammar, psycholinguistics, and historical linguistics, this book demonstrates that the assumption that grammars are immune to performance is false. It presents detailed empirical case studies and arguments for an alternative theory in which performance has shaped the conventions of grammars and thus the variation patterns found in the world’s languages. The innateness of language, the book argues, resides primarily in the mechanisms human beings have for processing and learning it.
Patients with chronic limb-threatening ischemia (CLTI) require revascularization to improve limb perfusion and thereby limit the risk of amputation. It is uncertain whether an initial strategy of ...endovascular therapy or surgical revascularization for CLTI is superior for improving limb outcomes.
In this international, randomized trial, we enrolled 1830 patients with CLTI and infrainguinal peripheral artery disease in two parallel-cohort trials. Patients who had a single segment of great saphenous vein that could be used for surgery were assigned to cohort 1. Patients who needed an alternative bypass conduit were assigned to cohort 2. The primary outcome was a composite of a major adverse limb event - which was defined as amputation above the ankle or a major limb reintervention (a new bypass graft or graft revision, thrombectomy, or thrombolysis) - or death from any cause.
In cohort 1, after a median follow-up of 2.7 years, a primary-outcome event occurred in 302 of 709 patients (42.6%) in the surgical group and in 408 of 711 patients (57.4%) in the endovascular group (hazard ratio, 0.68; 95% confidence interval CI, 0.59 to 0.79; P<0.001). In cohort 2, a primary-outcome event occurred in 83 of 194 patients (42.8%) in the surgical group and in 95 of 199 patients (47.7%) in the endovascular group (hazard ratio, 0.79; 95% CI, 0.58 to 1.06; P = 0.12) after a median follow-up of 1.6 years. The incidence of adverse events was similar in the two groups in the two cohorts.
Among patients with CLTI who had an adequate great saphenous vein for surgical revascularization (cohort 1), the incidence of a major adverse limb event or death was significantly lower in the surgical group than in the endovascular group. Among the patients who lacked an adequate saphenous vein conduit (cohort 2), the outcomes in the two groups were similar. (Funded by the National Heart, Lung, and Blood Institute; BEST-CLI ClinicalTrials.gov number, NCT02060630.).
CRISPR-Cas nucleoproteins target foreign DNA via base pairing with a crRNA. However, a quantitative description of protein binding and nuclease activation at off-target DNA sequences remains elusive. ...Here, we describe a chip-hybridized association-mapping platform (CHAMP) that repurposes next-generation sequencing chips to simultaneously measure the interactions between proteins and ∼107 unique DNA sequences. Using CHAMP, we provide the first comprehensive survey of DNA recognition by a type I-E CRISPR-Cas (Cascade) complex and Cas3 nuclease. Analysis of mutated target sequences and human genomic DNA reveal that Cascade recognizes an extended protospacer adjacent motif (PAM). Cascade recognizes DNA with a surprising 3-nt periodicity. The identity of the PAM and the PAM-proximal nucleotides control Cas3 recruitment by releasing the Cse1 subunit. These findings are used to develop a model for the biophysical constraints governing off-target DNA binding. CHAMP provides a framework for high-throughput, quantitative analysis of protein-DNA interactions on synthetic and genomic DNA.
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•CHAMP enables massively parallel profiling of protein-nucleic acid interactions•CHAMP was used to measure off-target DNA binding by a CRISPR-Cas complex•Cascade decodes extended PAMs and binds DNA with a 3-nt periodicity•Cas3 binding is dependent on the PAM and PAM-proximal crRNA-DNA mismatches
Discarded next-gen sequencing chips provide a platform for analyzing protein-DNA interactions that reveals a novel proofreading mechanism used by the Cascade/Cas3 complex.
Rhabdomyosarcoma is a soft-tissue sarcoma with molecular and cellular features of developing skeletal muscle. Rhabdomyosarcoma has two major histologic subtypes, embryonal and alveolar, each with ...distinct clinical, molecular, and genetic features. Genomic analysis shows that embryonal tumors have more structural and copy number variations than alveolar tumors. Mutations in the RAS/NF1 pathway are significantly associated with intermediate- and high-risk embryonal rhabdomyosarcomas (ERMS). In contrast, alveolar rhabdomyosarcomas (ARMS) have fewer genetic lesions overall and no known recurrently mutated cancer consensus genes. To identify therapeutics for ERMS, we developed and characterized orthotopic xenografts of tumors that were sequenced in our study. High-throughput screening of primary cultures derived from those xenografts identified oxidative stress as a pathway of therapeutic relevance for ERMS.
•There are higher rates of mutation in ERMS than in ARMS tumors•RAS pathway mutations are associated with intermediate- and high-risk ERMS•ERMS tumor cells have elevated oxidative stress•ERMS tumors are sensitive to drugs that target oxidative stress
The evolution of fungicide resistance Lucas, John A; Hawkins, Nichola J; Fraaije, Bart A
Advances in applied microbiology,
01/2015, Letnik:
90
Journal Article
Recenzirano
Fungicides are widely used in developed agricultural systems to control disease and safeguard crop yield and quality. Over time, however, resistance to many of the most effective fungicides has ...emerged and spread in pathogen populations, compromising disease control. This review describes the development of resistance using case histories based on four important diseases of temperate cereal crops: eyespot (Oculimacula yallundae and Oculimacula acuformis), Septoria tritici blotch (Zymoseptoria tritici), powdery mildew (Blumeria graminis), and Fusarium ear blight (a complex of Fusarium and Microdochium spp). The sequential emergence of variant genotypes of these pathogens with reduced sensitivity to the most active single-site fungicides, methyl benzimidazole carbamates, demethylation inhibitors, quinone outside inhibitors, and succinate dehydrogenase inhibitors illustrates an ongoing evolutionary process in response to the introduction and use of different chemical classes. Analysis of the molecular mechanisms and genetic basis of resistance has provided more rapid and precise methods for detecting and monitoring the incidence of resistance in field populations, but when or where resistance will occur remains difficult to predict. The extent to which the predictability of resistance evolution can be improved by laboratory mutagenesis studies and fitness measurements, comparison between pathogens, and reconstruction of evolutionary pathways is discussed. Risk models based on fungal life cycles, fungicide properties, and exposure to the fungicide are now being refined to take account of additional traits associated with the rate of pathogen evolution. Experimental data on the selection of specific mutations or resistant genotypes in pathogen populations in response to fungicide treatments can be used in models evaluating the most effective strategies for reducing or preventing resistance. Resistance management based on robust scientific evidence is vital to prolong the effective life of fungicides and safeguard their future use in crop protection.
Diagnostic imaging of cardiac amyloidosis Martinez-Naharro, Ana; Baksi, A John; Hawkins, Philip N ...
Nature reviews cardiology,
07/2020, Letnik:
17, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Systemic amyloidosis encompasses a debilitating, under-diagnosed but increasingly recognized group of disorders characterized by the extracellular deposition of misfolded proteins in one or more ...organs. Cardiac amyloid deposition leads to an infiltrative or restrictive cardiomyopathy and is the major contributor to poor prognosis in patients with systemic amyloidosis. In total, >30 proteins can form amyloid fibrils, but the two main types of amyloid that can infiltrate the heart are monoclonal immunoglobulin light-chain amyloid and transthyretin amyloid. Cardiac amyloidosis can be acquired in older individuals or inherited from birth. Given the nonspecific symptoms of these disorders, a high index of suspicion is paramount in making the correct diagnosis, which can involve the use of non-invasive imaging methods such as echocardiography, bone scintigraphy and cardiovascular MRI. In the past decade, the use of cardiovascular MRI with tissue characterization and bone scintigraphy to diagnose cardiac amyloidosis has revolutionized our understanding of the disease, leading to changes in patient care. However, a need remains for improved awareness and expertise, and greater clinical suspicion, because the initial clues provided by electrocardiography and echocardiography might not be typical. With specific treatments now available, timely diagnosis of cardiac amyloidosis is more important than ever. In this Review, we discuss the current and novel approaches for the diagnostic imaging of cardiac amyloidosis.
Many large-scale, high-throughput experiments use DNA barcodes, short DNA sequences prepended to DNA libraries, for identification of individuals in pooled biomolecule populations. However, DNA ...synthesis and sequencing errors confound the correct interpretation of observed barcodes and can lead to significant data loss or spurious results. Widely used error-correcting codes borrowed from computer science (e.g., Hamming, Levenshtein codes) do not properly account for insertions and deletions (indels) in DNA barcodes, even though deletions are the most common type of synthesis error. Here, we present and experimentally validate filled/truncated right end edit (FREE) barcodes, which correct substitution, insertion, and deletion errors, even when these errors alter the barcode length. FREE barcodes are designed with experimental considerations in mind, including balanced guanine-cytosine (GC) content, minimal homopolymer runs, and reduced internal hairpin propensity. We generate and include lists of barcodeswith different lengths and error correction levels thatmay be useful in diverse high-throughput applications, including >10⁶ single-error–correcting 16-mers that strike a balance between decoding accuracy, barcode length, and library size. Moreover, concatenating two or more FREE codes into a single barcode increases the available barcode space combinatorially, generating lists with >1015 errorcorrecting barcodes. The included software for creating barcode libraries and decoding sequenced barcodes is efficient and designed to be user-friendly for the general biology community.
Synthetic DNA is rapidly emerging as a durable, high-density information storage platform. A major challenge for DNA-based information encoding strategies is the high rate of errors that arise during ...DNA synthesis and sequencing. Here, we describe the HEDGES (Hash Encoded, Decoded by Greedy Exhaustive Search) error-correcting code that repairs all three basic types of DNA errors: insertions, deletions, and substitutions. HEDGES also converts unresolved or compound errors into substitutions, restoring synchronization for correction via a standard Reed–Solomon outer code that is interleaved across strands. Moreover, HEDGES can incorporate a broad class of user-defined sequence constraints, such as avoiding excess repeats, or too high or too low windowed guanine–cytosine (GC) content. We test our code both via in silico simulations and with synthesized DNA. From its measured performance, we develop a statistical model applicable to much larger datasets. Predicted performance indicates the possibility of error-free recovery of petabyte- and exabyte-scale data from DNA degraded with as much as 10% errors. As the cost of DNA synthesis and sequencing continues to drop, we anticipate that HEDGES will find applications in large-scale error-free information encoding.
Cardiac magnetic resonance (CMR) is a sensitive noninvasive method for detecting intracardiac thrombi, offering a comparable and equally specific alternative to TEE for evaluation of thrombus in the ...left atrial appendage (LAA) (2). The presence of intracardiac thrombi was significantly higher in patients with more severe biventricular systolic dysfunction (stroke volume p < 0.01; ejection fraction p < 0.05; mitral annular plane systolic excursion p < 0.01; tricuspid annular plane systolic excursion p < 0.01; and global longitudinal strain p < 0.01), atrial dilatation (left atrium p < 0.05; right atrium p < 0.01), and more severe degree of amyloid infiltration (ECV p < 0.01). Intracardiac thrombi were also found in a significant number of patients in sinus rhythm, meriting further research to determine whether these patients benefit from prophylactic anticoagulation.
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