The CRISPR-Cas9 system provides a versatile toolkit for genome engineering that can introduce various DNA lesions at specific genomic locations. However, a better understanding of the nature of these ...lesions and the repair pathways engaged is critical to realizing the full potential of this technology. Here we characterize the different lesions arising from each Cas9 variant and the resulting repair pathway engagement. We demonstrate that the presence and polarity of the overhang structure is a critical determinant of double-strand break repair pathway choice. Similarly, single nicks deriving from different Cas9 variants differentially activate repair: D10A but not N863A-induced nicks are repaired by homologous recombination. Finally, we demonstrate that homologous recombination is required for repairing lesions using double-stranded, but not single-stranded DNA as a template. This detailed characterization of repair pathway choice in response to CRISPR-Cas9 enables a more deterministic approach for designing research and therapeutic genome engineering strategies.
Burkholderia pseudomallei is an aerobic, motile, non-spore-forming gram-negative bacillus found in tropical endemic environments that causes the disease melioidosis. Melioidosis displays a diversity ...of clinical presentations ranging from septic shock to chronic latent infection, often with characteristic abscesses in multiple organs. Melioidosis is an opportunistic infection, with risk factors, including diabetes, alcohol use, chronic lung disease, and chronic renal disease, and these risk factors increase the severity of disease (Wiersinga et al., 2006) 1. In this case report, we illustrate a case of a 32 year old man with several risk factors and recent travel to an endemic region presenting with melioidosis. Our case demonstrates the challenges in obtaining a diagnosis in a non-endemic location, highlights a complex presentation of this disease, and describes the multifaceted clinical management required to care for this patient. As global travel increases, there is an increased need for clinician awareness of this disease in non-endemic regions.
By careful analysis of the embedding of a simplicial set into its image under Kan’s
Ex
∞
functor we obtain a new and combinatorial proof that it is a weak homotopy equivalence. Moreover, we obtain a ...presentation of it as a
strong anodyne extension
. From this description we can quickly deduce some basic facts about
Ex
∞
and hence provide a new construction of the Kan–Quillen model structure on simplicial sets, one which avoids the use of topological spaces or minimal fibrations.
We present a modular semantic account of Bayesian inference algorithms for probabilistic programming languages, as used in data science and machine learning. Sophisticated inference algorithms are ...often explained in terms of composition of smaller parts. However, neither their theoretical justification nor their implementation reflects this modularity. We show how to conceptualise and analyse such inference algorithms as manipulating intermediate representations of probabilistic programs using higher-order functions and inductive types, and their denotational semantics.
Semantic accounts of continuous distributions use measurable spaces. However, our use of higher-order functions presents a substantial technical difficulty: it is impossible to define a measurable space structure over the collection of measurable functions between arbitrary measurable spaces that is compatible with standard operations on those functions, such as function application. We overcome this difficulty using quasi-Borel spaces, a recently proposed mathematical structure that supports both function spaces and continuous distributions.
We define a class of semantic structures for representing probabilistic programs, and semantic validity criteria for transformations of these representations in terms of distribution preservation. We develop a collection of building blocks for composing representations. We use these building blocks to validate common inference algorithms such as Sequential Monte Carlo and Markov Chain Monte Carlo. To emphasize the connection between the semantic manipulation and its traditional measure theoretic origins, we use Kock's synthetic measure theory. We demonstrate its usefulness by proving a quasi-Borel counterpart to the Metropolis-Hastings-Green theorem.
Probability theory can be studied synthetically as the computational effect embodied by a commutative monad. In the recently proposed Markov categories, one works with an abstraction of the Kleisli ...category and then defines deterministic morphisms equationally in terms of copying and discarding. The resulting difference between ‘pure’ and ‘deterministic’ leads us to investigate the ‘sober’ objects for a probability monad, for which the two concepts coincide. We propose natural conditions on a probability monad which allow us to identify the sober objects and define an idempotent sobrification functor. Our framework applies to many examples of interest, including the Giry monad on measurable spaces, and allows us to sharpen a previously given version of de Finetti’s theorem for Markov categories.
Concrete categories and higher-order recursion Matache, Cristina; Moss, Sean; Staton, Sam
Proceedings of the 37th Annual ACM/IEEE Symposium on Logic in Computer Science,
08/2022
Conference Proceeding
We study concrete sheaf models for a call-by-value higher-order language with recursion. Our family of sheaf models is a generalization of many examples from the literature, such as models for ...probabilistic and differentiable programming, and fully abstract logical relations models. We treat recursion in the spirit of synthetic domain theory. We provide a general construction of a lifting monad starting from a class of admissible monomorphisms in the site of the sheaf category. In this way, we obtain a family of models parametrized by a concrete site and a class of monomorphisms, for which we prove a general computational adequacy theorem.
Solid organ transplant (SOT) recipients are a complex, immunocompromised population in whom greater coronavirus disease 2019 (COVID-19) mortality has been reported compared with the general ...population.
We examined a retrospective cohort of 58 SOT recipients with first-wave COVID-19, comparing patients with severe and nonsevere illness. Additionally, SOT recipients are compared with general patients with first-wave COVID-19.
Organs transplanted included 38 kidneys, 8 livers, 5 hearts, and 3 pancreases. Average SOT recipient age was 57.4 years; 62% were male; 46.6% were African American 36.2% were white. Comorbidities included hypertension (86%), chronic kidney disease (86%), diabetes mellitus (50%), coronary artery disease (26%), and chronic obstructive pulmonary disease (14%). Twenty patients had severe COVID-19 (34.5%) and 38 had nonsevere disease (65.5%). Severe disease was more common in older SOT recipients with comorbidities and was associated with cough, dyspnea, pneumonia, C-reactive protein >10 mg/L, and platelet count <150/μL. Sex, race, body mass index, time from transplant, baseline immunosuppression, and diagnosis month did not differ among those with severe and nonsevere COVID-19. Seventy percent of SOT recipients were hospitalized vs 27.2% of general patients with COVID-19 and inpatient SOT recipients had a higher mechanical ventilation rate. Though a trend toward longer length of stay, higher intensive care unit admission, and greater inpatient mortality was observed (19.5% vs 14.8%), these differences were not significant.
The severe acute respiratory syndrome coronavirus 2 has greatly impacted SOT recipients. One-third of our SOT recipients seen during the first wave had severe illness with associated standard risk factors for poor outcome. Compared with general first-wave patients, more SOT recipients were hospitalized, although inpatient COVID-19 mortality did not significantly differ.
Dialectica models of type theory Moss, Sean K.; von Glehn, Tamara
Proceedings of the 33rd Annual ACM/IEEE Symposium on Logic in Computer Science,
07/2018
Conference Proceeding
Odprti dostop
We present two Dialectica-like constructions for models of intensional Martin-Löf type theory based on Gödel's original Dialectica interpretation and the Diller-Nahm variant, bringing dependent types ...to categorical proof theory. We set both constructions within a logical predicates style theory for display map categories where we show that 'quasifibred' versions of dependent products and universes suffice to construct their standard counterparts. To support the logic required for dependent products in the first construction, we propose a new semantic notion of finite sum for dependent types, generalizing finitely-complete extensive categories. The second avoids extensivity assumptions using biproducts in a Kleisli category for a fibred additive monad.
Background
Bronchial stenosis is a known complication of lung transplantation, but there are limited data regarding whether transplant recipients with bronchial stenosis develop more infectious ...complications than those without bronchial stenosis.
Methods
We conducted a retrospective single‐center observational cohort study between January 1, 2011 and September 29, 2016 of 35 lung transplant recipients diagnosed with bronchial stenosis and a random sample of 35 lung transplant recipients without bronchial stenosis. Data collected included donor/recipient demographic and anatomic information, respiratory cultures, episodes of respiratory infections diagnosed using CDC‐NNIS criteria, hospitalizations, and 1‐year all‐cause mortality. Patients were followed up to 1 year after transplant.
Results
Bronchial stenosis occurred at a median of 54 days post‐transplant (range 5‐365 days). Bronchial stenosis patients spent more time in the hospital (87.4 vs 46.8 days, P = 0.011) and had more total hospitalizations (4.54 vs 2.37, P < 0.01) than their counterparts. The relative risk of pneumonia among cases vs controls was 4.0 (95% CI 2.2‐7.3, P < 0.01); for purulent tracheobronchitis the relative risk was 3.1 (95% CI 1.6‐6.1, P < 0.01). Patients with bronchial stenosis were significantly more likely to have respiratory cultures growing Staphylococcus aureus (RR 5.0; P = 0.001) and Pseudomonas aeruginosa (RR 2.1, P = 0.026). Mortality within the first year following transplant was equal in both the groups (14.3% vs 14.3%).
Conclusions
There was no significant increase in 1‐year mortality for lung transplant patients who developed bronchial stenosis. However, bronchial stenosis patients had significantly higher risks of pneumonia and tracheobronchitis, and spent more days in the hospital than those without bronchial stenosis.
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