Evidence for the chimeric origin of a pheromone-coding gene in Euplotes raikovi

Ciliates, unique among eukaryotes, evolved two types of nucleus which are distinct in both structure and function. A diploid transcriptionally silent germline micronucleus (MIC) with an orthodox chromosomicstructure coexists in the same cytoplasm with a polyploid transcriptionally active somatic macronucleus (MAC) showing a unique sub-chromosomic structure. This structure is acquired in coincidence with every sexual event, when the ex-conjugant (or ex-autogamic) cell initiates a new life cycle developing a new MAC from a mitotic product of the synkaryon. In spirotrichous ciliates such as Euplotes, the chromosomes of this product undergo impressive phenomena of polytenization, fragmentation in thousands of DNA fragments known as ‘Macronuclear Destined Sequences’ (MDSs), and DNA elimination. Under the guide of noncoding RNA templates synthesized by the old MAC before being destroyed, theseMDSs are assembled into sub-chromosomic (‘gene-size’)DNA molecules which,amplified to thousands of copies, compose the new MAC.The way to a correct MDSassembly may be crossed by errors, with the consequent generation of functional chimeric genes which can stably be integrated and expressed in the MAC genome.One of these chimeric genes came to light by studying the genetic basis of the pheromone-mediated self/not-self recognition mechanism in E. raikovi. The genome of type I cells secreting pheromone Er-1 was found to contain two structurally distinct MAC Er-1 coding genes,both expressed via a mechanism of intron splicing responsible for the synthesis of the Er-1 soluble form and a membrane-bound Er-1 isoform functioning as autocrine pheromone receptor. The sequence of one gene resulted unmistakably homologous throughout its length with the sequences of other members of the E. raikovipheromone gene family. In contrast, the sequence of the second gene resulted unique at level of a 359-bp segment of the 5’ region destined to specify the cytoplasmic domain of the Er-1 membrane-bound isoform. By showing that this segment arises from a wrong assembly of a MDS destined to a 2417-bp gene with no relationship with the signaling pheromone system, we provide additional evidence that the generation of functionally active chimeric genesfrom not-programmed phenomena of somatic MDS recombination is an effective and MIC-independent source of gene variants in the ciliate MAC genome

Not too big for its mouth: direct evidence of a macrodasyidan gastrotrich preyed in nature by a dileptid ciliate

Nearly ubiquitous and usually speciose in most aquatic habitats, the meiofaunal-sized gastrotrichs are recognized as an important component of marine and freshwater ecosystems. The common observations that gastrotrichs feed on bacteria, microalgae and biodetritus strongly imply that they play a relevant role in linking the microbial loop to the higher trophic levels. Which are the organisms that in turn prey on gastrotrichs is, however, a substantially unexplored question. Inspecting meiofauna samples collected from shallow sites of the Tyrrhenian coast, we had the chance to spot a wild case of a macrodasyidan gastrotrich predated by a dileptid ciliate. This case is documented here with a set of in-vivo photos, jointly with an unequivocal taxonomic identification of the preyed gastrotrich with Paraturbanella teissieri and a tentative identification of the predator ciliate with Pseudomonilicaryon marinus

Combining checkpointing and data compression for large scale seismic inversion

Seismic inversion and imaging are adjoint-based optimization problems that processes up to terabytes of data, regularly exceeding the memory capacity of available computers. Data compression is an effective strategy to reduce this memory requirement by a certain factor, particularly if some loss in accuracy is acceptable. A popular alternative is checkpointing, where data is stored at selected points in time, and values at other times are recomputed as needed from the last stored state. This allows arbitrarily large adjoint computations with limited memory, at the cost of additional recomputations. In this paper we combine compression and checkpointing for the first time to compute a realistic seismic inversion. The combination of checkpointing and compression allows larger adjoint computations compared to using only compression, and reduces the recomputation overhead significantly compared to using only checkpointing

Full-waveform inversion, Part 3: Optimization

This tutorial is the third part of a full-waveform inversion (FWI) tutorial series with a step-by-step walkthrough of setting up forward and adjoint wave equations and building a basic FWI inversion framework. For discretizing and solving wave equations, we use Devito (http://www.opesci.org/devito-public), a Python-based domain-specific language for automated generation of finite-difference code (Lange et al., 2016). The first two parts of this tutorial (Louboutin et al., 2017, 2018) demonstrated how to solve the acoustic wave equation for modeling seismic shot records and how to compute the gradient of the FWI objective function using the adjoint-state method. With these two key ingredients, we will now build an inversion framework that can be used to minimize the FWI least-squares objective function

Towards self-verification in finite difference code generation

Code generation from domain-specific languages is becoming increasingly popular as a method to obtain optimised low-level code that performs well on a given platform and for a given problem instance. Ensuring the correctness of generated codes is crucial. At the same time, testing or manual inspection of the code is problematic, as the generated code can be complex and hard to read. Moreover, the generated code may change depending on the problem type, domain size, or target platform, making conventional code review or testing methods impractical. As a solution, we propose the integration of formal verification tools into the code generation process. We present a case study in which the CIVL verification tool is combined with the Devito finite difference framework that generates optimised stencil code for PDE solvers from symbolic equations. We show a selection of properties of the generated code that can be automatically specified and verified during the code generation process. Our approach allowed us to detect a previously unknown bug in the Devito code generation tool

Architecture and performance of Devito, a system for automated stencil computation

Stencil computations are a key part of many high-performance computing applications, such as image processing, convolutional neural networks, and finite-difference solvers for partial differential equations. Devito is a framework capable of generating highly-optimized code given symbolic equations expressed in Python, specialized in, but not limited to, affine (stencil) codes. The lowering process -- from mathematical equations down to C++ code -- is performed by the Devito compiler through a series of intermediate representations. Several performance optimizations are introduced, including advanced common sub-expressions elimination, tiling and parallelization. Some of these are obtained through well-established stencil optimizers, integrated in the back-end of the Devito compiler. The architecture of the Devito compiler, as well as the performance optimizations that are applied when generating code, are presented. The effectiveness of such performance optimizations is demonstrated using operators drawn from seismic imaging applications

Contemporary economic burden in a real-world heart failure population with Commercial and Medicare supplemental plans

Background Limited real-world data exist on healthcare resource utilization (HCRU) and associated costs of patients with heart failure (HF) with reduced ejection fraction (HFrEF) and preserved EF (HFpEF), including urgent HF visits, which are assumed to be less burdensome than HF hospitalizations (hHFs) Hypothesis This study aimed to quantify the economic burden of HFrEF and HFpEF, via a retrospective, longitudinal cohort study, using IBM(R) linked claims/electronic health records (Commercial and Medicare Supplemental data only). Methods Adult patients, indexed on HF diagnosis (ICD-10-CM: I50.x) from July 2012 through June 2018, with 6-month minimum baseline period and varying follow-up, were classified as HFrEF (I50.2x) or HFpEF (I50.3x) according to last-observed EF-specific diagnosis. HCRU/costs were assessed during follow-up. Results About 109 721 HF patients (22% HFrEF, 31% HFpEF, 47% unclassified EF; median 18 months' follow-up) were identified. There were 3.2 all-cause outpatient visits per patient-month (HFrEF, 3.3; HFpEF, 3.6); 69% of patients required inpatient stays (HFrEF, 80%; HFpEF, 78%). Overall, 11% of patients experienced hHFs (HFrEF, 23%; HFpEF, 16%), 9% experienced urgent HF visits (HFrEF, 15%; HFpEF, 12%); 26% were hospitalized less than 30 days after first urgent HF visit versus 11% after first hHF. Mean monthly total direct healthcare cost per patient was $9290 (HFrEF,$11 053; HFpEF, $7482). Conclusions HF-related HCRU is substantial among contemporary real-world HF patients in US Commercial or Medicare supplemental health plans. Patients managed in urgent HF settings were over twice as likely to be hospitalized within 30 days versus those initially hospitalized, suggesting urgent HF visits are important clinical events and quality improvement targets

A combination of gemcitabine and 5-fluorouracil in advanced pancreatic cancer, a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD)

In a randomized clinical trial, gemcitabine (GEM) was more effective than 5-fluorouracil (5-FU) in advanced pancreatic cancer patients. GEM and 5-FU have different mechanisms of action and their combination, from a theoretical point of view, could result in a higher activity. To test activity and feasibility of such a combination, a multi-institutional phase II study was initiated in November 1996 by the Italian Group for the study of Digestive Tract Cancer (GISCAD). Primary objectives of this study were to determine the activity in terms of response rate and clinical benefit, while the secondary objective was toxicity. According to the optimal two-stage phase II design, 54 patients were enrolled. Schedule was: GEM 1000 mg m(-2) intravenous (i.v.), and 5-FU 600 mg m(-2) bolus i.v. weekly for 3 weeks out of every 4. All the 54 patients were symptomatic (pain, weight loss, dyspepsia). A clinical benefit was obtained in 28 patients (51\%) (95\% confidence interval (CI) 38-64\%). Two patients achieved a partial response and 34 a stable disease. Median survival for all the patients was 7 months. Side-effects were mild: no gastrointestinal or haematological grade 3-4 toxicity (WHO) were recorded. We observed only six episodes of grade 2 (WHO) leukopenia and seven episodes of thrombocytopenia. Although the non-randomized design of this study suggests caution in the interpretation of these data, in consideration of the low incidence of toxicity and the favourable results obtained in terms of clinical benefit, it may be worthwhile to test more active schedules of 5-FU (continuous infusion) in combination with gemcitabine