Type-Inference Based Short Cut Deforestation (nearly) without Inlining

Deforestation optimises a functional program by transforming it into another one that does not create certain intermediate data structures. In [ICFP'99] we presented a type-inference based deforestation algorithm which performs extensive inlining. However, across module boundaries only limited inlining is practically feasible. Furthermore, inlining is a non-trivial transformation which is therefore best implemented as a separate optimisation pass. To perform short cut deforestation (nearly) without inlining, Gill suggested to split definitions into workers and wrappers and inline only the small wrappers, which transfer the information needed for deforestation. We show that Gill's use of a function build limits deforestation and note that his reasons for using build do not apply to our approach. Hence we develop a more general worker/wrapper scheme without build. We give a type-inference based algorithm which splits definitions into workers and wrappers. Finally, we show that we can deforest more expressions with the worker/wrapper scheme than the algorithm with inlining

Effect of pressure profile of shock waves on lipid membrane deformation

Use of shock waves to temporarily increase the permeability of the cell membrane is a promising approach in drug delivery and gene therapy to allow the translocation of macromolecules and small polar molecules into the cytoplasm. Our understanding of how the characteristics of the pressure profile of shock waves, such as peak pressure and pulse duration, influences membrane properties is limited. Here we study the response of lipid bilayer membranes to shock pulses with different pressure profiles using atomistic molecular dynamics simulations. From our simulation results, we find that the transient deformation/disordering of the membrane depends on both the magnitude and the pulse duration of the pressure profile of the shock pulse. For a low pressure impulse, peak pressure has a dominant effect on membrane structural changes, while for the high pressure impulse, we find that there exists an optimal pulse duration at which membrane deformation/disordering is maximized

The Power of Non-Determinism in Higher-Order Implicit Complexity

We investigate the power of non-determinism in purely functional programming languages with higher-order types. Specifically, we consider cons-free programs of varying data orders, equipped with explicit non-deterministic choice. Cons-freeness roughly means that data constructors cannot occur in function bodies and all manipulation of storage space thus has to happen indirectly using the call stack. While cons-free programs have previously been used by several authors to characterise complexity classes, the work on non-deterministic programs has almost exclusively considered programs of data order 0. Previous work has shown that adding explicit non-determinism to cons-free programs taking data of order 0 does not increase expressivity; we prove that this - dramatically - is not the case for higher data orders: adding non-determinism to programs with data order at least 1 allows for a characterisation of the entire class of elementary-time decidable sets. Finally we show how, even with non-deterministic choice, the original hierarchy of characterisations is restored by imposing different restrictions.Comment: pre-edition version of a paper accepted for publication at ESOP'1

Acceptance of the bodypainting as supportive method to learn the surface locomotor apparatus anatomy of the horse

Although bodypainting has been reported as a great resource for teaching surface anatomy of humans, its use in veterinary anatomy has not been scientifically reported. In the present study, bodypainting was performed on 4 horses for anatomy teaching purposes of the equine locomotor apparatus. We aimed to use the bodypainting method as an additional tool to classic teaching and to test the relevance of our purpose. Twenty one Brazilian veterinary students were given a 90-min session, which included a presentation of painted horses, with opportunities for the students to ask questions and to palpate anatomic locations on the horses. Based on a questionnaire, there was unanimous student satisfaction with this technique. Furthermore, student scores on practical tests to evaluate the attention retain given immediately before and 1 h after the session were 33.9 ± 19.8% and 69.0 ± 18.4%, respectively (p < 0.001). We concluded that bodypainting has great potential for support the classic lectures of the equine locomotor apparatus

The H3K27M mutation alters stem cell growth, epigenetic regulation, and differentiation potential

BACKGROUND: Neurodevelopmental disorders increase brain tumor risk, suggesting that normal brain development may have protective properties. Mutations in epigenetic regulators are common in pediatric brain tumors, highlighting a potentially central role for disrupted epigenetic regulation of normal brain development in tumorigenesis. For example, lysine 27 to methionine mutation (H3K27M) in the H3F3A gene occurs frequently in Diffuse Intrinsic Pontine Gliomas (DIPGs), the most aggressive pediatric glioma. As H3K27M mutation is necessary but insufficient to cause DIPGs, it is accompanied by additional mutations in tumors. However, how H3K27M alone increases vulnerability to DIPG tumorigenesis remains unclear. RESULTS: Here, we used human embryonic stem cell models with this mutation, in the absence of other DIPG contributory mutations, to investigate how H3K27M alters cellular proliferation and differentiation. We found that H3K27M increased stem cell proliferation and stem cell properties. It interfered with differentiation, promoting anomalous mesodermal and ectodermal gene expression during both multi-lineage and germ layer-specific cell specification, and blocking normal differentiation into neuroectoderm. H3K27M mutant clones exhibited transcriptomic diversity relative to the more homogeneous wildtype population, suggesting reduced fidelity of gene regulation, with aberrant expression of genes involved in stem cell regulation, differentiation, and tumorigenesis. These phenomena were associated with global loss of H3K27me3 and concordant loss of DNA methylation at specific genes in H3K27M-expressing cells. CONCLUSIONS: Together, these data suggest that H3K27M mutation disrupts normal differentiation, maintaining a partially differentiated state with elevated clonogenicity during early development. This disrupted response to early developmental cues could promote tissue properties that enable acquisition of additional mutations that cooperate with H3K27M mutation in genesis of DMG/DIPG. Therefore, this work demonstrates for the first time that H3K27M mutation confers vulnerability to gliomagenesis through persistent clonogenicity and aberrant differentiation and defines associated alterations of histone and DNA methylation

Gross morphometry of the heart of the Common marmoset

  The Callithrix jacchus is a Brazilian endemic species that has been widely used asan experimental model in biomedical research. Anatomical data are necessary to support experimental studies with this species. Eleven hearts of C. jacchus from the German Primate Centre (DPZ) have been studied in order to characterize their gross morphometry and compare them with other animal models and human. Biometric data were also obtained. The mean values for morphometry of the hearts did not show any significant difference between male and female. The relative heart weight was similar to human, bovine and equine species. Considering those aspects, the C. jacchus could be used as non-human primate experimental modelfor biomedical studies on heart.

Mapping interactions with the chaperone network reveals factors that protect against tau aggregation.

A network of molecular chaperones is known to bind proteins ('clients') and balance their folding, function and turnover. However, it is often unclear which chaperones are critical for selective recognition of individual clients. It is also not clear why these key chaperones might fail in protein-aggregation diseases. Here, we utilized human microtubule-associated protein tau (MAPT or tau) as a model client to survey interactions between ~30 purified chaperones and ~20 disease-associated tau variants (~600 combinations). From this large-scale analysis, we identified human DnaJA2 as an unexpected, but potent, inhibitor of tau aggregation. DnaJA2 levels were correlated with tau pathology in human brains, supporting the idea that it is an important regulator of tau homeostasis. Of note, we found that some disease-associated tau variants were relatively immune to interactions with chaperones, suggesting a model in which avoiding physical recognition by chaperone networks may contribute to disease

A Domain-Specific Language for Incremental and Modular Design of Large-Scale Verifiably-Safe Flow Networks (Preliminary Report)

We define a domain-specific language (DSL) to inductively assemble flow networks from small networks or modules to produce arbitrarily large ones, with interchangeable functionally-equivalent parts. Our small networks or modules are "small" only as the building blocks in this inductive definition (there is no limit on their size). Associated with our DSL is a type theory, a system of formal annotations to express desirable properties of flow networks together with rules that enforce them as invariants across their interfaces, i.e, the rules guarantee the properties are preserved as we build larger networks from smaller ones. A prerequisite for a type theory is a formal semantics, i.e, a rigorous definition of the entities that qualify as feasible flows through the networks, possibly restricted to satisfy additional efficiency or safety requirements. This can be carried out in one of two ways, as a denotational semantics or as an operational (or reduction) semantics; we choose the first in preference to the second, partly to avoid exponential-growth rewriting in the operational approach. We set up a typing system and prove its soundness for our DSL.Comment: In Proceedings DSL 2011, arXiv:1109.032

NRP/Optineurin Cooperates with TAX1BP1 to Potentiate the Activation of NF-κB by Human T-Lymphotropic Virus Type 1 Tax Protein

Nuclear factor (NF)-κB is a major survival pathway engaged by the Human T-Lymphotropic Virus type 1 (HTLV-1) Tax protein. Tax1 activation of NF-κB occurs predominantly in the cytoplasm, where Tax1 binds NF-κB Essential Modulator (NEMO/IKKγ) and triggers the activation of IκB kinases. Several independent studies have shown that Tax1-mediated NF-κB activation is dependent on Tax1 ubiquitination. Here, we identify by co-immunoprecipitation assays NEMO-Related Protein (NRP/Optineurin) as a binding partner for Tax1 in HTLV-1 infected and Tax1/NRP co-expressing cells. Immunofluorescence studies reveal that Tax1, NRP and NEMO colocalize in Golgi-associated structures. The interaction between Tax1 and NRP requires the ubiquitin-binding activity of NRP and the ubiquitination sites of Tax1. In addition, we observe that NRP increases the ubiquitination of Tax1 along with Tax1-dependent NF-κB signaling. Surprisingly, we find that in addition to Tax1, NRP interacts cooperatively with the Tax1 binding protein TAX1BP1, and that NRP and TAX1BP1 cooperate to modulate Tax1 ubiquitination and NF-κB activation. Our data strongly suggest for the first time that NRP is a critical adaptor that regulates the assembly of TAX1BP1 and post-translationally modified forms of Tax1, leading to sustained NF-κB activation

Value of the First Post-Transplant Biopsy for Predicting Long-Term Cardiac Allograft Vasculopathy (CAV) and Graft Failure in Heart Transplant Patients

BACKGROUND: Cardiac allograft vasculopathy (CAV) is the principal cause of long-term graft failure following heart transplantation. Early identification of patients at risk of CAV is essential to target invasive follow-up procedures more effectively and to establish appropriate therapies. We evaluated the prognostic value of the first heart biopsy (median: 9 days post-transplant) versus all biopsies obtained within the first three months for the prediction of CAV and graft failure due to CAV. METHODS AND FINDINGS: In a prospective cohort study, we developed multivariate regression models evaluating markers of atherothrombosis (fibrin, antithrombin and tissue plasminogen activator [tPA]) and endothelial activation (intercellular adhesion molecule-1) in serial biopsies obtained during the first three months post-transplantation from 172 patients (median follow-up = 6.3 years; min = 0.37 years, max = 16.3 years). Presence of fibrin was the dominant predictor in first-biopsy models (Odds Ratio [OR] for one- and 10-year graft failure due to CAV = 38.70, p = 0.002, 95% CI = 4.00-374.77; and 3.99, p = 0.005, 95% CI = 1.53-10.40) and loss of tPA was predominant in three-month models (OR for one- and 10-year graft failure due to CAV = 1.81, p = 0.025, 95% CI = 1.08-3.03; and 1.31, p = 0.001, 95% CI = 1.12-1.55). First-biopsy and three-month models had similar predictive and discriminative accuracy and were comparable in their capacities to correctly classify patient outcomes, with the exception of 10-year graft failure due to CAV in which the three-month model was more predictive. Both models had particularly high negative predictive values (e.g., First-biopsy vs. three-month models: 99% vs. 100% at 1-year and 96% vs. 95% at 10-years). CONCLUSIONS: Patients with absence of fibrin in the first biopsy and persistence of normal tPA in subsequent biopsies rarely develop CAV or graft failure during the next 10 years and potentially could be monitored less invasively. Presence of early risk markers in the transplanted heart may be secondary to ischemia/reperfusion injury, a potentially modifiable factor