Regular Combinators for String Transformations

We focus on (partial) functions that map input strings to a monoid such as the set of integers with addition and the set of output strings with concatenation. The notion of regularity for such functions has been defined using two-way finite-state transducers, (one-way) cost register automata, and MSO-definable graph transformations. In this paper, we give an algebraic and machine-independent characterization of this class analogous to the definition of regular languages by regular expressions. When the monoid is commutative, we prove that every regular function can be constructed from constant functions using the combinators of choice, split sum, and iterated sum, that are analogs of union, concatenation, and Kleene-*, respectively, but enforce unique (or unambiguous) parsing. Our main result is for the general case of non-commutative monoids, which is of particular interest for capturing regular string-to-string transformations for document processing. We prove that the following additional combinators suffice for constructing all regular functions: (1) the left-additive versions of split sum and iterated sum, which allow transformations such as string reversal; (2) sum of functions, which allows transformations such as copying of strings; and (3) function composition, or alternatively, a new concept of chained sum, which allows output values from adjacent blocks to mix.Comment: This is the full version, with omitted proofs and constructions, of the conference paper currently in submissio

Two-Way Visibly Pushdown Automata and Transducers

Automata-logic connections are pillars of the theory of regular languages. Such connections are harder to obtain for transducers, but important results have been obtained recently for word-to-word transformations, showing that the three following models are equivalent: deterministic two-way transducers, monadic second-order (MSO) transducers, and deterministic one-way automata equipped with a finite number of registers. Nested words are words with a nesting structure, allowing to model unranked trees as their depth-first-search linearisations. In this paper, we consider transformations from nested words to words, allowing in particular to produce unranked trees if output words have a nesting structure. The model of visibly pushdown transducers allows to describe such transformations, and we propose a simple deterministic extension of this model with two-way moves that has the following properties: i) it is a simple computational model, that naturally has a good evaluation complexity; ii) it is expressive: it subsumes nested word-to-word MSO transducers, and the exact expressiveness of MSO transducers is recovered using a simple syntactic restriction; iii) it has good algorithmic/closure properties: the model is closed under composition with a unambiguous one-way letter-to-letter transducer which gives closure under regular look-around, and has a decidable equivalence problem

Characterization of a biomethane-like synthetic gas mixture through accurate density measurements from (240 to 350) K and pressures up to 14 MPa

Producción CientíficaIn this work the thermodynamic behavior of a synthetic four-component biomethane-like mixture, composed mainly of methane (96.48%), with small amounts of carbon dioxide (2.00%), nitrogen (1.50%), and traces of oxygen (0.02%), is studied using accurate (p,ρ,T) experimental data. Two mixtures of identical nominal compositions were prepared by the gravimetric method at the Spanish National Metrology Institute (Centro Español de Metrología, CEM) and at the Slovak National Metrology Institute (Slovenský Metrologický Ústav, SMÚ). The composition was double checked by Gas Chromatography, at both NMI and at the beginning and end of the measurements. An additional test of the consistency of the given compositions was performed by measuring the density of both mixtures at selected points, with two different techniques, in two different laboratories. Accurate density measurements have been taken over a wide temperature range, from (240 to 350) K, and pressures up to 14 MPa, using a single-sinker densimeter with magnetic suspension coupling. Experimental data are compared with the densities calculated with the GERG-2008 and AGA8-DC92 equations of state. Deviations between experimental and GERG-2008-estimated densities are within a ±0.03% band at all temperatures, which shows the outstanding performance of the current reference equation for natural gases when describing a biomethane-like mixture. Deviations between experimental and AGA-8-estimated densities are higher than 0.04% at 250 K for pressures greater than 10 MPa and also at 240 K for pressures higher than 9 MPa. This work is part of the research project ‘Metrology for Biogas’ supported by the European Metrology Research Program.2019-06-152019-06-15ENE2013-47812-RJunta de Castilla y León VA035U16European Metrology Research Program ENG5

Tumour regression and improved gastrointestinal tolerability from controlled release of SN-38 from novel polyoxazoline-modified dendrimers

Irinotecan is used clinically for the treatment of colorectal cancer; however, its utility is limited by its narrow therapeutic index. We describe the use of a generation 5 l-lysine dendrimer that has been part-modified with a polyoxazoline as a drug delivery vehicle for improving the therapeutic index of SN-38, the active metabolite of irinotecan. By conjugating SN-38 to the dendrimer via different linker technologies we sought to vary the release rate of the drug to generate diverse pharmacokinetic profiles. Three conjugates with plasma release half-lives of 2.5 h, 21 h, and 72 h were tested for efficacy and toxicity using a mouse SW620 xenograft model. In this model, the linker with a plasma release half-life of 21 h achieved sustained SN-38 exposure in blood, above the target concentration. Control over the release rate of the drug from the linker, combined with prolonged circulation of the dendrimer, enabled administration of an efficacious dose of SN-38, achieving significant regression of the SW620 tumours. The conjugates with 2.5 and 72 h release half-lives did not achieve an anti-tumour effect. Intraperitoneal dosing of the clinically used prodrug irinotecan produces high initial and local concentrations of SN-38, which are associated with gastrointestinal toxicity. Administration of the 21 h release dendrimer conjugate did not produce a high initial Cmax of SN-38. Consequently, a marked reduction in gastrointestinal toxicity was observed relative to irinotecan treatment. Additional studies investigating the dose concentrations and dose scheduling showed that a weekly dosing schedule of 4 mg SN-38/kg was the most efficacious regimen. After 4 doses at weekly intervals, the survival period of the mice extended beyond 70 days following the final dose. These extensive studies have allowed us to identify a linker, dose and dosing regimen for SN-38 conjugated to polyoxazoline-modified dendrimer that maximised efficacy and minimised adverse side effects

Ultrasound Measurement of Vascular Density to Evaluate Response to Anti-angiogenic Therapy in Renal Cell Carcinoma

Background: Functional and molecular changes often precede gross anatomical changes, so early assessment of a tumor's functional and molecular response to therapy can help reduce a patient's exposure to the side effects of ineffective chemotherapeutics or other treatment strategies. Objective: Our intent was to test the hypothesis that an ultrasound microvascular imaging approach might provide indications of response to therapy prior to assessment of tumor size. Methods: Mice bearing clear-cell renal cell carcinoma xenograft tumors were treated with antiangiogenic and Notch inhibition therapies. An ultrasound measurement of microvascular density was used to serially track the tumor response to therapy. Results: Data indicated that ultrasound-derived microvascular density can indicate response to therapy a week prior to changes in tumor volume and is strongly correlated with physiological characteristics of the tumors as measured by histology (ρ = 0.75). Furthermore, data demonstrated that ultrasound measurements of vascular density can determine response to therapy and classify between-treatment groups with high sensitivity and specificity. Conclusion/Significance: Results suggests that future applications utilizing ultrasound imaging to monitor tumor response to therapy may be able to provide earlier insight into tumor behavior from metrics of microvascular density rather than anatomical tumor size measurements

CpG-Methylation Regulates a Class of Epstein-Barr Virus Promoters

DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian gene regulation. In general, cytosine-phosphatidyl-guanosine (CpG)-methylated promoters are transcriptionally repressed and nuclear proteins such as MECP2, MBD1, MBD2, and MBD4 bind CpG-methylated DNA and contribute to epigenetic silencing. Methylation of viral DNA also regulates gene expression of Epstein-Barr virus (EBV), which is a model of herpes virus latency. In latently infected human B cells, the viral DNA is CpG-methylated, the majority of viral genes is repressed and virus synthesis is therefore abrogated. EBV's BZLF1 encodes a transcription factor of the AP-1 family (Zta) and is the master gene to overcome viral gene repression. In a genome-wide screen, we now identify and characterize those viral genes, which Zta regulates. Among them are genes essential for EBV's lytic phase, which paradoxically depend on strictly CpG-methylated promoters for their Zta-induced expression. We identified novel DNA recognition motifs, termed meZRE (methyl-Zta-responsive element), which Zta selectively binds in order to ‘read’ DNA in a methylation- and sequence-dependent manner unlike any other known protein. Zta is a homodimer but its binding characteristics to meZREs suggest a sequential, non-palindromic and bipartite DNA recognition element, which confers superior DNA binding compared to CpG-free ZREs. Our findings indicate that Zta has evolved to transactivate cytosine-methylated, hence repressed, silent promoters as a rule to overcome epigenetic silencing

Loss of the Urothelial Differentiation Marker FOXA1 Is Associated with High Grade, Late Stage Bladder Cancer and Increased Tumor Proliferation

Approximately 50% of patients with muscle-invasive bladder cancer (MIBC) develop metastatic disease, which is almost invariably lethal. However, our understanding of pathways that drive aggressive behavior of MIBC is incomplete. Members of the FOXA subfamily of transcription factors are implicated in normal urogenital development and urologic malignancies. FOXA proteins are implicated in normal urothelial differentiation, but their role in bladder cancer is unknown. We examined FOXA expression in commonly used in vitro models of bladder cancer and in human bladder cancer specimens, and used a novel in vivo tissue recombination system to determine the functional significance of FOXA1 expression in bladder cancer. Logistic regression analysis showed decreased FOXA1 expression is associated with increasing tumor stage (p<0.001), and loss of FOXA1 is associated with high histologic grade (p<0.001). Also, we found that bladder urothelium that has undergone keratinizing squamous metaplasia, a precursor to the development of squamous cell carcinoma (SCC) exhibited loss of FOXA1 expression. Furthermore, 81% of cases of SCC of the bladder were negative for FOXA1 staining compared to only 40% of urothelial cell carcinomas. In addition, we showed that a subpopulation of FOXA1 negative urothelial tumor cells are highly proliferative. Knockdown of FOXA1 in RT4 bladder cancer cells resulted in increased expression of UPK1B, UPK2, UPK3A, and UPK3B, decreased E-cadherin expression and significantly increased cell proliferation, while overexpression of FOXA1 in T24 cells increased E-cadherin expression and significantly decreased cell growth and invasion. In vivo recombination of bladder cancer cells engineered to exhibit reduced FOXA1 expression with embryonic rat bladder mesenchyme and subsequent renal capsule engraftment resulted in enhanced tumor proliferation. These findings provide the first evidence linking loss of FOXA1 expression with histological subtypes of MIBC and urothelial cell proliferation, and suggest an important role for FOXA1 in the malignant phenotype of MIBC

Reversing SKI-SMAD4-mediated suppression is essential for TH17 cell differentiation

T helper 17 (TH17) cells are critically involved in host defence, inflammation, and autoimmunity. Transforming growth factor β (TGFβ) is instrumental in TH17 cell differentiation by cooperating with interleukin-6 (refs 6, 7). Yet, the mechanism by which TGFβ enables TH17 cell differentiation remains elusive. Here we reveal that TGFβ enables TH17 cell differentiation by reversing SKI-SMAD4-mediated suppression of the expression of the retinoic acid receptor (RAR)-related orphan receptor γt (RORγt). We found that, unlike wild-type T cells, SMAD4-deficient T cells differentiate into TH17 cells in the absence of TGFβ signalling in a RORγt-dependent manner. Ectopic SMAD4 expression suppresses RORγt expression and TH17 cell differentiation of SMAD4-deficient T cells. However, TGFβ neutralizes SMAD4-mediated suppression without affecting SMAD4 binding to the Rorc locus. Proteomic analysis revealed that SMAD4 interacts with SKI, a transcriptional repressor that is degraded upon TGFβ stimulation. SKI controls histone acetylation and deacetylation of the Rorc locus and TH17 cell differentiation via SMAD4: ectopic SKI expression inhibits H3K9 acetylation of the Rorc locus, Rorc expression, and TH17 cell differentiation in a SMAD4-dependent manner. Therefore, TGFβ-induced disruption of SKI reverses SKI-SMAD4-mediated suppression of RORγt to enable TH17 cell differentiation. This study reveals a critical mechanism by which TGFβ controls TH17 cell differentiation and uncovers the SKI-SMAD4 axis as a potential therapeutic target for treating TH17-related diseases

Prostate Cancer Induced by Loss of Apc Is Restrained by TGFβ Signaling

Recent work with mouse models of prostate cancer (CaP) has shown that inactivation of TGFβ signaling in prostate epithelium can cooperate with deletion of the Pten tumor suppressor to drive locally aggressive cancer and metastatic disease. Here, we show that inactivating the TGFβ pathway by deleting the gene encoding the TGFβ type II receptor (Tgfbr2) in combination with a deletion of the Apc tumor suppressor gene specifically in mouse prostate epithelium, results in the rapid onset of invasive CaP. Micro-metastases were observed in the lymph nodes and lungs of a proportion of the double mutant mice, whereas no metastases were observed in Apc single mutant mice. Prostate-specific Apc;Tgfbr2 mutants had a lower frequency of metastasis and survived significantly longer than Pten;Tgfbr2 double mutants. However, all Apc;Tgfbr2 mutants developed invasive cancer by 30 weeks of age, whereas invasive cancer was rarely observed in Apc single mutant animals, even by one year of age. Further comparison of the Pten and Apc models of CaP revealed additional differences, including adenosquamous carcinoma in the Apc;Tgfbr2 mutants that was not seen in the Pten model, and a lack of robust induction of the TGFβ pathway in Apc null prostate. In addition to causing high-grade prostate intra-epithelial neoplasia (HGPIN), deletion of either Pten or Apc induced senescence in affected prostate ducts, and this restraint was overcome by loss of Tgfbr2. In summary, this work demonstrates that TGFβ signaling restrains the progression of CaP induced by different tumor suppressor mutations, suggesting that TGFβ signaling exerts a general tumor suppressive effect in prostate.This work was supported by a Program Project Grant from the National Cancer Institute (2P01CA104106 to B. Paschal and D. Wotton), and by a pilot grant from the UVA Cancer Center (funded from the CCSG P30 CA44579, the James and Rebecca CraigFoundation, and UVA Women's Oncology fund) to D. Wotton. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Sharon Birdsall for technical assistance, Anindya Dutta and Dan Gioeli for helpful discussions, and Chun-Song Yang for advice and reagent