Analyzing Automata with Presburger Arithmetic and Uninterpreted Function Symbols

We study a class of extended automata defined by guarded commands over Presburger arithmetic with uninterpreted functions. On the theoretical side, we show that the bounded reachability problem is decidable in this model. On the practical side, the class is useful for modeling programs with unbounded data structures, and the reachability procedure can be used for symbolic simulation, testing, and verification.     

The Hydrophilic Loop of Arabidopsis PIN1 Auxin Efflux Carrier Harbors Hallmarks of an Intrinsically Disordered Protein

Much of plant development depends on cell-to-cell redistribution of the plant hormone auxin, which is facilitated by the plasma membrane (PM) localized PIN FORMED (PIN) proteins. Auxin export activity, developmental roles, subcellular trafficking, and polarity of PINs have been well studied, but their structure remains elusive besides a rough outline that they contain two groups of 5 alpha-helices connected by a large hydrophilic loop (HL). Here, we focus on the PIN1 HL as we could produce it in sufficient quantities for biochemical investigations to provide insights into its secondary structure. Circular dichroism (CD) studies revealed its nature as an intrinsically disordered protein (IDP), manifested by the increase of structure content upon thermal melting. Consistent with IDPs serving as interaction platforms, PIN1 loops homodimerize. PIN1 HL cytoplasmic overexpression in Arabidopsis disrupts early endocytic trafficking of PIN1 and PIN2 and causes defects in the cotyledon vasculature formation. In summary, we demonstrate that PIN1 HL has an intrinsically disordered nature, which must be considered to gain further structural insights. Some secondary structures may form transiently during pairing with known and yet-to-be-discovered interactors.     

Early Postoperative Immunothrombosis of Bioprosthetic Mitral Valve and Left Atrium: A Case Report

A 72-year-old female patient with mixed rheumatic mitral valve disease and persistent atrial fibrillation underwent mitral valve replacement and suffered from a combined thrombosis of the bioprosthetic valve and the left atrium as soon as 2 days post operation. The patient immediately underwent repeated valve replacement and left atrial thrombectomy. Yet, four days later the patient died due to the recurrent prosthetic valve and left atrial thrombosis which both resulted in an extremely low cardiac output. In this patient’s case, the thrombosis was notable for the resistance to anticoagulant therapy as well as for aggressive neutrophil infiltration and release of neutrophil extracellular traps (NETs) within the clot, as demonstrated by immunostaining. The reasons behind these phenomena remained unclear, as no signs of sepsis or contamination of the BHV were documented, although the patient was diagnosed with inherited thrombophilia that could impede the fibrinolysis. The described case highlights the hazard of immunothrombosis upon valve replacement and elucidates its mechanisms in this surgical setting.     

Superior Cerebellar Atrophy: An Imaging Clue to Diagnose ITPR1-Related Disorders

The inositol 1,4,5-triphosphate receptor type 1 (ITPR1) gene encodes an InsP₃-gated calcium channel that modulates intracellular Ca²⁺ release and is particularly expressed in cerebellar Purkinje cells. Pathogenic variants in the ITPR1 gene are associated with different types of autosomal dominant spinocerebellar ataxia: SCA15 (adult onset), SCA29 (early-onset), and Gillespie syndrome. Cerebellar atrophy/hypoplasia is invariably detected, but a recognizable neuroradiological pattern has not been identified yet. With the aim of describing ITPR1-related neuroimaging findings, the brain MRI of 14 patients with ITPR1 variants (11 SCA29, 1 SCA15, and 2 Gillespie) were reviewed by expert neuroradiologists. To further evaluate the role of superior vermian and hemispheric cerebellar atrophy as a clue for the diagnosis of ITPR1-related conditions, the ITPR1 gene was sequenced in 5 patients with similar MRI pattern, detecting pathogenic variants in 4 of them. Considering the whole cohort, a distinctive neuroradiological pattern consisting in superior vermian and hemispheric cerebellar atrophy was identified in 83% patients with causative ITPR1 variants, suggesting this MRI finding could represent a hallmark for ITPR1-related disorders.     

Dispirooxindole-β-Lactams: Synthesis via Staudinger Ketene-Imine Cycloaddition and Biological Evaluation

In this work, we present the first synthesis of dispirooxindole-β-lactams employing optimized methodology of one-pot Staudinger ketene-imine cycloaddition with N-aryl-2-oxo-pyrrolidine-3-carboxylic acids as the ketene source. Spiroconjugation of indoline-2-one with β-lactams ring is considered to be able to provide stabilization and wide scope of functionalization to resulting scaffolds. The dispipooxindoles obtained demonstrated medium cytotoxicity in the MTT test on A549, MCF7, HEK293, and VA13 cell lines, and one of the compounds demonstrated antibacterial activity against E. coli strain LPTD.     

A Novel Morphological Parameter Predicting Fibrotic Evolution in Myeloproliferative Neoplasms: New Evidence and Molecular Insights

Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) represent a group of hematological disorders that are traditionally considered as indistinct slow progressing conditions; still, a subset of cases shows a rapid evolution towards myelofibrotic bone marrow failure. Specific abnormalities in the megakaryocyte lineage seem to play a central role in this evolution, especially in the bone marrow fibrosis but also in the induction of myeloproliferation. In this review, we analyze the current knowledge of prognostic factors of MPNs related to their evolution to myelofibrotic bone marrow failure. Moreover, we focused the role of the megakaryocytic lineage in the various stages of MPNs, with updated examples of MPNs in vitro and in vivo models and new therapeutic implications.     

Novel Models of Crohn’s Disease Pathogenesis Associated with the Occurrence of Mitochondrial Dysfunction in Intestinal Cells

Crohn’s disease remains one of the challenging problems of modern medicine, and the development of new and effective and safer treatments against it is a dynamic field of research. To make such developments possible, it is important to understand the pathologic processes underlying the onset and progression of Crohn’s disease at the molecular and cellular levels. During the recent years, the involvement of mitochondrial dysfunction and associated chronic inflammation in these processes became evident. In this review, we discuss the published works on pathogenetic models of Crohn’s disease. These models make studying the role of mitochondrial dysfunction in the disease pathogenesis possible and advances the development of novel therapies.     

Chelating Polymers for Targeted Decontamination of Actinides: Application of PEI-MP to Hydroxyapatite-Th(IV)

In case of an incident in the nuclear industry or an act of war or terrorism, the dissemination of plutonium could contaminate the environment and, hence, humans. Human contamination mainly occurs via inhalation and/or wounding (and, less likely, ingestion). In such cases, plutonium, if soluble, reaches circulation, whereas the poorly soluble fraction (such as small colloids) is trapped in alveolar macrophages or remains at the site of wounding. Once in the blood, the plutonium is delivered to the liver and/or to the bone, particularly into its mineral part, mostly composed of hydroxyapatite. Countermeasures against plutonium exist and consist of intravenous injections or inhalation of diethylenetetraminepentaacetate salts. Their effectiveness is, however, mainly confined to the circulating soluble forms of plutonium. Furthermore, the short bioavailability of diethylenetetraminepentaacetate results in its rapid elimination. To overcome these limitations and to provide a complementary approach to this common therapy, we developed polymeric analogs to indirectly target the problematic retention sites. We present herein a first study regarding the decontamination abilities of polyethyleneimine methylcarboxylate (structural diethylenetetraminepentaacetate polymer analog) and polyethyleneimine methylphosphonate (phosphonate polymeric analog) directed against Th(IV), used here as a Pu(IV) surrogate, which was incorporated into hydroxyapatite used as a bone model. Our results suggest that polyethylenimine methylphosphonate could be a good candidate for powerful bone decontamination action.     

A neural network based intelligent system for tile prefetching in web map services

Web mapping has become a popular way of distributing interactive digital maps over the internet. Instead of dynamically generating map images on the fly, those can be pre-generated and served from a server-side cache for faster retrieval. However, these caches can grow unmanageably in size when the cartography covers mid to large areas for multiple rendering scales. This forces modest organizations to use partial caches containing just a subset of the total tiles, and makes their services less attractive than other mapping services like Google Maps or Microsoft Bing Maps. This work proposes a neural-network-based intelligent system that predicts which areas are likely to be requested in the future from a catalog of geographic features and a short history of past requests. These priority regions can be used by a tile prefetching policy to achieve an optimal population of the cache. Neural networks are trained and validated using supervised learning with real data-sets from a public nation-wide web map service. Trace-driven simulations demonstrate that accurate long-term predictions, up to 90% in terms of cache-hit ratio, can be obtained with the proposed model by prefetching a low fraction, only the 20% of the total tiles, and with a short training period.     

Mechanical squeezing of an elastomeric nanochannel device: numerical simulations and ionic current characterization

Peculiar transport phenomena appear at nanoscale, since surface effects strongly affect the behaviour of fluids. Electrostatic and steric interactions, capillary forces and entropic effects play a key role in the behaviour of fluids and biomolecules. Since these effects strongly depend on the size of the nanofluidic system, a careful characterization of the fluidic environment is necessary. Moreover, the possibility to dynamically modulate the size of nanochannels is very appealing in the field of biomolecule manipulation. Recently, we have developed a lab-on-chip made of poly(dimethylsiloxane) (PDMS). This polymeric device is based on a tuneable nanochannel able to dynamically change its dimension in order to fit the application of interest. In fact, a mechanical compression applied on the top of the elastomeric device squeezes the nanochannel, reducing the channel cross section and allowing a dynamical optimization of the nanostructures. In this paper, this squeezing process is fully characterized both numerically and experimentally. This analysis provides information on the reduction of the nanochannel dimensions induced by compression as a function of the work of adhesion and of the stiffness of the materials composing the device. Moreover, calculations demonstrate the possibility to predict the change of the nanochannel size and shape induced by the compression. The possibility to dynamically tune the channel size opens up new opportunities in biomolecular sensing or sieving and in the study of new hydrodynamics effects.