A chunking mechanism in a neural system for the parallel processing of a propositional production rules

The problem of extracting more compact rules from a rule-based knowledge base is approached by means of a chunking mechanism implemented via a neural system. Taking advantage of the parallel processing potentialities of neural systems, the computational problem normally arising when introducing chuncking processes is overcome. Also the memory saturation effect is coped with using some sort of "forgetting" mechanism which allows the system to eliminate previously stored, but less often used chunks. Even though some connection weights are changed in the process of storing or discarding chunks, we emphasize that this neural system cannot be regarded as a "connectionist" system, since a localist semantic interpretation is adopted and no classical learning algorithm is employed

A chunking mechanism in a neural system for the parallel processing of a propositional production rules

The problem of extracting more compact rules from a rule-based knowledge base is approached by means of a chunking mechanism implemented via a neural system. Taking advantage of the parallel processing potentialities of neural systems, the computational problem normally arising when introducing chuncking processes is overcome. Also the memory saturation effect is coped with using some sort of "forgetting" mechanism which allows the system to eliminate previously stored, but less often used chunks. Even though some connection weights are changed in the process of storing or discarding chunks, we emphasize that this neural system cannot be regarded as a "connectionist" system, since a localist semantic interpretation is adopted and no classical learning algorithm is employed

ONE-POT SYNTHESIS OF THIO-GLYCOMIMETICS THROUGH RING OPENING REACTIONS

Glycomimetics are compounds able to mimic structural and functional aspects of the corresponding natural carbohydrates. The main goal of using these mimetics, e.g. as therapeutic agents, is the manipulation of the chemical information encoded by sugars, controlling and altering the flow of these information. Sugars, and their mimetics, are selectively recognised by certain proteins, called lectins. An example of these lectins is DC-SIGN. DC-SIGN (Dendritic Cell-Specific ICAM-3 Grabbing Non-integrin) is a tetrameric calcium dependent (C-type) lectin expressed by dermal dendritic cells (DCs) and it is known to play a crucial role in the immunological system. In particular, DC-SIGN is the primary target of Human Immunodeficiency Virus type I (HIV-1) that hijacks DCs to disseminate the infection in the human body. With the aim to develop DC-SIGN antagonists able to mimic the main natural ligand, the Bernardi\u2019s group has developed a series of mono- and multivalent ligands that all contain a mannose unit (whose hydroxyl groups in position 3 and 4 are involved in the interaction with the calcium ion of the Carbohydrate Recognition Domain (CRD) of DC-SIGN) connected with a conformationally locked cyclohexandiol moiety (the aglycon part, that is known to exploit additional interaction with residues present in the binding site). In the course of my PhD, I have developed a straightforward synthesis for a new class of glycomimetic DC-SIGN ligands more metabolically stable, thanks to the presence of a sulfur atom in the interglycosidic position rather than the oxygen atom of the previous library of compounds. The key step of the preparation of these thio-glycomimetics is a one-pot ring opening reaction of an enantiomerically pure epoxide by an S-acetyl-\u3b1-mannose that affords the desired pseudo-thiodisaccharide as a single isomer in 77% yield after 1 hour at 60\ub0C under micro-wave irradiation. To further improve the process, the same reaction was also performed into a flow micro-reactor at different flow rates, temperatures and residence times. Although at certain conditions a promising conversion of 69% was observed, the results were not competitive with the ones already achieved by using a MW system, which allowed also the scale up of the process. Computational studies supported by NMR analysis showed that the new thio-glycomimetic shares a very similar conformational behaviour as the corresponding O-linked pseudo-disaccharide. Furthermore, SPR inhibition assay revealed that they share also the same affinity towards DC-SIGN (IC50 value of 0.8 mM). However, a stability test, performed against an \u3b1-mannosidase enzyme, proved that the presence of the sulfur in the interglycosidic position makes the structure significantly more stable than that of the same molecule bearing instead an oxygen in that position. The low sub-millimolar activity of monovalent ligands is characteristic of oligosaccharide-protein interactions and is overcome both in Nature and in the development of biological active glycomimetics by exploiting multivalent interactions. With this aim, the free hydroxyl group of the cyclohexane moiety of the pseudo-thiodisaccharide was functionalized with an azide-terminated linker through an esterification reaction. Afterwards, this compound was employed in the construction of multivalent systems, by exploiting click chemistry between the terminal azide of the ligand and the free terminal alkyne functions of a counterpart (work carried out during my visit in Sevilla, at the \u201cIstituto de Investigaciones Quimicas-IIQ\u201d, under the supervision of Dr. Javier Rojo). In particular, I have synthetized two different types of multivalent scaffolds: dendrimers and glyconanogels. These structures are still under biological investigation. Since the ester linkage of the azido-linker, introduced to allow the construction of multivalents, remained a weak point of the molecule, we decided to further increase the stability of the thio-glycomimetic, developing a new synthetic strategy that involved the ring opening of an aziridine ring rather than an epoxide. After the optimization of the synthetic procedure of the starting free aziridine, it was functionalized with different acylating reagents obtaining a series of N-acylated aziridines which were finally opened in a one-pot manner again by the \u3b1-thioacetate. The biological activity of the final compounds was finally investigated through SPR inhibition assay and all of them showed IC50 values very close to each other\u2019s but in particular very similar to the original O-linked pseudo-disaccharide. In conclusion, two new synthetic approaches were devised for the synthesis of thio-dimannoside mimics designed to be stable against enzymatic and chemical hydrolysis. The pseudo-anomeric position of the aglycon of these compounds could be functionalized with a nitrogen atom, which allows to thether the glycomimetic structure to linkers/scaffolds/peptidic chains using a non-labile amide linkage

Simultaneous Bilateral Spontaneous Pneumothorax Revealed Birt-Hogg-Dube Syndrome

Simultaneous bilateral spontaneous pneumothorax is a very rare clinical event, comprising approximately 1% of all spontaneous pneumothoraces. Clinical signs and symptomsmay vary frommild chest pain and dyspnea to severe respiratory failure; nevertheless immediate treatment is mandatory as this condition can deteriorate and progress to tension pneumothorax. An underlying lung disease has been commonly described; in most istances primary or secondary tumors, interstitial diseases, and infectious diseases. Birt-Hogg-Dube syndrome is a rare inherited disorder clinically characterized by multiple fibrofolliculomas, renal tumors, lung cysts, and, in similar to 24% of the patients, occurrence of spontaneous pneumothorax. In this case, we firstly report the concurrence of these rare conditions, as a patient presenting a simultaneous bilateral spontaneous pneumothorax was diagnosed with Birt-HoggDube syndrome based on the typical radiological findings and genetic testing of the folliculin gene located on chromosome 17

Trichinella pseudospiralis outbreak in France.

Four persons became ill with trichinellosis after eating meat from a wild boar hunted in Camargue, France. Nonencapsulated larvae of Trichinella pseudospiralis were detected in meat and muscle biopsy specimens. The diagnoses were confirmed by molecular typing. Surveillance for the emerging T. pseudospiralis should be expanded

Deep learning for genomics using Janggu

In recent years, numerous applications have demonstrated the potential of deep learning for an improved understanding of biological processes. However, most deep learning tools developed so far are designed to address a specific question on a fixed dataset and/or by a fixed model architecture. Here we present Janggu, a python library facilitates deep learning for genomics applications, aiming to ease data acquisition and model evaluation. Among its key features are special dataset objects, which form a unified and flexible data acquisition and pre-processing framework for genomics data that enables streamlining of future research applications through reusable components. Through a numpy-like interface, these dataset objects are directly compatible with popular deep learning libraries, including keras or pytorch. Janggu offers the possibility to visualize predictions as genomic tracks or by exporting them to the bigWig format as well as utilities for keras-based models. We illustrate the functionality of Janggu on several deep learning genomics applications. First, we evaluate different model topologies for the task of predicting binding sites for the transcription factor JunD. Second, we demonstrate the framework on published models for predicting chromatin effects. Third, we show that promoter usage measured by CAGE can be predicted using DNase hypersensitivity, histone modifications and DNA sequence features. We improve the performance of these models due to a novel feature in Janggu that allows us to include high-order sequence features. We believe that Janggu will help to significantly reduce repetitive programming overhead for deep learning applications in genomics, and will enable computational biologists to rapidly assess biological hypotheses

The peculiar structural features of kiwi fruit pectin methylesterase: amino acid sequence, oligosaccharides structure, and modeling of the interaction with its natural proteinaceous inhibitor

Pectin methylesterase (PME) from kiwi fruit (Actinidia deliciosa) is a glycoprotein, showing an apparent molecular mass of 50 kDa upon size exclusion chromatography and SDS-PAGE. The primary structure, elucidated by direct sequencing of the protein, comprises 321 amino acid residues providing a molecular mass of 35 kDa. The protein has an acetylated Thr residue at the amino terminus and five N-glycosylation consensus sequences, four of which are actually glycosylated. A careful investigation of the oligosaccharide structures demonstrated that PME glycans belong to complex type oligosaccharides essentially consisting of xylosylated polyfucosylated biantennary structures. Alignment with known mature plant PME sequences indicates that the postulated active site residues are conserved. Kiwi PME activity is inhibited following the interaction with the proteinaceous inhibitor PMEI, isolated from the same source. Gel-filtration experiments show that kiwi PME/PMEI complex is stable in a large pH range and dissociates only at pH 10.0. Modeling of the interaction with the inhibitor was performed by using the crystal structure of the complex between kiwi PMEI and tomato PME as a template. The model shows that the binding site is the same reported for tomato PME. However, additional salt link interactions are found to connect the external loops of kiwi PME to PMEI. This finding may explain the higher pH stability of the complex formed by the two kiwi proteins respect to that formed by PMEI and tomato PME