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Categorization of business processes is an important part of auditing. Large amounts of transnational data in auditing can be represented as transactions between financial accounts using weighted bipartite graphs. We view such bipartite graphs as many-valued formal contexts, which we use to obtain explainable categorization of these business processes in terms of financial accounts involved in a business process by using methods in formal concept analysis. The specific explainability feature of the methodology introduced in the present paper provides several advantages over e.g.~non-explainable machine learning techniques, and in fact, it can be taken as a basis for the development of algorithms which perform the task of clustering on transparent and accountable principles. Here, we focus on obtaining and studying different ways to categorize according to different extents of interest in different financial accounts, or interrogative agendas, of various agents or sub-tasks in audit. We use Dempster-Shafer mass functions to represent agendas showing different interest in different set of financial accounts. We propose two new methods to obtain categorizations from these agendas. We also model some possible deliberation scenarios between agents with different interrogative agendas to reach an aggregated agenda and categorization. The framework developed in this paper provides a formal ground to obtain and study explainable categorizations from the data represented as bipartite graphs according to the agendas of different agents in an organization (e.g.~an audit firm), and interaction between these through deliberation.

We prove an algebraic canonicity theorem for normal LE-logics of arbitrary signature, in a generalized setting in which the non-lattice connectives are interpreted as operations mapping tuples of elements of the given lattice to closed or open elements of its canonical extension. Interestingly, the syntactic shape of LE-inequalities which guarantees their canonicity in this generalized setting turns out to coincide with the syntactic shape of analytic inductive inequalities, which guarantees LE-inequalities to be equivalently captured by analytic structural rules of a proper display calculus. We show that this canonicity result connects and strengthens a number of recent canonicity results in two different areas: subordination algebras, and transfer results via G\"odel-McKinsey-Tarski translations., Comment: arXiv admin note: text overlap with arXiv:1603.08515, arXiv:1603.08341

Cortical networksin vivoexhibit highly irregular spiking activity to repeated stimuli. One source of such variability is network chaos, ever-present in spiking network models. In order to reliably and robustly represent and transmit information, cortical networks must implement active mechanisms to quench undesired changes in spiking patterns. Neuronal oscillations have been proposed as a mechanism to flexibly gate information flow across the cortex, but whether these collective rhythms would actually contribute to quenching spiking unreliability and tame network chaos by synchronizing activity, or on the contrary, intensify chaos by acting as a common drive to the network, is not easily predictable. Here we investigate the dynamical properties of network models with respect to two known control parameters regulating collective oscillatory activity: delayed re-current inhibition and an external periodic drive. To do so, we advanced the tractability of large spiking networks of exactly solvable neuronal models by developing a strategy that allows for exact characterization of the dynamics on the attractor of effectively delayed network models in a system with fixed and finite degrees of freedom. We find that, below the transition to collective oscillations, neuronal networks have a stereotypical dependence on the delay so far only described for scalar systems and low-dimensional maps. We demonstrate that the emergence of internally generated oscillations induces a complete dynamical reconfiguration, by increasing the dimensionality of the chaotic attractor, the speed at which nearby trajectories separate from one another, and the rate at which the network produces entropy. Our results suggest that simple temporal dynamics of the mean activity can have a profound effect on the structure of the spiking patterns and therefore on the information processing capability of neuronal networks.Significance StatementRecordingsin vivoshow that spiking patterns in response to repeated stimuli in cortex are highly variable. Here we investigate whether collective oscillations, either internally generated through delayed recurrent inhibition or by external feed-forward drive, are able to quench chaotic variability by structuring spiking patterns or if they contribute to intensifying chaos. We develop a strategy that allowed us to completely characterize the dynamics of delayed spiking circuit models by means of classic ergodic theory measures. We find that chaos is intensified at the onset of collective oscillations, but that transient oscillatory input, where the dynamics are most resembling those found in biological networks, has only a mild effect on chaos and hence on network variability.

The ability to optogenetically perturb neural circuits opens an unprecedented window into mechanisms governing circuit function. We analyzed and theoretically modeled neuronal responses to visual and optogenetic inputs in mouse and monkey V1. In both species, optogenetic stimulation of excitatory neurons strongly modulated the activity of single neurons, yet had weak or no effects on the distribution of firing rates across the population. Thus, the optogenetic inputs reshuffled firing rates across the network. Key statistics of mouse and monkey responses lay on a continuum, with mice/monkeys occupying the low/high rate regions, respectively. We show that neuronal reshuffling emerges generically in randomly connected excitatory/inhibitory networks, provided the coupling strength (combination of recurrent coupling and external input) is sufficient that powerful inhibitory feedback cancels the mean optogenetic input. A more realistic model, distinguishing tuned visual vs. untuned optogenetic input in a structured network, reduces the coupling strength needed to explain reshuffling.

N-glycan analyses may serve uncovering disease-associated biomarkers, as well as for profiling distinctive changes supporting diagnosis of genetic disorders of glycan biosynthesis named congenital disorders of glycosylation (CDG). Strategies based on liquid chromatography (LC) preferentially coupled to electrospray ionization (ESI) - mass spectrometry (MS) have emerged as powerful analytical methods for N-glycan identification and characterization. To enhance detection sensitivity, glycans are commonly labelled with a functional tag prior to LC-MS analysis. Since most derivatization techniques are notoriously time-consuming, some commercial analytical kits have been developed to speed up N-deglycosylation and N-glycan labelling of glycoproteins of pharmaceutical and biological interest such as monoclonal antibodies (mAbs). We exploited the analytical capabilities of RapiFluor-MS (RFMS) to perform, by a slightly modified protocol, a detailed N-glycan characterization of total serum and single serum glycoproteins from specific patients with CDG (MAN1B1-CDG, ALG12-CDG, MOGS-CDG, TMEM199-CDG). This strategy, accomplished by Hydrophilic Interaction Chromatography (HILIC)-UPLC-ESI-MS separation of the RFMS derivatized N-glycans, allowed us to uncover structural details of patients serum released N-glycans, thus extending the current knowledge on glycan profiles in these individual glycosylation diseases. The applied methodology enabled to differentiate in some cases either structural isomers and isomers differing in the linkage type. All the here reported applications demonstrated that RFMS method, coupled to HILIC-UPLC-ESI-MS, represents a sensitive high throughput approach for serum N-glycome analysis and a valuable option for glycan detection and separation particularly for isomeric species.

We study LFD, a base logic of functional dependence introduced by Baltag and van Benthem (2021) and its connections with the guarded fragment GF of first-order logic. Like other logics of dependence, the semantics of LFD uses teams: sets of permissible variable assignments. What sets LFD apart is its ability to express local dependence between variables and local dependence of statements on variables. Known features of LFD include decidability, explicit axiomatization, finite model property, and a bisimulation characterization. Others, including the complexity of satisfiability, remained open so far. More generally, what has been lacking is a good understanding of what makes the LFD approach to dependence computationally well-behaved, and how it relates to other decidable logics. In particular, how do allowing variable dependencies and guarding quantifiers compare as logical devices? We provide a new compositional translation from GF into LFD, and conversely, we translate LFD into GF in an `almost compositional' manner. Using these two translations, we transfer known results about GF to LFD in a uniform manner, yielding, e.g., tight complexity bounds for LFD satisfiability, as well as Craig interpolation. Conversely, e.g., the finite model property of LFD transfers to GF. Thus, local dependence and guarding turn out to be intricately entangled notions., Comment: Proceedings of AIML 2022

The present paper establishes systematic connections among the first-order correspondents of Sahlqvist modal reduction principles in various relational semantic settings which include crisp and many-valued Kripke frames, and crisp and many-valued polarity-based frames (aka enriched formal contexts). Building on unified correspondence theory, we aim at introducing a theoretical environment which makes it possible to: (a) compare and inter-relate the various frame correspondents (in different relational settings) of any given Sahlqvist modal reduction principle; (b) recognize when first-order sentences in the frame-correspondence languages of different types of relational structures encode the same "modal content"; (c) meaningfully transfer and represent well known relational properties such as reflexivity, transitivity, symmetry, seriality, confluence, density, across different semantic contexts. These results can be understood as a first step in a research program aimed at making correspondence theory not just (methodologically) unified, but also (effectively) parametric., Comment: This is a revision of the previous version

By exploiting the algebraic and order theoretic mechanisms behind Sahlqvist correspondence, the theory of unified correspondence provides powerful tools for correspondence and canonicity across different semantics and signatures, covering all the logics whose algebraic semantics are given by normal (distributive) lattice expansions (referred to as (D)LEs). In particular, the algorithm ALBA, parametric in each (D)LE, effectively computes the first order correspondents of (D)LE-inductive formulas. We present an algorithm that makes use of ALBA's rules and algebraic language to invert its steps in the DLE setting; therefore effectively computing an inductive formula starting from its first order correspondent.

We introduce proper display calculi for basic monotonic modal logic, the conditional logic CK and a number of their axiomatic extensions. These calculi are sound, complete, conservative, and enjoy cut elimination and subformula property. Our proposal applies the multi-type methodology in the design of proper display calculi, starting from a semantic analysis which motivates syntactic translations from single-type non-normal modal logics to multi-type normal poly-modal logics.

Congenital disorders of glycosylation (CDG) are genetic diseases characterized by deficient synthesis (CDG type I) and/or abnormal processing (CDG type II) of glycan moieties linked to protein and lipids. The impact of the molecular defects on protein glycosylation and in turn on the clinical phenotypes of patients with CDG is not yet understood. ALG12-CDG is due to deficiency of ALG12 α1,6-mannosyltransferase that adds the eighth mannose residue on the dolichol-PP-oligosaccharide precursor in the endoplasmic reticulum. ALG12-CDG is a severe multisystem disease associated with low to deficient serum immunoglobulins and recurrent infections. We thoroughly investigated the glycophenotype in a patient with novel ALG12 variants and immunodeficiency. We analyzed serum native transferrin, as first line test for CDG and we profiled serum IgG and total serum N-glycans by a combination of consolidated (N-glycan analysis by MALDI MS) and innovative mass spectrometry-based protocols, such as GlycoWorks RapiFluor N-glycan analysis coupled with LC-ESI MS. Intact serum transferrin showed, as expected for a CDG type I defect, underoccupancy of N-glycosylation sites. Surprisingly, total serum proteins and IgG N-glycans showed some specific changes, consisting in accumulating amounts of definite high-mannose and hybrid structures. As a whole, ALG12-CDG behaves as a dual CDG (CDG-I and II defects) and it is associated with distinct, abnormal glycosylation of total serum and IgG N-glycans. Glycan profiling of target glycoproteins may endorse the molecular defect unraveling the complex clinical phenotype of CDG patients.

We extend the theory of unified correspondence to a broad class of logics with algebraic semantics given by varieties of normal lattice expansions (LEs), also known as ‘lattices with operators’. Specifically, we introduce a syntactic definition of the class of Sahlqvist formulas and inequalities which applies uniformly to each LE-signature and is given purely in terms of the order-theoretic properties of the algebraic interpretations of the logical connectives. We also introduce the algorithm ALBA, parametric in each LE-setting, which effectively computes first-order correspondents of LE-inequalities, and is guaranteed to succeed on a wide class of inequalities (the so-called inductive inequalities) which significantly extend the Sahlqvist class. Further, we show that every inequality on which ALBA succeeds is canonical. Projecting these results on specific signatures yields state-of-the-art correspondence and canonicity theory for many well known modal expansions of classical and intuitionistic logic and for substructural logics, from classical poly-modal logics to (bi-)intuitionistic modal logics to the Lambek calculus and its extensions, the Lambek-Grishin calculus, orthologic, the logic of (not necessarily distributive) De Morgan lattices, and the multiplicative-additive fragment of linear logic.

The cortical microcircuit can dynamically adjust to dramatic changes in the strength, scale, and complexity of its input. In the primary visual cortex (V1), pyramidal cells (PCs) integrate widely across space when signals are weak, but narrowly when signals are strong, a phenomenon known as contrast-dependent surround suppression. Theoretical work has proposed that local interneurons could mediate a shift from cooperation to competition of PCs across cortical space, underlying this computation. We combined calcium imaging and electrophysiology to constrain a stabilized supralinear network model that explains how the four principal cell types in layer 2/3 (L2/3) of mouse V1– somatostatin (SST), parvalbumin (PV), and vasoactive intestinal peptide (VIP) interneurons, and PCs– transform inputs from layer 4 (L4) PCs to encode drifting gratings of varying size and contrast. Using bidirectional optogenetic perturbations, we confirmed key predictions of the model. Our data and modeling showed that recurrent amplification drives a transition from a positive PC→VIP⊣SST⊣PC feedback loop at small size and low contrast to a negative PC→SST⊣PC feedback loop at large size and high contrast to contribute to this flexible computation. This may represent a widespread mechanism for gating competition across cortical space to optimally meet task demands.

The search for novel lipid A analogues from any biological source that can act as antagonists, displaying inhibitory activity towards the production of pro-inflammatory cytokines, or as immunomodulators in mammals, is a very topical issue. To this aim, the structure and immunological properties of the lipopolysaccharide lipid A from the purple nonsulfur bacterium Rhodopseudomonas palustris strain BisA53 have been determined. This lipid A displays a unique structural feature, with a non-phosphorylated skeleton made up of the tetrasaccharide Manp-α-(1→4)-GlcpN3N-β-1→6-GlcpN3N-α-(1→1)-α-GalpA, and four primary amide-linked 14:0(3-OH) and, as secondary O-acyl substituents, a 16:0 and the very long-chain fatty acid 26:0(25-OAc), appended on the GlcpN3N units. This lipid A architecture is definitely rare, so far identified only in the genus Bradyrhizobium. Immunological tests on both murine bone-marrow-derived and human monocyte-derived macrophages revealed an extremely low immunostimulant capability of this LPS lipid A.

Predicting the response of the cortical microcircuit to perturbations is a prerequisite to determine the mechanisms that mediate its response to stimulus; yet, an encompassing perspective that describes the full ensemble of the network’s response in models that accurately recapitulate recorded data is still lacking. Here we develop a class of mathematically tractable models that exactly describe the modulation of the distribution of cell-type-specific calcium-imaging activity with the contrast of a visual stimulus. The inferred parameters recover signatures of the connectivity structure found in mouse visual cortex. Analysis of this structure subsequently reveals parameter-independent relations between the responses of different cell types to perturbations and each interneuron’s role in circuit-stabilization. Leveraging recent theoretical approaches, we derive explicit expressions for the distribution of responses to partial perturbations which reveal a novel, counter intuitive effect in the sign of response functions. Finally applying the theory to inferring feedback to V1 during locomotion, we find that it is predominantly mediated by both SOM and VIP modulation.

An inhibition-stabilized network (ISN) is a network of excitatory and inhibitory cells at a stable fixed point of firing rates for a given input, for which the excitatory subnetwork would be unstable if inhibitory rates were frozen at their fixed point values. It has been shown that in a low-dimensional model (one unit per neuronal subtype) of an ISN with a single excitatory and single inhibitory cell type, the inhibitory unit shows a “paradoxical” response, lowering (raising) its steady-state firing rate in response to addition to it of excitatory (inhibitory) input. This has been generalized to an ISN with multiple inhibitory cell types: if input is given only to inhibitory cells, the steady-state inhibition received by excitatory cells changes paradoxically, that is, it decreases (increases) if the steady-state excitatory firing rates decrease (increase).We generalize these analyses of paradoxical effects to low-dimensional networks with multiple cell types of both excitatory and inhibitory neurons. The analysis depends on the connectivity matrix of the network linearized about a given fixed point, and its eigenvectors or “modes”. We show the following: (1) A given cell type shows a paradoxical change in steady-state rate in response to input it receives, if and only if the network with that cell type omitted has an odd number of unstable modes. Excitatory neurons can show paradoxical responses when there are two or more inhibitory subtypes. (2) More generally, if the cell types are divided into two nonoverlapping subsets A and B, then subset B has an odd (even) number of modes that show paradoxical response if and only if subset A has an odd (even) number of unstable modes. (3) The net steady-state inhibition received by any unstable mode of the excitatory subnetwork will change paradoxically, i.e. in the same direction as the change in amplitude of that mode. In particular, this means that a sufficient condition to determine that a network is an ISN is if, in response to an input only to inhibitory cells, the firing rates of and inhibition received by all excitatory cell types all change in the same direction. This in turn will be true if all E cells and all inhibitory cell types that connect to E cells change their firing rates in the same direction.

Considerable concern has emerged for the potential harm in the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor inhibitors (ARBs) in COVID-19 patients, given that ACEIs and ARBs may increase the expression of ACE2 receptors that represent the way for coronavirus 2 to entry into the cell and cause severe acute respiratory syndrome. Assess the effect of ACEI/ARBs on outcome in COVID-19 patients. Hospital-based prospective study. A total of 431 patients consecutively presenting at the Emergency Department and found to be affected by COVID-19 were assessed. Relevant clinical and laboratory variables were recorded, focusing on the type of current anti hypertensive treatment. Outcome variables were NO, MILD, SEVERE respiratory distress (RD) operationally defined and DEATH. Hypertension was the single most frequent comorbidity (221/431 = 51%). Distribution of antihypertensive treatment was: ACEIs 77/221 (35%), ARBs 63/221 (28%), OTHER than ACEIs or ARBs 64/221 (29%). In 17/221 (8%) antihypertensive medication was unknown. The proportion of patients taking ACEIs, ARBs or OTHERs who developed MILD or SEVERE RD was 43/77 (56%), 33/53 (52%), 39/64 (61%) and 19/77 (25%), 16/63 (25%) and 16/64 (25%), respectively, with no statistical difference between groups. Despite producing a RR for SEVERE RD of 2.59 (95% CI 1.93–3.49), hypertension was no longer significant in a logistic regression analysis that identified age, CRP and creatinine as the sole independent predictors of SEVERE RD and DEATH. ACEIs and ARBs do not promote a more severe outcome of COVID-19. There is no reason why they should be withheld in affected patients.

Glycosylation is a fundamental post-translational modification of proteins that boosts their structural diversity providing subtle and specialized biological properties and functions. All those genetic diseases due to a defective glycan biosynthesis and attachment to the nascent glycoproteins fall within the wide area of congenital disorders of glycosylation (CDG), mostly causing multisystem involvement. In the present paper we detailed the unique serum N- glycosylation of a CDG-candidate patient with an unexplained neurological phenotype and liver adenomatosis harbouring a recurrent pathogenic HNF1α variant. Serum transferrin IEF showed a surprising N-glycosylation pattern consisting on hyposialylation as well as remarkable hypersialylation. Mass spectrometry-based glycomic analyses of individual serum glycoproteins enabled to unveil hypersialylated complex N-glycans comprising up to two sialic acids per antenna. Further advanced MS analysis showed the additional sialic acid is bonded through an α2-6 linkage to the peripheral N-acetylglucosamine residue, giving rise to disialo-epitopes never described in human N-glycoproteins.

We discuss an ongoing line of research in the relational (non topological) semantics of non-distributive logics. The developments we consider are technically rooted in dual characterization results and insights from unified correspondence theory. However, they also have broader, conceptual ramifications for the intuitive meaning of non-distributive logics, which we explore., Comment: 36 pages

In Gram-negative bacteria, lipopolysaccharide (LPS) contributes to the robust permeability barrier of the outer membrane (OM), preventing the entry of toxic molecules, such as detergents and antibiotics. LPS is transported from the inner membrane (IM) to the OM by the Lpt multiprotein machinery. Defects in LPS transport compromise LPS assembly at the OM and result in increased antibiotic sensitivity. LptA is a key component of the Lpt machine that interacts with the IM protein LptC and chaperones LPS through the periplasm. We report here the construction of lptA41 , a quadruple mutant in four conserved amino acids potentially involved in LPS or LptC binding. Although viable, the mutant displays increased sensitivity to several antibiotics (bacitracin, rifampin, and novobiocin) and the detergent SDS, suggesting that lptA41 affects LPS transport. Indeed, lptA41 is defective in Lpt complex assembly, and its lipid A carries modifications diagnostic of LPS transport defects. We also selected and characterized two phenotypic bacitracin-resistant suppressors of lptA41 . One mutant, in which only bacitracin sensitivity is suppressed, harbors a small in-frame deletion in mlaA , which codes for an OM lipoprotein involved in maintaining OM asymmetry by reducing accumulation of phospholipids in the outer leaflet. The other mutant, in which bacitracin, rifampin, and SDS sensitivity is suppressed, harbors an additional amino acid substitution in LptA41 and a nonsense mutation in opgH , encoding a glycosyltransferase involved in periplasmic membrane-derived oligosaccharide synthesis. Characterization of the suppressor mutants highlights different strategies adopted by the cell to overcome OM defects caused by impaired LPS transport. IMPORTANCE Lipopolysaccharide (LPS) is the major constituent of the outer membrane (OM) of most Gram-negative bacteria, forming a barrier against antibiotics. LPS is synthesized at the inner membrane (IM), transported across the periplasm, and assembled at the OM by the multiprotein Lpt complex. LptA is the periplasmic component of the Lpt complex, which bridges IM and OM and ferries LPS across the periplasm. How the cell coordinates the processes involved in OM biogenesis is not completely understood. We generated a mutant partially defective in lptA that exhibited increased sensitivity to antibiotics and selected for suppressors of the mutant. The analysis of two independent suppressors revealed different strategies adopted by the cell to overcome defects in LPS biogenesis.

Congenital disorders of glycosylation (CDG) are due to defective glycosylation of glycoconjugates. Conserved oligomeric Golgi (COG)-CDG are genetic diseases due to defects of the COG complex subunits 1-8 causing N-glycan and O-glycan processing abnormalities. In COG-CDG, isoelectric focusing separation of undersialylated glycoforms of serum transferrin and apolipoprotein C-III (apoC-III) allows to detect N-glycosylation and O-glycosylation defects, respectively. COG5-CDG (COG5 subunit deficiency) is a multisystem disease with dysmorphic features, intellectual disability of variable degree, seizures, acquired microcephaly, sensory defects and autistic behavior. We applied matrix-assisted laser desorption/ionization-MS for a high-throughput screening of differential serum O-glycoform and N-glycoform in five patients with COG5-CDG. When compared with age-matched controls, COG5-CDG showed a significant increase of apoC-III0a (aglycosylated glycoform), whereas apoC-III1 (mono-sialylated glycoform) decreased significantly. Serum N-glycome of COG5-CDG patients was characterized by the relative abundance of undersialylated and undergalactosylated biantennary and triantennary glycans as well as slight increase of high-mannose structures and hybrid glycans. Using advanced and well-established MS-based approaches, the present findings reveal novel aspects on O-glycan and N-glycan profiling in COG5-CDG patients, thus providing an increase of current knowledge on glycosylation defects caused by impairment of COG subunits, in support of clinical diagnosis. Copyright © 2017 John Wiley & Sons, Ltd.

CSF diagnostics has proved to be a formidable testing ground for N-glycoproteomic analysis of neurological diseases. To characterize specific N-glycan profiles of CSF in early and advanced phases of Alzheimer's disease, as well as in lysosomal storage disorders such as Tay-Sachs disease, we set up in our lab a robust and feasible protocol by coupling bioanalytical methods and mass spectrometry analysis.Starting from a few microliters of CSF, after protein denaturation, reduction, and alkylation, N-glycans are released from glycoproteins using the peptide-N-glycosidase F (PNGase F) and purified. The analysis of permethylated N-glycans by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and MALDI-TOF MS/MS allowed us to identify specific glyco-structures and also to distinguish between isobaric N-glycans.

We introduce proper display calculi for basic monotonic modal logic,the conditional logic CK and a number of their axiomatic extensions. These calculi are sound, complete, conservative and enjoy cut elimination and subformula property. Our proposal applies the multi-type methodology in the design of display calculi, starting from a semantic analysis based on the translation from monotonic modal logic to normal bi-modal logic.

CSF diagnostics has proved to be a formidable testing ground for N-glycoproteomic analysis of neurological diseases. To characterize specific N-glycan profiles of CSF in early and advanced phases of Alzheimer's disease, as well as in lysosomal storage disorders such as Tay-Sachs disease, we set up in our lab a robust and feasible protocol by coupling bioanalytical methods and mass spectrometry analysis. Starting from a few microliters of CSF, after protein denaturation, reduction, and alkylation, N-glycans are released from glycoproteins using the peptide-N-glycosidase F (PNGase F) and purified. The analysis of permethylated N-glycans by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and MALDI-TOF MS/MS allowed us to identify specific glyco-structures and also to distinguish between isobaric N-glycans.

We introduce a complete many-valued semantics for two normal lattice-based modal logics. This semantics is based on reflexive many-valued graphs. We discuss an interpretation and possible applications of this logical framework in the context of the formal analysis of the interaction between (competing) scientific theories., Comment: To appear in the proceedings of EUSFLAT 2019. Pre-final version with expanded proofs

By 'informational entropy', we understand an inherent boundary to knowability, due e.g. to perceptual, theoretical, evidential or linguistic limits. In this paper, we discuss a logical framework in which this boundary is incorporated into the semantic and deductive machinery, and outline how this framework can be used to model various situations in which informational entropy arises., Comment: To appear in proceedings of WoLLIC 2019, Remark 1 added

The structural characterization of the lipopolysaccharide (LPS) from extremophiles has important implications in several biomedical and therapeutic applications. The polyextremophile Gram-negative bacterium Halobacteroides lacunaris TB21, isolated from one of the most extreme habitats on our planet, the deep-sea hypersaline anoxic basin Thetis, represents a fascinating microorganism to investigate in terms of its LPS component. Here we report the elucidation of the full structure of the R-type LPS isolated from H. lacunaris TB21 that was attained through a multi-technique approach comprising chemical analyses, NMR spectroscopy, and Matrix-Assisted Laser Desorption Ionization (MALDI) mass spectrometry. Furthermore, cellular immunology studies were executed on the pure R-LPS revealing a very interesting effect on human innate immunity as an inhibitor of the toxic Escherichia coli LPS.

In this chapter, we present the methodology currently applied in our laboratory for the structural elucidation of the cerebrospinal fluid (CSF) N-glycome. N-glycans are released from denatured carboxymethylated glycoproteins by digestion with peptide-N-glycosidase F (PNGase F) and purified using both C18 Sep-Pak

Dynamic Logics (DLs) form a large family of nonclassical logics, and perhaps the one enjoying the widest range of applications. Indeed, they are designed to formalize change caused by actions of diverse nature: updates on the memory state of a computer, displacements of moving robots in an environment, measurements in models of quantum physics, belief revisions, knowledge updates, etc. In each of these areas, DL-formulas express properties of the model encoding the present state of affairs, as well as the preand post-conditions of a given action. Actions are semantically represented as transformations of one model into another, encoding the state of affairs after the action has taken place. DL-languages are expansions of classical (static) logic with dynamic operators, parametrized with actions; dynamic operators are modalities interpreted in terms of the transformation of models corresponding to their action-parameters. However, when dynamic logics feature both dynamic and ‘static’ modalities, as in the case of the Dynamic Epistemic Logics (DEL), they typically lose many desirable properties, such as the closure under uniform substitution, which facilitate a smooth algebraic and proof-theoretic treatment. This and other difficulties make their algebraic and proof-theoretic theory presently underdeveloped, and the few existing proposals seem quite ad hoc: in particular, no proposed calculus in the literature enjoys the minimal conditions enabling the specification of the meaning of a logical symbol in the sense of proof-theoretic semantics. We developed a family of display-style, cut-free sequent calculi for dynamic epistemic logics on both an intuitionistic and a classical base [7]. Like the standard display calculi, these calculi are modular: just by modifying the structural rules according to Dosen’s principle [12], these calculi are generalizable both to different Dynamic Logics (Epistemic, Deontic, etc.) and to different propositional bases (Linear, Relevant, etc.). Moreover, the rules they feature agree with the standard relational semantics for dynamic epistemic logics, while a ‘natural’ coalgebraic semantics was introduced in [7]. However, these calculi still feature a peculiar set of contextual rules, i.e. structural and operational rules involving a context (understood as the precondition for the applicability of an action), which make them non-standard as display calculi. To fix this shortcoming, in [8] we propose a new class of more general sequent calculi (which we call dynamic calculi) that overcome the need of contextual rules and enjoy other benefits, including a natural proof-theoretic semantics. In this talk we present two concrete examples of dynamic calculi for one specific dynamic epistemic logic [2], both in its classical and in its intuitionistic version, where the Intuitionistic logic for Epistemic Action and Knowledge was intoduced via duality in [10] defining dynamic algebraic semantics on intuitionistic base. These calculi can be understood as generalizations of the display calculi [4], since they feature: 1. constituents of several types (e.g. of type AG for ‘agents’ or ACT for ‘actions’), along with propositional constituents, which in their turn can be of different types (e.g. intuitionistic propositions iPROP, or classical propositions cPROP, etc.); N. Galatos, A. Kurz, C. Tsinakis (eds.), TACL 2013 (EPiC Series, vol. 25), pp. 85–87 85 Sequent calculus for dynamic epistemic logic Greco, Kurz and Palmigiano 2. non-contextual1 structural connectives (structural conjunction and disjunction, implication and disimplication — also called exclusion —, and their neutral elements) by which structures are built, where a structure can be homogeneous (e.g. α ∧ β is of type ACT ×ACT ) or heterogeneous (e.g. α ∧ A is of type ACT × PROP).2 3. structural introduction rules, which constitues a pure structural calculus because the structural and operational level are now completely separated (e.g. (X ` Y)∧ (W ` Z) / X∧W ` Y∧ Z); 4. unary translation rules, to pass from structural to operational level: the flattening rule, making it possible to transform homogeneous structures into operational formulas (e.g. A ∧ B ` X / A∧B ` X, where A∧B is a propositional formula of type PROP×PROP→ PROP), and the currying rule, making it possible to transform heterogeneous structures into ‘parametrized’ operational formulas (e.g. α ∧ A ` X / 〈α〉A ` X, where 〈α〉A is a propositional modal formula of type ACT ×PROP→ PROP). These calculi are interesting from both a methodological and an applicative viewpoint. Methodologically, the dynamic calculi achieve a unified framework simultaneously accounting for different logical behaviors: modalities (e.g. exponentials or temporal operators) and quantifiers can be seen in terms of combinations of heterogeneous components by means of operational rules at the merging-level; the behavior of a single modal operator (e.g. monotonicity) or the interaction between modalities (e.g. dynamic and epistemic operators) can be captured by means of structural rules at the merging-level. We will also discuss the categorial semantics, which seems the most ‘appropriate’ for this kind of calculi. From the point of view of the applications, dynamic calculi provide a way of generating specific display calculi for a wide array of logics — which includes but is not limited to dynamic (epistemic) logics — simply by deriving the appropriate rules; this allows to obtain meta-theorems such as cut elimination [8] uniformly for each specific calculus as a byproduct of the general theory of dynamic calculi. The dynamic calculi enjoy the strong version of Wansing’s fundamental properties of segregation, symmetricity and explicitness [12]. Therefore, they share all the benefits that come from the display calculi, but are more general: for instance they capture also dynamic poly-modal logics on substructural base.

The algorithmic correspondence theory is extended to mu-calculi with a non-classical base. We focus in particular on the language of bi-intuitionistic modal mu-calculus, and we enhance the algorithm, or calculus for correspondence, ALBA for the elimination of monadic second order variables, so as to guarantee its success over a class including the Sahlqvist mu-formulas. Key to the soundness of this enhancement are the order-theoretic properties of the algebraic interpretation of the fixed point operators.

Sahlqvist-style correspondence results remain a perennial theme and an active topic of research within modal logic. Recently there has been interest in extending classical results in this area to the modal mu-calculus. We show how the `calculus of correspondence' and the ALBA algorithm (Conradie and Palmigiano, 2012) can be extended to the intuitionistic mu-calculus, and be used to derive FO+LFP frame correspondents for formulas of that logic. We define the class of recursive mu-inequalities, which we compare it with related classes in the literature including the Sahlqvist mu-formulas of van Benthem, Bezhanishvili and Hodkinson. We show that the ALBA algorithm succeeds in reducing every recursive mu-inequality, and hence that every recursive mu-inequality has a frame correspondent in FO+LFP.

In this paper we extend the research programme in algebraic proof theory from axiomatic extensions of the full Lambek calculus to logics algebraically captured by certain varieties of normal lattice expansions (normal LE-logics). Specifically, we generalise the residuated frames in [16] to arbitrary signatures of normal lattice expansions (LE). Such a generalization provides a valuable tool for proving important properties of LE-logics in full uniformity. We prove semantic cut elimination for the display calculi D.LE associated with the basic normal LE-logics and their axiomatic extensions with analytic inductive axioms. We also prove the finite model property (FMP) for each such calculus D.LE, as well as for its extensions with analytic structural rules satisfying certain additional properties.

Taking an algebraic perspective on the basic structures of Rough Concept Analysis as the starting point, in this paper we introduce some varieties of lattices expanded with normal modal operators which can be regarded as the natural rough algebra counterparts of certain subclasses of rough formal contexts, and introduce proper display calculi for the logics associated with these varieties which are sound, complete, conservative and with uniform cut elimination and subformula property. These calculi modularly extend the multi-type calculi for rough algebras to a `nondistributive' (i.e. general lattice-based) setting.

In this chapter, we present the methodology currently applied in our laboratory for the structural elucidation of the cerebrospinal fluid (CSF) N-glycome. book cover N-glycans are released from denatured carboxymethylated glycoproteins by digestion with peptide-N-glycosidase F (PNGase F) and purified using both C18 Sep-Pak® and porous graphitized carbon (PGC) HyperSepTM HypercarbTM solid-phase extraction (SPE) cartridges. The glycan pool is subsequently permethylated to increase mass spectrometry sensitivity. Molecular assignments are performed through matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI TOF MS) analysis considering either the protein N-inked glycosylation pathway or MALDI TOF MS/MS data. Each stage has been optimized to obtain high-quality mass spectra in reflector mode with an optimal signal-to-noise ratio up to m/z 4800. This method has been successfully adopted to associate specific N-glycome profiles to the early and the advanced phases of Alzheimer's disease.

In the present paper, we introduce a multi-type calculus for the logic of measurable Kleene algebras, for which we prove soundness, completeness, conservativity, cut elimination and subformula property. Our proposal imports ideas and techniques developed in formal linguistics around the notion of structural control.

N-glycosylation is one the main post-translational modification involving proteins that belong to all the three domains of life and plays a pivotal role in a number of biological functions including intercellular signaling and recognition. Glycosylation analysis in humans is an added value and a fundamental tool to characterize those genetic defects concerning glycan biosynthesis, such as Congenital Disorders of Glycosylation (CDG). Also, glycan alterations are associated to pathophysiology of major diseases as cancer and neurodegenerative dysfunctions. Concurrently, there is a growing interest of biopharmaceutical industries for the development of high-throughput methods for glycan analysis of therapeutic glycoproteins. N-linked glycans are commonly analyzed by liquid chromatography (LC) interfaced with fluorescence detection, but in recent years a growing number of research laboratories extended the application by coupling LC with mass spectrometry (MS) techniques. Furthermore, LC-MS has become the primary device for smart high-throughput analyses. Here we report an outline of the prevailing LC-MS techniques set up for N-glycan analysis, paying special attention to N-glycomic characterization of human serum, as the most available and informative biological source for diagnosis and disease investigations.

Protein N-glycosylation consists in the synthesis and processing of the oligosaccharide moiety (N-glycan) linked to a protein and it serves several functions for the proper central nervous system (CNS) development and function. Previous experimental and clinical studies have shown the importance of proper glycoprotein sialylation for the synaptic function and the occurrence of autism spectrum disorders (ASD) in the presence of sialylation deficiency in the CNS. Late-onset Tay Sachs disease (LOTSD) is a lysosomal disorder caused by mutations in the HEXA gene resulting in GM2-ganglioside storage in the CNS. It is characterized by progressive neurological impairment and high co-occurrence of psychiatric disturbances. We studied the N-glycome profile of the cerebrospinal fluid (CSF) in a 14 year-old patient with GM2-gangliosidosis (LOTSD). At the age of 4, the patient presented regressive autism fulfilling criteria for childhood disintegrative disorder (CDD). A CSF sample was obtained in the course of diagnostic work-up for the suspicion of an underlying neurodegenerative disorder. We found definite changes of CSF N-glycans due to a dramatic decrease of sialylated biantennary and triantennary structures and an increase of asialo-core fucosylated bisected N-glycans. No changes of total plasma N-glycans were found. Herein findings highlight possible relationships between the early onset psychiatric disturbance featuring CDD in the patient and defective protein sialylation in the CNS. In conclusion, the study first shows aberrant N-glycan structures of CSF proteins in LOTSD; unveils possible pathomechanisms of GM2-gangliosidosis; supports existing relationships between neuropsychiatric disorders and unproper protein glycosylation in the CNS.

The synthesis of middle-to-late-replicating DNA can be affected independently of the rest of the genome by down-regulating the tumor suppressor PREP1 (PKNOX1). Indeed, DNA combing shows that PREP1 down-regulation affects DNA replication rate, increases the number of simultaneously firing origins and the asymmetry of DNA replication, leading to DNA damage. Genome-wide analysis of replication timing by Repli-seq shows that, upon PREP1 down-regulation, 25% of the genome is replicated earlier in the S-phase. The targeted DNA sequences correspond to Lamin-Associated Domains (LADs), and include late-replicating (LRRs) and temporal transition regions (TTRs). Notably, the distribution of PREP1 DNA binding sites and of its target genes indicates that DNA replication defects are independent of the overall PREP1 transcriptional activity. Finally, PREP1 down-regulation causes a substantial decrease in Lamin B1 levels. This suggests that DNA is released from the nuclear lamina earlier than in the control cells and is available for replication, thus explaining timing defects and DNA damage.This is the first evidence that the replication timing of a specific fraction of the human genome is affected by PREP1 tumor suppressor. This previously unknown function might significantly contribute to the genomic instability observed in human tumors.

Toll-like receptor 4 (TLR4) initiates immune response against Gram-negative bacteria upon specific recognition of lipid A moiety of lipopolysaccharide (LPS), the major component of their cell wall. Some natural differences between LPS variants in their ability to interact with TLR4 may lead to either insufficient activation that may not prevent bacterial growth, or excessive activation which may lead to septic shock. In this study we evaluated the biological activity of LPS isolated from pathogenic strain of Campylobacter jejuni, the most widespread bacterial cause of foodborne diarrhea in humans. With the help of hydrophobic chromatography and MALDI-TOF mass spectrometry we showed that LPS from a C. jejuni strain O2A consists of both hexaacyl and tetraacyl forms. Since such hypoacylation can result in a reduced immune response in humans, we assessed the activity of LPS from C. jejuni in mouse macrophages by measuring its capacity to activate TLR4-mediated proinflammatory cytokine and chemokine production, as well as NFκB-dependent reporter gene transcription. Our data support the hypothesis that LPS acylation correlates with its bioactivity.

In rhizobium strains, the lipid A is modified by the addition of a very long-chain fatty acid (VLCFA) shown to play an important role in rigidification of the outer membrane, thereby facilitating their dual life cycle, outside and inside the plant. In Bradyrhizobium strains, the lipid A is more complex with the presence of at least two VLCFAs, one covalently linked to a hopanoid molecule, but the importance of these modifications is not well-understood. In this study, we identified a cluster of VLCFA genes in the photosynthetic Bradyrhizobium strain ORS278, which nodulates Aeschynomene plants in a Nod factor-independent process. We tried to mutate the different genes of the VLCFA gene cluster to prevent the synthesis of the VLCFAs, but only one mutant in the lpxXL gene encoding an acyltransferase was obtained. Structural analysis of the lipid A showed that LpxXL is involved in the transfer of the C26:25OH VLCFA to the lipid A but not in the one of the C30:29OH VLCFA which harbors the hopanoid molecule. Despite maintaining the second VLCFA, the ability of the mutant to cope with various stresses (low pH, high temperature, high osmolarity, and antimicrobial peptides) and to establish an efficient nitrogen-fixing symbiosis was drastically reduced. In parallel, we investigated whether the BRADO0045 gene, which encodes a putative acyltransferase displaying a weak identity with the apo-lipoprotein N-acyltransferase Lnt, could be involved in the transfer of the C30:29OH VLCFA to the lipid A. Although the mutant exhibited phenotypes similar to the lpxXL mutant, no difference in the lipid A structure was observed from that in the wild-type strain, indicating that this gene is not involved in the modification of lipid A. Our results advance our knowledge of the biosynthesis pathway and the role of VLCFAs-modified lipid A in free-living and symbiotic states of Bradyrhizobium strains.

The importance of the outer membrane and of its main constituent, lipopolysaccharide, in the symbiosis between rhizobia and leguminous host plants has been well studied. Here, the first complete structural characterization of the entire lipopolysaccharide from an O‐chain‐deficient Bradyrhizobium ORS285 rfaL mutant is achieved by a combination of chemical analysis, NMR spectroscopy, MALDI MS and MS/MS. The lipid A structure is shown to be consistent with previously reported Bradyrhizobium lipid A, that is, a heterogeneous blend of penta‐ to hepta‐acylated species carrying a nonstoichiometric hopanoid unit and possessing very‐long‐chain fatty acids ranging from 26:0(25‐OH) to 32:0(31‐OH). The structure of the core oligosaccharide region, fully characterized for the first time here, is revealed to be a nonphosphorylated linear chain with methylated sugar residues, with a heptose residue exclusively present in the outer core region, and with the presence of two singly substituted 3‐deoxy‐d‐manno‐oct‐2‐ulosonic acid (Kdo) residues, one of which is located in the outer core region. The lipid A moiety is linked to the core moiety through an uncommon 4‐substituted Kdo unit.

Congenital disorders of glycosylation (CDG) are due to defective glycosylation of glycoconjugates. Conserved oligomeric Golgi (COG)-CDG are genetic diseases due to defects of the COG complex subunits 1-8 causing N-glycan and O-glycan processing abnormalities. In COG-CDG, isoelectric focusing separation of undersialylated glycoforms of serum transferrin and apolipoprotein C-III (apoC-III) allows to detect N-glycosylation and O-glycosylation defects, respectively. COG5-CDG (COG5 subunit deficiency) is a multisystem disease with dysmorphic features, intellectual disability of variable degree, seizures, acquired microcephaly, sensory defects and autistic behavior. We applied matrix-assisted laser desorption/ionization-MS for a high-throughput screening of differential serum O-glycoform and N-glycoform in five patients with COG5-CDG. When compared with age-matched controls, COG5-CDG showed a significant increase of apoC-III

In the present paper, we prove canonicity results for lattice-based fixed point logics in a constructive meta-theory. Specifically, we prove two types of canonicity results, depending on how the fixed-point binders are interpreted. These results smoothly unify the constructive canonicity results for inductive inequalities, proved in a general lattice setting, with the canonicity results for fixed point logics on a bi-intuitionistic base, proven in a non-constructive setting.

We introduce a proper display calculus for (non-distributive) Lattice Logic which is sound, complete, conservative, and enjoys cut-elimination and subformula property. Properness (i.e. closure under uniform substitution of all parametric parts in rules) is the main interest and added value of the present proposal, and allows for the smoothest Belnap-style proof of cut-elimination, and for the most comprehensive account of axiomatic extensions and expansions of Lattice Logic in a single overarching framework. Our proposal builds on an algebraic and order-theoretic analysis of the semantic environment of lattice logic, and applies the guidelines of the multi-type methodology in the design of display calculi.

We introduce a proper multi-type display calculus for semi De Morgan logic which is sound, complete, conservative, and enjoys cut-elimination and subformula property. Our proposal builds on an algebraic analysis of semi De Morgan algebras and applies the guidelines of the multi-type methodology in the design of display calculi.

The structure and the immunology of the lipopolysaccharide (LPS) of Pseudomonas entomophila, an entomopathogenic bacterium isolated from the fruit fly Drosophila melanogaster, was characterized. The O-antigen portion was established and resulted to be built up of a repetitive unit constituted by four monosaccharide residues, all L configured, all deoxy at C-6 and with an acetamido function at C-2: -> 3)-alpha-L-FucNAc-(1 -> 4)-alpha-L-FucNAc-(1 -> 3)-alpha-L-FucNAc-(1 -> 3)-beta-L-QuiNAc-(1 -> The structural analysis of lipid A, showed a mixture of different species. The diphosphorylated glucosamine backbone carries six fatty acids consistent with the composition C10:0 3(OH), C12:0 2(OH) and C12:0 3(OH), whereas other species differs by the number of phosphates and/or of fatty acids. The immunology experiments demonstrated that the LPS structure of P. entomophila displayed a low ability to engage the TLR4-mediated signaling correlated to a significant antagonistic activity toward hexa-acylated LPS structures. (C) 2015 Elsevier Ltd. All rights reserved.

MUC1 protein overexpressed in human epithelial carcinoma is a target in development of novel anticancer vaccines. Multiple units of immunodominant B-cell epitope PDTRP MUC1 core sequence were conjugated to calix[4,8]arene platforms containing TLR2 ligand, to produce two novel anticancer self-adjuvant vaccine candidates. The immunogenicity of the synthetic constructs was investigated by immunization of mice in vivo. ELISA assay evidenced that the vaccine candidates stimulate anti MUC1 IgG antibody production (major for the octavalent construct) and no additive effect but a multivalency effect was observed when compared to an analogous monovalent. Octa- and tetravalent constructs lacking in PDTRP peptide moieties did not show anti MUC1 IgG antibody production in mice. The antibodies induced by the synthesized constructs are able to recognize the MUC1 structures present on MCF7 tumor cells. The results display that calixarenes are convenient platforms for building multicomponent self-adjuvant vaccine constructs promising as immunotherapeutic anticancer agents.