Matrix Product Belief Propagation for reweighted stochastic dynamics over graphs.

Stochastic processes on graphs can describe a great variety of phenomena ranging from neural activity to epidemic spreading. While many existing methods can accurately describe typical realizations of such processes, computing properties of extremely rare events is a hard task, particularly so in the case of recurrent models, in which variables may return to a previously visited state. Here, we build on the matrix product cavity method, extending it fundamentally in two directions: First, we show how it can be applied to Markov processes biased by arbitrary reweighting factors that concentrate most of the probability mass on rare events. Second, we introduce an efficient scheme to reduce the computational cost of a single node update from exponential to polynomial in the node degree. Two applications are considered: inference of infection probabilities from sparse observations within the SIRS epidemic model and the computation of both typical observables and large deviations of several kinetic Ising models.

Structure of the type IX group B Streptococcus capsular polysaccharide and its evolutionary relationship with types V and VII.

The Group B Streptococcus capsular polysaccharide type IX was isolated and purified, and the structure of its repeating unit was determined. Type IX capsule → 4)[NeupNAc-α-(2 → 3)-Galp-ß-(1 → 4)-GlcpNAc-ß-(1 → 6)]-ß-GlcpNAc-(1 → 4)-ß-Galp-(1 → 4)-ß-Glcp-(1 → appears most similar to types VII and V, although it contains two GlcpNAc residues. Genetic analysis identified differences in cpsM, cpsO, and cpsI gene sequences as responsible for the differentiation between the three capsular polysaccharide types, leading us to hypothesize that type V emerged from a recombination event in a type IX background.

Defined conjugation of glycans to the lysines of CRM197 guided by their reactivity mapping.

Systematic characterisation of the reactivity of the lysine moieties in CRM197 towards N-hydroxysuccinimide linkers bearing alkynes or azides is described. This involves two-step conjugation of various glycans to CRM197 by click chemistry in a well-defined manner. By semiquantitative LC-MS/MS analysis of proteolytic digests of the conjugates formed, the reactivity of lysine residues in the protein was mapped and ranked. Computational analysis of the solvent accessibility of each lysine residue (based on the CRM197 crystal structure) established a correlation between reactivity and surface exposure. By this approach, conjugation involving lysine residues (normally a random process) can be controlled. It enables the preparation of lysine-mediated glycoconjugates with improved batch-to-batch reproducibility, thereby producing neo-glycoconjugates with more-consistent biological activity.

Tyrosine-directed conjugation of large glycans to proteins via copper-free click chemistry.

We have demonstrated that the insertion of alkyne-containing bifunctional linkers into the tyrosine residues of the carrier protein, followed by the copper mediated azide-alkyne [3 + 2] cycloaddition of carbohydrates, is a robust approach for the preparation of glycoconjugates with defined glycans, carrier, and connectivity. Conjugation of Group B Streptococcus (GBS) capsular polysaccharides to streptococcal pilus protein could extend the vaccine coverage to a variety of strains. Application of our protocol to these large charged polysaccharides occurred at low yields. Herein we developed a tyrosine-directed conjugation approach based on the copper-free click chemistry of sugars modified with cyclooctynes, which enables efficient condensation of synthetic carbohydrates. Most importantly, this strategy was demonstrated to be more effective than the corresponding copper catalyzed reaction for the insertion of GBS onto the tyrosine residues of GBS pilus proteins, previously selected as vaccine antigens through the so-called reverse vaccinology. Integrity of protein epitopes in the modified proteins was ascertained by competitive ELISA, and conjugation of polysaccharide to protein was confirmed by SDS page electrophoresis and immunoblot assays. The amount of conjugated polysaccharide was estimated by high-performance anion-exchange chromatography coupled with pulsed amperometric detection (HPAEC-PAD). The described technology is particularly suitable for proteins used with the dual role of vaccine antigen and carrier for the carbohydrate haptens.

Viscoelasticity of nematic liquid crystals at a glance.

Polarised microscopy is shown to be a powerful alternative to light scattering for the determination of the viscoelasticity of aligned nematic liquid crystals. We perform experiments in a wide range of temperatures by using an adapted version of the recently introduced differential dynamic microscopy technique, which enables us to extract scattering information directly from the microscope images. A dynamic analysis of the images acquired in different geometries provides the splay, twist and bend viscoelastic ratios. A static analysis allows a successful determination of the bend elastic constant. All our results are in excellent agreement with those obtained with the far more time-consuming depolarised light scattering techniques. Remarkably, a noteworthy extension of the investigated temperature-range is observed, owing to the lower sensitivity of microscopy to multiple scattered light. Moreover, we show that the unique space-resolving capacities of our method enable us to investigate nematics in the presence of spatial disorder, where traditional light scattering fails. Our findings demonstrate that the proposed scattering-with-images approach provides a space-resolved probe of the local sample properties, applicable also to other optically anisotropic soft materials.

Closest-vector problem and the zero-temperature p-spin landscape for lossy compression.

We consider a high-dimensional random constrained optimization problem in which a set of binary variables is subjected to a linear system of equations. The cost function is a simple linear cost, measuring the Hamming distance with respect to a reference configuration. Despite its apparent simplicity, this problem exhibits a rich phenomenology. We show that different situations arise depending on the random ensemble of linear systems. When each variable is involved in at most two linear constraints, we show that the problem can be partially solved analytically, in particular we show that upon convergence, the zero-temperature limit of the cavity equations returns the optimal solution. We then study the geometrical properties of more general random ensembles. In particular we observe a range in the density of constraints at which the system enters a glassy phase where the cost function has many minima. Interestingly, the algorithmic performances are only sensitive to another phase transition affecting the structure of configurations allowed by the linear constraints. We also extend our results to variables belonging to GF(q), the Galois field of order q. We show that increasing the value of q allows to achieve a better optimum, which is confirmed by the replica-symmetric cavity method predictions.

Rhodium-catalyzed enantioselective desymmetrization of bicyclic hydrazines with alkynylboronic esters.

The first successful asymmetric transfer of rhodium-alkynyl species to symmetrical strained alkenes has been realized starting from bicyclic hydrazines and alkynylboronic esters.

Regio- and stereoselective ring opening of enantiomerically enriched 2-aryl oxetanes and 2-aryl azetidines with aryl borates.

The regioselective ring opening of 2-aryl-substituted four-membered heterocyclic rings with phenols, including catechol, was achieved by the use of aryl borates in mild and neutral reaction conditions without the aid of any transition metal catalysts. While N-alkyl azetidines were found not to be reactive, optically active N-tosyl azetidines gave the corresponding beta-aryloxy amines in a racemic form, thus indicating the considerable carbocationic character of the transition state. The introduction of a hydroxyl group in the azetidine ring (i.e., an azetidinol), able to anchor the aryl borate and to direct the subsequent nucleophilic delivery, was shown to determine the ring-opening process with predominant inversion of configuration. When enantiomerically enriched 2-aryl oxetanes were used, the reduced extent of racemization observed (up to 93:7 er) was rationalized by an intramolecular delivery through a six-membered transition state, giving beta-aryloxy alcohols with a predominant retention of configuration (i.e., a syn-stereoselective ring opening). The aryloxy alcohols obtained, endowed with suitable functionalities, can be cyclized to give access to enantiomerically enriched 2-aryl-1,5-benzodioxepins.

Enantiopure cis-2,5-disubstituted 2,5-dihydropyrroles from D-glycal-derived vinyl aziridines.

Upon treatment with the K- and Li-enolates of a methylene active compound, such as dimethyl malonate and dibenzoylmethane, D-allal- and D-galactal-derived vinyl N-mesyl aziridines are stereoselectively transformed, in a unique step, into diastereoisomeric, highly functionalized, enantiopure cis-2,5-disubstituted N-mesyl-2,5-dihydropyrroles.

Copper-catalyzed Perkin-acyl-Mannich reaction of acetic anhydride with pyridine: expeditious entry to unconventional piperidines.

A regioselective introduction of a methoxycarbonyl methyl group at the C(2) position of unsubstituted pyridine has been accomplished with catalytic amounts of copper(II) triflate in mild reaction conditions. The N-acetyl-1,2-dihydropyridyl acetic acid methyl ester obtained is a valuable building block for the synthesis of new polyfunctionalized piperidine derivatives bearing unconventional substitution patterns.

Regioselective copper-catalyzed alkylation of [2.2.2]-acylnitroso cycloadducts: remarkable effect of the halide of Grignard reagents.

Ring opening with organometallic reagents of [2.2.2]-acylnitroso cycloadducts, including an enantioselective kinetic resolution of these compounds, has been accomplished for the first time. By the careful choice of reaction conditions, it was possible to obtain new cyclohexenyl hydroxamic acids with complete anti-stereoselectivity and a nice regioalternating control. A remarkable effect of the halogen of the Grignard reagent was observed during ring opening.

Nickel-catalyzed borylative ring opening of vinyl epoxides and aziridines.

A mild ring opening of vinyl epoxides and aziridines with B(2)Pin(2) catalyzed by Ni(0)-Binap affords new functionalized allylic boron derivatives which undergo sequential transformations. The uncatalyzed allylation of aldehydes allows obtaining challenging bishomoallylic alicyclic 1,3-diols and 1,3-amino alcohols with remarkably high stereoselectivities. Valuable trans-bisallylic 1,4-amino alcohols can be obtained by a simple oxidation.