Retreatment with HBV siRNA Results in Additional Reduction in HBV Antigenemia and Immune Stimulation in the AAV-HBV Mouse Model.

Background And Aims: Treatment with siRNAs that target HBV has demonstrated robust declines in HBV antigens. This effect is also observed in the AAV-HBV mouse model, which was used to investigate if two cycles of GalNAc-HBV-siRNA treatment could induce deeper declines in HBsAg levels or prevent rebound, and to provide insights into the liver immune microenvironment.

Methods: C57Bl/6 mice were transduced with one of two different titers of AAV-HBV for 28 days, resulting in stable levels of HBsAg of about 10 or 10 IU/mL.

N-glycosylation as a eukaryotic protective mechanism against protein aggregation.

The tendency for proteins to form aggregates is an inherent part of every proteome and arises from the self-assembly of short protein segments called aggregation-prone regions (APRs). While posttranslational modifications (PTMs) have been implicated in modulating protein aggregation, their direct role in APRs remains poorly understood. In this study, we used a combination of proteome-wide computational analyses and biophysical techniques to investigate the potential involvement of PTMs in aggregation regulation.

LRRC37B is a human modifier of voltage-gated sodium channels and axon excitability in cortical neurons.

The enhanced cognitive abilities characterizing the human species result from specialized features of neurons and circuits. Here, we report that the hominid-specific gene LRRC37B encodes a receptor expressed in human cortical pyramidal neurons (CPNs) and selectively localized to the axon initial segment (AIS), the subcellular compartment triggering action potentials. Ectopic expression of LRRC37B in mouse CPNs in vivo leads to reduced intrinsic excitability, a distinctive feature of some classes of human CPNs.

Exploiting the aggregation propensity of beta-lactamases to design inhibitors that induce enzyme misfolding.

There is an arms race between beta-lactam antibiotics development and co-evolving beta-lactamases, which provide resistance by breaking down beta-lactam rings. We have observed that certain beta-lactamases tend to aggregate, which persists throughout their evolution under the selective pressure of antibiotics on their active sites. Interestingly, we find that existing beta-lactamase active site inhibitors can act as molecular chaperones, promoting the proper folding of these resistance factors.

Enhanced therapeutic window for antimicrobial Pept-ins by investigating their structure-activity relationship.

The overconsumption and inappropriate use of antibiotics is escalating antibiotic resistance development, which is now one of the 10 top threats to global health. Introducing antibiotics with a novel mode of action into clinical use is urgently needed to address this issue. Deliberately inducing aggregation of target proteins and disrupting protein homeostasis in bacteria via amyloidogenic peptides, also called Pept-ins (from peptide interferors), can be lethal to bacteria and shows considerable promise as a novel antibiotic strategy.

An Nuclear Magnetic Resonance Fingerprint Matching Approach for the Identification and Structural Re-Evaluation of Pseudomonas Lipopeptides.

Cyclic lipopeptides (CLiPs) are secondary metabolites secreted by a range of bacterial phyla. CLiPs from Pseudomonas in particular, display diverse structural variations in terms of the number of amino acid residues, macrocycle size, amino acid identity, and stereochemistry (e.g.

Heterotypic Amyloid β interactions facilitate amyloid assembly and modify amyloid structure.

It is still unclear why pathological amyloid deposition initiates in specific brain regions or why some cells or tissues are more susceptible than others. Amyloid deposition is determined by the self-assembly of short protein segments called aggregation-prone regions (APRs) that favour cross-β structure. Here, we investigated whether Aβ amyloid assembly can be modified by heterotypic interactions between Aβ APRs and short homologous segments in otherwise unrelated human proteins.

Investigating the mechanism of action of aggregation-inducing antimicrobial Pept-ins.

Aggregation can be selectively induced by aggregation-prone regions (APRs) contained in the target proteins. Aggregation-inducing antimicrobial peptides (Pept-ins) contain sequences homologous to APRs of target proteins and exert their bactericidal effect by causing aggregation of a large number of proteins. To better understand the mechanism of action of Pept-ins and the resistance mechanisms, we analyzed the phenotypic, lipidomic, and transcriptomic as well as genotypic changes in laboratory-derived Pept-in-resistant E.

Structure-based machine-guided mapping of amyloid sequence space reveals uncharted sequence clusters with higher solubilities.

The amyloid conformation can be adopted by a variety of sequences, but the precise boundaries of amyloid sequence space are still unclear. The currently charted amyloid sequence space is strongly biased towards hydrophobic, beta-sheet prone sequences that form the core of globular proteins and by Q/N/Y rich yeast prions. Here, we took advantage of the increasing amount of high-resolution structural information on amyloid cores currently available in the protein databank to implement a machine learning approach, named Cordax (https://cordax.

Identification of the Molecular Determinants Involved in Antimicrobial Activity of Pseudodesmin A, a Cyclic Lipopeptide From the Viscosin Group.

Cyclic lipo(depsi)peptides (CLiPs) from constitute a class of natural products involved in a broad range of biological functions for their producers. They also display interesting antimicrobial potential including activity against Gram-positive bacteria. Literature has indicated that these compounds can induce membrane permeabilization, possibly through pore-formation, leading to the general view that the cellular membrane constitutes the primary target in their mode of action.

Autonomous aggregation suppression by acidic residues explains why chaperones favour basic residues.

Many chaperones favour binding to hydrophobic sequences that are flanked by basic residues while disfavouring acidic residues. However, the origin of this bias in protein quality control remains poorly understood. Here, we show that while acidic residues are the most efficient aggregation inhibitors, they are also less compatible with globular protein structure than basic amino acids.

Processing Induced Changes in Food Proteins: Amyloid Formation during Boiling of Hen Egg White.

Amyloid fibrils (AFs) are highly ordered protein nanofibers composed of cross β-structure that occur in nature, but that also accumulate in age-related diseases. Amyloid propensity is a generic property of proteins revealed by conditions that destabilize the native state, suggesting that food processing conditions may promote AF formation. This had only been shown for foie gras, but not in common foodstuffs.

WALTZ-DB 2.0: an updated database containing structural information of experimentally determined amyloid-forming peptides.

Transition of soluble proteins into insoluble amyloid fibrils is driven by self-propagating short sequence stretches. However, accurate prediction of aggregation determinants remains challenging. Here, we describe WALTZ-DB 2.

Categorical and dimensional psychopathology in Dutch and US offspring of parents with bipolar disorder: A preliminary cross-national comparison.

Objective: Accumulating evidence suggests cross-national differences in adults with bipolar disorder (BD), but also in the susceptibility of their offspring (bipolar offspring). This study aims to explore and clarify cross-national variation in the prevalence of categorical and dimensional psychopathology between bipolar offspring in the US and The Netherlands.

Methods: We compared levels of psychopathology in offspring of the Pittsburgh Bipolar Offspring Study (n=224) and the Dutch Bipolar Offspring Study (n=136) (age 10-18).

First total synthesis of WLIP: on the importance of correct protecting group choice.

Cyclic lipodepsipeptides (CLPs) are a group of metabolites produced by Pseudomonas bacteria, involved in various biological functions and displaying a wide range of properties, including antibacterial and antifungal activities. The white line-inducing principle (WLIP) is a member of the viscosin group featuring a Glu2 amino acid. Recently, a total synthesis of pseudodesmin A - the Gln2 counterpart of WLIP - was described, and we here expand this route to Glu2 containing CLPs.

Impact of a stereocentre inversion in cyclic lipodepsipeptides from the viscosin group: a comparative study of the viscosinamide and pseudodesmin conformation and self-assembly.

The viscosin group covers a series of cyclic lipodepsipeptides (CLPs) produced by Pseudomonas bacteria, with a range of biological functions and antimicrobial activities. Their oligopeptide moieties are composed of both L- and D-amino acids. Remarkably, the Leu5 amino acid-centrally located in the nonapeptide sequence-is the sole residue found to possess either an L or D configuration, depending on the producing strain.

Cyclic lipodepsipeptides produced by Pseudomonas spp. naturally present in raw milk induce inhibitory effects on microbiological inhibitor assays for antibiotic residue screening.

Two Pseudomonas strains, identified as closely related to Pseudomonas tolaasii, were isolated from milk of a farm with frequent false-positive Delvotest results for screening putative antibiotic residues in raw milk executed as part of the regulatory quality programme. Growth at 5 to 7°C of these isolates in milk resulted in high lipolysis and the production of bacterial inhibitors. The two main bacterial inhibitors have a molecular weight of 1168.

Rapid total synthesis of cyclic lipodepsipeptides as a premise to investigate their self-assembly and biological activity.

A rapid and efficient total synthesis is reported for the cyclic lipodepsipeptide pseudodesmin A. This member of the Pseudomonas viscosin group is active against Gram-positive bacteria and features self-assembling properties. A conserved serine residue within the lactone macrocycle is exploited for initial immobilization on 2-chlorotrityl chloride resin through ether formation with the side-chain alcohol.

Does assessment type matter? A measurement invariance analysis of online and paper and pencil assessment of the Community Assessment of Psychic Experiences (CAPE).

Background: The psychometric properties of an online test are not necessarily identical to its paper and pencil original. The aim of this study is to test whether the factor structure of the Community Assessment of Psychic Experiences (CAPE) is measurement invariant with respect to online vs. paper and pencil assessment.

The antimicrobial compound xantholysin defines a new group of Pseudomonas cyclic lipopeptides.

The rhizosphere isolate Pseudomonas putida BW11M1 produces a mixture of cyclic lipopeptide congeners, designated xantholysins. Properties of the major compound xantholysin A, shared with several other Pseudomonas lipopeptides, include antifungal activity and toxicity to Gram-positive bacteria, a supportive role in biofilm formation, and facilitation of surface colonization through swarming. Atypical is the lipopeptide's capacity to inhibit some Gram-negative bacteria, including several xanthomonads.

[An individual facial shield for a sportsman with an orofacial injury].

Facial shields are used when practising contact sports, high speed sports, sports using hard balls, sticks or bats, sports using protective shields or covers, and sports using hard boardings around the sports ground. Examples of facial shields are commercially available, per branch of sport standardised helmets. Fabricating individual protective shields is primarily restricted to mouth guards.

Water diffusion and acute stroke.

The occlusion of the middle cerebral artery was used as an experimental acute stroke model in 30 cats. The diffusion of water was followed by diffusion-sensitized MRI between 1 and 15 h after induction of stroke. It is demonstrated that images representing the trace of the diffusion tensor provide a much more accurate delineation of affected area than images representing the diffusion in one direction only.