Identification of mechanisms modulating chlorhexidine and octenidine susceptibility in Proteus mirabilis.

Aims: We aimed to identify mechanisms underlying the tolerance of Proteus mirabilis-a common cause of catheter associated urinary tract infection-to the clinically used biocides chlorhexidine (CHD) and octenidine (OCT).

Methods And Results: We adapted three clinical isolates to grow at concentrations of 512 µg ml-1 CHD and 128 µg ml-1 OCT. Genetic characterization and complementation studies revealed mutations inactivating the smvR repressor and increasing smvA efflux expression were associated with adaptation to both biocides.

Refinement of an ovine-based immunoglobulin therapy against SARS-CoV-2, with comparison of whole IgG versus F(ab') fragments.

The development of new therapies against SARS-CoV-2 is required to extend the toolkit of intervention strategies to combat the global pandemic. In this study, hyperimmune plasma from sheep immunised with whole spike SARS-CoV-2 recombinant protein has been used to generate candidate products. In addition to purified IgG, we have refined candidate therapies by removing non-specific IgG via affinity binding along with fragmentation to eliminate the Fc region to create F(ab') fragments.

Inhibition of phosphodiesterase 12 results in antiviral activity against several RNA viruses including SARS-CoV-2.

The 2',5'- oligoadenylate synthetase (OAS) - ribonuclease L (RNAseL) - phosphodiesterase 12 (PDE12) pathway is an essential interferon-induced effector mechanism against RNA virus infection. Inhibition of PDE12 leads to selective amplification of RNAseL activity in infected cells. We aimed to investigate PDE12 as a potential pan-RNA virus antiviral drug target and develop PDE12 inhibitors that elicit antiviral activity against a range of viruses.

Efflux-Related Carbapenem Resistance in Is Associated with Two-Component Regulatory Efflux Systems' Alteration and Insertion of ΔAbaR25-Type Island Fragment.

The efflux pumps, beside the class D carbapenem-hydrolysing enzymes (CHLDs), are being increasingly investigated as a mechanism of carbapenem resistance in . This study investigates the contribution of efflux mechanism to carbapenem resistance in 61 acquired -genes-carrying clinical strains isolated in Warsaw, Poland. Studies were conducted using phenotypic (susceptibility testing to carbapenems ± efflux pump inhibitors (EPIs)) and molecular (determining expression levels of efflux operon with regulatory-gene and whole genome sequencing (WGS)) methods.

Lipopolysaccharide structure modulates cationic biocide susceptibility and crystalline biofilm formation in .

Chlorhexidine (CHD) is a cationic biocide used ubiquitously in healthcare settings. , an important pathogen of the catheterized urinary tract, and isolates of this species are often described as "resistant" to CHD-containing products used for catheter infection control. To identify the mechanisms underlying reduced CHD susceptibility in , we subjected the CHD tolerant clinical isolate RS47 to random transposon mutagenesis and screened for mutants with reduced CHD minimum inhibitory concentrations (MICs).

Reagent prediction with a molecular transformer improves reaction data quality.

Automated synthesis planning is key for efficient generative chemistry. Since reactions of given reactants may yield different products depending on conditions such as the chemical context imposed by specific reagents, computer-aided synthesis planning should benefit from recommendations of reaction conditions. Traditional synthesis planning software, however, typically proposes reactions without specifying such conditions, relying on human organic chemists who know the conditions to carry out suggested reactions.

Streamlined Variational Inference for Linear Mixed Models with Crossed Random Effects.

We derive streamlined mean field variational Bayes algorithms for fitting linear mixed models with crossed random effects. In the most general situation, where the dimensions of the crossed groups are arbitrarily large, streamlining is hindered by lack of sparseness in the underlying least squares system. Because of this fact we also consider a hierarchy of relaxations of the mean field product restriction.

Future Speech Interfaces with Sensors and Machine Intelligence.

Speech is the most spontaneous and natural means of communication. Speech is also becoming the preferred modality for interacting with mobile or fixed electronic devices. However, speech interfaces have drawbacks, including a lack of user privacy; non-inclusivity for certain users; poor robustness in noisy conditions; and the difficulty of creating complex man-machine interfaces.

Efflux-mediated tolerance to cationic biocides, a cause for concern?

With an increase in the number of isolates resistant to multiple antibiotics, infection control has become increasingly important to help combat the spread of multi-drug-resistant pathogens. An important component of this is through the use of disinfectants and antiseptics (biocides). Antibiotic resistance has been well studied in bacteria, but little is known about potential biocide resistance genes and there have been few reported outbreaks in hospitals resulting from a breakdown in biocide effectiveness.

Development of a cost-effective ovine antibody-based therapy against SARS-CoV-2 infection and contribution of antibodies specific to the spike subunit proteins.

Antibodies against SARS-CoV-2 are important to generate protective immunity, with convalescent plasma one of the first therapies approved. An alternative source of polyclonal antibodies suitable for upscaling would be more amendable to regulatory approval and widespread use. In this study, sheep were immunised with SARS-CoV-2 whole spike protein or one of the subunit proteins: S1 and S2.

Mutations in SilS and CusS/OmpC represent different routes to achieve high level silver ion tolerance in Klebsiella pneumoniae.

Background: Silver ions have potent broad-spectrum antimicrobial activity and are widely incorporated into a variety of products to limit bacterial growth. In Enterobacteriaceae, decreased silver susceptibility has been mapped to two homologous operons; the chromosomally located cus operon and the plasmid based sil operon. Here we characterised the mechanisms and clinical impact of induced silver tolerance in Klebsiella pneumoniae.

Streamlined variational inference for higher level group-specific curve models.

A two-level group-specific curve model is such that the mean response of each member of a group is a separate smooth function of a predictor of interest. The three-level extension is such that one grouping variable is nested within another one, and higher level extensions are analogous. Streamlined variational inference for higher level group-specific curve models is a challenging problem.

Pseudomonas aeruginosa adapts to octenidine via a combination of efflux and membrane remodelling.

Pseudomonas aeruginosa is an opportunistic pathogen capable of stably adapting to the antiseptic octenidine by an unknown mechanism. Here we characterise this adaptation, both in the laboratory and a simulated clinical setting, and identify a novel antiseptic resistance mechanism. In both settings, 2 to 4-fold increase in octenidine tolerance was associated with stable mutations and a specific 12 base pair deletion in a putative Tet-repressor family gene (smvR), associated with a constitutive increase in expression of the Major Facilitator Superfamily (MFS) efflux pump SmvA.

Fast approximate inference for multivariate longitudinal data.

Collecting information on multiple longitudinal outcomes is increasingly common in many clinical settings. In many cases, it is desirable to model these outcomes jointly. However, in large data sets, with many outcomes, computational burden often prevents the simultaneous modeling of multiple outcomes within a single model.

Long-Term Exposure to Octenidine in a Simulated Sink Trap Environment Results in Selection of Pseudomonas aeruginosa, , and Isolates with Mutations in Efflux Pump Regulators.

Octenidine-based disinfection products are becoming increasingly popular for infection control of multidrug-resistant (MDR) Gram-negative isolates. When a waste trap was removed from a hospital and allowed to acclimatize in a standard tap rig in our laboratory, it was shown that , , and and spp. were readily isolated.

User training for machine learning controlled upper limb prostheses: a serious game approach.

Background: Upper limb prosthetics with multiple degrees of freedom (DoFs) are still mostly operated through the clinical standard Direct Control scheme. Machine learning control, on the other hand, allows controlling multiple DoFs although it requires separable and consistent electromyogram (EMG) patterns. Whereas user training can improve EMG pattern quality, conventional training methods might limit user potential.

Profiling protein expression in Klebsiella pneumoniae with a carbohydrate-based covalent probe.

We report the application of a covalent probe based on a d-glucosamine scaffold for the profiling of the bacterial pathogen Klebsiella pneumoniae. Incubation of K. pneumoniae lysates with the probe followed by electrophoretic separation and in-gel fluorescence detection allowed the generation of strain-specific signatures and the differentiation of a carbapenem-resistant strain.