Improvement of Aglycone π-Stacking Yields Nanomolar to Sub-nanomolar FimH Antagonists

Antimicrobial resistance has become a serious concern for the treatment of urinary tract infections. In this context, an anti-adhesive approach targeting FimH, a bacterial lectin enabling the attachment of E. coli to host cells, has attracted considerable interest. FimH can adopt a low/medium-affinity state in the absence and a high-affinity state in the presence of shear forces. Until recently, mostly the high-affinity state has been investigated, despite the fact that a therapeutic antagonist should bind predominantly to the low-affinity state. In this communication, we demonstrate that fluorination of biphenyl α-d -mannosides leads to compounds with perfect π–π stacking interactions with the tyrosine gate of FimH, yielding low nanomolar to sub-nanomolar K_D values for the low- and high-affinity states, respectively. The face-to-face alignment of the perfluorinated biphenyl group of FimH ligands and Tyr48 was confirmed by crystal structures as well as ¹H,¹⁵N-HSQC NMR analysis. Finally, fluorination improves pharmacokinetic parameters predictive for oral availability.     

Interleukins 6 and 15 Levels Are Higher in Subcutaneous Adipose Tissue,but Obesity Is Associated with Their Increased Content in Visceral Fat Depots

Excess adiposity is associated with chronic inflammation, which takes part in the development of obesity-related complications. The aim of this study was to establish whether subcutaneous (SAT) or visceral (VAT) adipose tissue plays a major role in synthesis of pro-inflammatory cytokines. Concentrations of interleukins (IL): 1β, 6, 8 and 15 were measured at the protein level by an ELISA-based method and on the mRNA level by real-time PCR in VAT and SAT samples obtained from 49 obese (BMI > 40 kg/m²) and 16 normal-weight (BMI 20–24.9 kg/m²) controls. IL-6 and IL-15 protein concentrations were higher in SAT than in VAT for both obese (p = 0.003 and p < 0.0001, respectively) and control individuals (p = 0.004 and p = 0.001, respectively), while for IL-1β this was observed only in obese subjects (p = 0.047). What characterized obese individuals was the higher expression of IL-6 and IL-15 at the protein level in VAT compared to normal-weight controls (p = 0.047 and p = 0.016, respectively). Additionally, obese individuals with metabolic syndrome had higher IL-1β levels in VAT than did obese individuals without this syndrome (p = 0.003). In conclusion, concentrations of some pro-inflammatory cytokines were higher in SAT than in VAT, but it was the increased pro-inflammatory activity of VAT that was associated with obesity and metabolic syndrome.     

Interpretable segmentation of medical free-text records based on word embeddings

Journal of Intelligent Information Systems - Medical free-text records store a lot of useful information that can be exploited in developing computer-supported medicine. However, extracting the...     

Evaluation of Damage Degree of Inconel 718 Alloy with the Use of Non-Destructive Methods

The article presents results of the investigation of the quantitative evaluation of the degree of damage, described by the measure of accumulated plastic strain obtained in a static tensile test, using selected non-destructive techniques. Inconel 718 alloy was tested. The tests were conducted using a new type of specimens of variable cross-sectional area of measuring part. This provided a continuous distribution of plastic strain in the gage part of the specimen. The permanent deformation that varies along the sample axis enables an analysis of damage induced by a plastic deformation. The proposed method enables replacing the series of specimens by one sample. Degradation of the alloy corresponds with the changes of the electromagnetic properties of the material—the phase angle of the complex impedance of the eddy current, as well as with acoustics properties of material—acoustic birefringence of ultrasonic waves. It allows to determine the degree of damage of the material using noninvasive, non-destructive methods. Using the damage parameter proposed by Johnson it is possible to obtain the correlation between the non-destructive results and a damage degree of the material. The presented testing method delivers information about changes in the material structure caused by permanent deformation.

     

The Impact of Selected Bacterial Sexually Transmitted Diseases on Pregnancy and Female Fertility

Sexually transmitted infections (STIs) caused by Neisseria gonorrhoeae, Chlamydia trachomatis and Mycoplasma genitalium are a common cause of pelvic inflammatory disease (PID) which can lead to tubal factor infertility (TFI). TFI is one of the most common causes of infertility, accounting for 30% of female fertility problems. STIs can also have an impact on pregnancy, leading to adverse pregnancy outcomes. Escalating antibiotic resistance in Neisseria gonorrhoeae and Mycoplasma genitalium represents a significant problem and can be therapeutically challenging. We present a comprehensive review of the current treatment options, as well as the molecular approach to this subject. We have given special attention to molecular epidemiology, molecular diagnostics, current and new treatments, and drug resistance.     

A non-local fractional stress–strain gradient theory

International Journal of Mechanics and Materials in Design - A generalized non-local stress–strain gradient theory is presented using fractional calculus. The proposed theory includes as a...     

Nanomotion Detection Method for Testing Antibiotic Resistance and Susceptibility of Slow‐Growing Bacteria

Infectious diseases are caused by pathogenic microorganisms and are often severe. Time to fully characterize an infectious agent after sampling and to find the right antibiotic and dose are important factors in the overall success of a patient's treatment. Previous results suggest that a nanomotion detection method could be a convenient tool for reducing antibiotic sensitivity characterization time to several hours. Here, the application of the method for slow‐growing bacteria is demonstrated, taking Bordetella pertussis strains as a model. A low‐cost nanomotion device is able to characterize B. pertussis sensitivity against specific antibiotics within several hours, instead of days, as it is still the case with conventional growth‐based techniques. It can discriminate between resistant and susceptible B. pertussis strains, based on the changes of the sensor's signal before and after the antibiotic addition. Furthermore, minimum inhibitory and bactericidal concentrations of clinically applied antibiotics are compared using both techniques and the suggested similarity is discussed.