Mutational background influences P. aeruginosa ciprofloxacin resistance evolution but preserves collateral sensitivity robustness.

Collateral sensitivity is an evolutionary trade-off whereby acquisition of the adaptive phenotype of resistance to an antibiotic leads to the nonadaptive increased susceptibility to another. The feasibility of harnessing such a trade-off to design evolutionary-based approaches for treating bacterial infections has been studied using model strains. However, clinical application of collateral sensitivity requires its conservation among strains presenting different mutational backgrounds. Particularly relevant is studying collateral sensitivity robustness of already-antibiotic-resistant mutants when challenged with a new antimicrobial, a common situation in clinics that has hardly been addressed. We submitted a set of diverse Pseudomonas aeruginosa antibiotic-resistant mutants to short-term evolution in the presence of different antimicrobials. Ciprofloxacin selects different clinically relevant resistance mutations in the preexisting resistant mutants, which gave rise to the same, robust, collateral sensitivity to aztreonam and tobramycin. We then experimentally determined that alternation of ciprofloxacin with aztreonam is more efficient than ciprofloxacin­tobramycin alternation in driving the extinction of the analyzed antibiotic-resistant mutants. Also, we show that the combinations ciprofloxacin­aztreonam or ciprofloxacin­tobramycin are the most effective strategies for eliminating the tested P. aeruginosa antibiotic-resistant mutants. These findings support that the identification of conserved collateral sensitivity patterns may guide the design of evolution-based strategies to treat bacterial infections, including those due to antibiotic-resistant mutants. Besides, this is an example of phenotypic convergence in the absence of parallel evolution that, beyond the antibiotic-resistance field, could facilitate the understanding of evolution processes, where the selective forces giving rise to new, not clearly adaptive phenotypes remain unclear.

Diagnostic imaging of the diabetic foot: an EANM evidence-based guidance.

PURPOSE: Consensus on the choice of the most accurate imaging strategy in diabetic foot infective and non-infective complications is still lacking. This document provides evidence-based recommendations, aiming at defining which imaging modality should be preferred in different clinical settings. METHODS: This working group includes 8 nuclear medicine physicians appointed by the European Association of Nuclear Medicine (EANM), 3 radiologists and 3 clinicians (one diabetologist, one podiatrist and one infectious diseases specialist) selected for their expertise in diabetic foot. The latter members formulated some clinical questions that are not completely covered by current guidelines. These questions were converted into statements and addressed through a systematic analysis of available literature by using the PICO (Population/Problem-Intervention/Indicator-Comparator-Outcome) strategy. Each consensus statement was scored for level of evidence and for recommendation grade, according to the Oxford Centre for Evidence-Based Medicine (OCEBM) criteria. RESULTS: Nine clinical questions were formulated by clinicians and used to provide 7 evidence-based recommendations: (1) A patient with a positive probe-to-bone test, positive plain X-rays and elevated ESR should be treated for presumptive osteomyelitis (OM). (2) Advanced imaging with MRI and WBC scintigraphy, or [18F]FDG PET/CT, should be considered when it is needed to better evaluate the location, extent or severity of the infection, in order to plan more tailored treatment. (3) In a patient with suspected OM, positive PTB test but negative plain X-rays, advanced imaging with MRI or WBC scintigraphy + SPECT/CT, or with [18F]FDG PET/CT, is needed to accurately assess the extent of the infection. (4) There are no evidence-based data to definitively prefer one imaging modality over the others for detecting OM or STI in fore- mid- and hind-foot. MRI is generally the first advanced imaging modality to be performed. In case of equivocal results, radiolabelled WBC imaging or [18F]FDG PET/CT should be used to detect OM or STI. (5) MRI is the method of choice for diagnosing or excluding Charcot neuro-osteoarthropathy; [18F]FDG PET/CT can be used as an alternative. (6) If assessing whether a patient with a Charcot foot has a superimposed infection, however, WBC scintigraphy may be more accurate than [18F]FDG PET/CT in differentiating OM from Charcot arthropathy. (7) Whenever possible, microbiological or histological assessment should be performed to confirm the diagnosis. (8) Consider appealing to an additional imaging modality in a patient with persisting clinical suspicion of infection, but negative imaging. CONCLUSION: These practical recommendations highlight, and should assist clinicians in understanding, the role of imaging in the diagnostic workup of diabetic foot complications.

Transcriptomic profiling of an evolved Yarrowia lipolytica strain: tackling hexanoic acid fermentation to increase lipid production from short-chain fatty acids.

BACKGROUND: Short-chain fatty acids (SCFAs) are cost-effective carbon sources for an affordable production of lipids. Hexanoic acid, the acid with the longest carbon chain in the SCFAs pool, is produced in anaerobic fermentation of organic residues and its use is very challenging, even inhibiting oleaginous yeasts growth. RESULTS: In this investigation, an adaptive laboratory evolution (ALE) was performed to improve Yarrowia lipolytica ACA DC 50109 tolerance to high hexanoic acid concentrations. Following ALE, the transcriptomic analysis revealed several genetic adaptations that improved the assimilation of this carbon source in the evolved strain compared to the wild type (WT). Indeed, the evolved strain presented a high expression of the up-regulated gene YALI0 E16016g, which codes for FAT1 and is related to lipid droplets formation and responsible for mobilizing long-chain acids within the cell. Strikingly, acetic acid and other carbohydrate transporters were over-expressed in the WT strain. CONCLUSIONS: A more tolerant yeast strain able to attain higher lipid content under the presence of high concentrations of hexanoic acid has been obtained. Results provided novel information regarding the assimilation of hexanoic acid in yeasts.

Magnetoelastic Coupling Evidence by Anisotropic Crossed Thermal Expansion in Magnetocaloric RSrCoFeO6 (R = Sm, Eu) Double Perovskites.

Double perovskite oxides, characterized by their tunable magnetic properties and robust interconnection between the lattice and magnetic degrees of freedom, present an enticing foundation for advanced magnetic refrigeration materials. Herein, we delve into the influence of rare-earth elements on RSrCoFeO6 (R = Sm, Eu) disordered double perovskites by examining their structural, electronic, magnetic, and magnetocaloric properties. Temperature-dependent synchrotron X-ray diffraction analysis confirmed the stability of the orthorhombic phase (Pnma) across a wide temperature range. X-ray photoemission spectroscopy revealed that both Sm and Eu are in the 3+ state, whereas multiple states for Co2+/3+ and Fe3+/4+ are identified. The magnetic investigation and magnetocaloric effect (MCE) analysis brought to light the presence of a long-range antiferromagnetic (AFM) order with a second-order phase transition (SOPT) in both samples. The maximum magnetic entropy change ΔSMmax was approximately 0.9 J/kg K for both samples at applied field 0-7 T, manifesting prominently above Neel temperatures TN ≈ 93 K (Sm) and 84 K (Eu). Nevertheless, different relative cooling powers (RCP) of 112.6 J/kg (Sm) and 95.5 J/kg (Eu) were observed. A detailed analysis of the temperature-dependent lattice parameters shed light on a distinct magnetocaloric effect across the magnetic transition temperature, unveiling an anisotropic thermal expansion [αV = 1.41 × 10-5 K-1 (Sm) and αV = 1.54 × 10-5 K-1 (Eu)] wherein the thermal expansion axial ratio αbSm/αbEu = 0.61 became lower with increasing temperature, which suggests that the Eu sample experiences a greater thermal expansion in the b-axis direction. At the atomic bonding level, the evidence for magnetoelastic coupling around the magnetic transition temperatures TN was found through the anomalies along the average Co/Fe-O bond distance, formal valence, octahedral distortion, as well as an anisotropic lattice expansion.

Unveiling the Structural Properties, Optical Behavior, and Thermoelectric Performance of 2D CsSn2Br5 Halide Obtained by Mechanochemistry.

Metal halide perovskites with a two-dimensional structure are utilized in photovoltaics and optoelectronics. High-crystallinity CsSn2Br5 specimens have been synthesized via ball milling. Differential scanning calorimetry curves show melting at 553 K (endothermic) and recrystallization at 516 K (exothermic). Structural analysis using synchrotron X-ray diffraction data, collected from 100 to 373 K, allows for the determination of Debye model parameters. This analysis provides insights into the relative Cs-Br and Sn-Br chemical bonds within the tetragonal structure (space group: I4/mcm), which remains stable throughout the temperature range studied. Combined with neutron data, X-N techniques permit the identification of the Sn2+ lone electron pair (5s2) in the two-dimensional framework, occupying empty space opposite to the four Sn-Br bonds of the pyramidal [SnBr4] coordination polyhedra. Additionally, diffuse reflectance UV-vis spectroscopy unveils an indirect optical gap of approximately ∼3.3 eV, aligning with the calculated value from the B3LYP-DFT method (∼3.2 eV). The material exhibits a positive Seebeck coefficient as high as 6.5 × 104 µV K-1 at 350 K, which evolves down to negative values of -3.0 × 103 µV K-1 at 550 K, surpassing values reported for other halide perovskites. Notably, the thermal conductivity remains exceptionally low, between 0.32 and 0.25 W m-1 K-1.

Inter-observer reliability of the Onychomycosis Severity Index depending on clinical experience: A review of 50 cases.

BACKGROUND: Onychomycosis (ONM) is the most prevalent nail unit pathology, and its severity and monitoring are often based on the visual judgement of clinicians. OBJECTIVE: The objective of this study is to assess the reliability of the Onychomycosis Severity Index (OSI) classification when utilized by three clinicians with varying levels of clinical experience: an experienced podiatrist (with 5 years of experience), a moderately experienced podiatrist (with 2 years of experience) and an inexperienced podiatrist (a recent graduate familiar with the OSI classification but lacking clinical experience). Additionally, we compared the severity assessments made through visual inspection with those determined using the OSI by different clinicians. METHODS: We evaluated reliability using the intraclass correlation index (ICC), analysing 50 images of ONM. RESULTS: The OSI demonstrated a very high level of reliability (ICC: 0.889) across clinicians, irrespective of their experience levels. Conversely, a statistically significant increase in severity was observed when comparing visual assessments with the OSI (p < .001) for ONM severity evaluation. CONCLUSION: The OSI proves to be a reproducible classification system, regardless of the clinical experience of the practitioner employing it.

Evaluation of usability, adherence, and clinical efficacy of therapeutic footwear in persons with diabetes at moderate to high risk of diabetic foot ulcers: A multicenter prospective study.

OBJECTIVE: To evaluate therapeutic footwear expectations and usability of individuals with diabetes and foot complications. DESIGN: A prospective multicenter study was conducted on participants with a high risk of developing a diabetic foot ulcer. SETTING: Participants were enrolled in 11 different specialized diabetic foot units in Spain between March 2022 and June 2023. SUBJECTS: Patients with diabetes at moderate to high risk of foot ulceration receiving first therapeutic footwear prescription. INTERVENTIONS: All the patients included in the research were prescribed with their first pair of therapeutic footwear. MAIN MEASURES: Primary outcome measures were MOS-pre and MOS-post questionnaires evaluating use and usability of prescribed therapeutic footwear. Secondary outcome measures aimed to evaluate footwear clinical efficacy as ulceration rate and self-reported perceived walking distance per day. RESULTS: The use of therapeutic footwear exceeded the patient's pre-provision prediction of their anticipated use in 94% of people (n = 126). Based on the visual analogic satisfaction scale, the median satisfaction of daily wearing their therapeutic footwear was 7 points, Interquartile Range (IQR) [5-8.25]. During the follow-up period, 39 participants (29.1%) experienced diabetic foot ulcer. Perceived walking distance participants reported an improvement in their perceived walking ability during various daily life activities. CONCLUSIONS: Diabetes patients at moderate to high risk of diabetic foot ulcer improved their perception of walking ability after therapeutic footwear prescription. Adherence to the therapeutic footwear prescription resulted in less ulcerations.

Randomized Double-blind Cost-effectiveness Comparison of Two 10% Urea Creams in Patients with Diabetic Foot Syndrome.

OBJECTIVE: To evaluate the cost-effectiveness of two 10% urea creams in patients with diabetic foot syndrome. METHODS: This was a prospective, longitudinal, single-center, randomized, double-blind, prospective clinical trial that evaluated the skin quality of 20 feet belonging to 10 patients with diabetic foot syndrome after the application of two 10% urea creams purchased from pharmacies and supermarkets. RESULTS: At follow-up, 19 (95%) of the participants' feet showed improved skin quality, irrespective of the cream applied. On visual inspection, participants had a decreased presence of xerosis, hyperkeratosis, and preulcerative signs such as subkeratotic bruising and areas of redness on the dorsum of the toes. At the 3-month follow-up, nine (90%) of the participants stated that they had continued to apply the cream as a method of self-management to prevent complications. CONCLUSIONS: Creams containing 10% urea purchased in supermarkets improve foot skin quality in patients with diabetic foot syndrome, regardless of their cost. Based on these findings, the authors recommend creams containing 10% urea as a self-management tool for patients with diabetic foot syndrome.

Health-related quality of life among Spanish patients with diabetic foot ulcer according to Diabetic Foot Ulcer Scale - Short Form.

AIM: The aim of this study was to investigate the health-related quality of life of Spanish outpatients with diabetic foot ulcer using the Diabetic Foot Scale-Short Form (DFS-SF). MATERIALS AND METHODS: This cross-sectional observational study included 141 outpatients with diabetic foot ulcers (DFU). The DFS-SF was applied in personal interviews conducted by a trained investigator to assess health-related quality of life (HRQoL). RESULTS: The domain related to "worried about ulcers" had the lowest in score [50 (27.5-65.0)], and the highest score was in the physical health domain [76 (60.0-88.0)]. There was a statistically significant difference in the ulcer type and the physical health subscale, finding the lowest values in the physical health subscale in patients with ischaemic diabetic foot ulcers [58 (39.0-70.0), p = 0.007]. In the multivariable analysis the domains Leisure (OR 0.98, 95% CI 0.97-0.99) and worried about ulcers/feet (OR 0.98, 95% CI 0.96-0.99) were identified as significant independent domains in patients with the experience of a previous minor amputation. A significant negative correlation was observed between the SINBAD DFU score and leisure (r = -0.181, p = 0.032), physical health (r = -0.202, p = 0.016), dependence/daily life (r = -0.232, p = 0.006), and the "bothered by ulcer care" (r = -0.239, p = 0.004) domains of the DFS-SF. The ulcer duration had a significant negative correlation with all the domains of DFS-SF. CONCLUSION: The DFS-SF survey is a specific instrument that could be implemented in diabetic foot units as part of the management of patients with DFU to evaluate HRQoL. The domain of "worried about ulcers" had the lowest score in our population suggesting that clinicians should try to work on the emotional state of patients with DFU. The mean duration of DFU was the most influential factor related to worse scores followed by previous amputations. The SINBAD score had significant negative correlations suggesting that HRQoL may be related to the severity of DFU in this study population.

Role of bacterial multidrug efflux pumps during infection.

Multidrug efflux pumps are protein complexes located in the cell envelope that enable bacteria to expel, not only antibiotics, but also a wide array of molecules relevant for infection. Hence, they are important players in microbial pathogenesis. On the one hand, efflux pumps can extrude exogenous compounds, including host-produced antimicrobial molecules. Through this extrusion, pathogens can resist antimicrobial agents and evade host defenses. On the other hand, efflux pumps also have a role in the extrusion of endogenous compounds, such as bacterial intercommunication signaling molecules, virulence factors or metabolites. Therefore, efflux pumps are involved in the modulation of bacterial behavior and virulence, as well as in the maintenance of the bacterial homeostasis under different stresses found within the host. This review delves into the multifaceted roles that efflux pumps have, shedding light on their impact on bacterial virulence and their contribution to bacterial infection. These observations suggest that strategies targeting bacterial efflux pumps could both reinvigorate the efficacy of existing antibiotics and modulate the bacterial pathogenicity to the host. Thus, a comprehensive understanding of bacterial efflux pumps can be pivotal for the development of new effective strategies for the management of infectious diseases.

Fluid handling by foam wound dressings: From engineering theory to advanced laboratory performance evaluations.

This article describes the contemporary bioengineering theory and practice of evaluating the fluid handling performance of foam-based dressings, with focus on the important and clinically relevant engineering structure-function relationships and on advanced laboratory testing methods for pre-clinical quantitative assessments of this common type of wound dressings. The effects of key wound dressing material-related and treatment-related physical factors on the absorbency and overall fluid handling of foam-based dressings are thoroughly and quantitively analysed. Discussions include exudate viscosity and temperature, action of mechanical forces and the dressing microstructure and associated interactions. Based on this comprehensive review, we propose a newly developed testing method, experimental metrics and clinical benchmarks that are clinically relevant and can set the standard for robust fluid handling performance evaluations. The purpose of this evaluative framework is to translate the physical characteristics and performance determinants of a foam dressing into achievable best clinical outcomes. These guiding principles are key to distinguishing desirable properties of a dressing that contribute to optimal performance in clinical settings.

Rapid Decline of Ceftazidime Resistance in Antibiotic-Free and Sublethal Environments Is Contingent on Genetic Background.

Trade-offs of antibiotic resistance evolution, such as fitness cost and collateral sensitivity (CS), could be exploited to drive evolution toward antibiotic susceptibility. Decline of resistance may occur when resistance to other drug leads to CS to the first one and when compensatory mutations, or genetic reversion of the original ones, reduce fitness cost. Here we describe the impact of antibiotic-free and sublethal environments on declining ceftazidime resistance in different Pseudomonas aeruginosa resistant mutants. We determined that decline of ceftazidime resistance occurs within 450 generations, which is caused by newly acquired mutations and not by reversion of the original ones, and that the original CS of these mutants is preserved. In addition, we observed that the frequency and degree of this decline is contingent on genetic background. Our results are relevant to implement evolution-based therapeutic approaches, as well as to redefine global policies of antibiotic use, such as drug cycling.

Cryotherapy versus topical nitric-zinc complex solution for the treatment of plantar warts: A randomized controlled trial.

Cryotherapy is commonly regarded as the primary treatment method for plantar warts. A new medical device called nitric-zinc complex solution (NZCS) has also emerged as a potential alternative for wart treatment. The main aim of this study was to analyze and compare the effectiveness of cryotherapy using liquid nitrogen and NZCS in treating plantar warts. We conducted a randomized and controlled clinical trial involving patients with plantar warts. A total of 62 patients were enrolled in the study and monitored for 12 weeks or until their warts were completely resolved. The patients received either cryotherapy or NZCS, with a maximum of six treatment applications. The cure rate was 65.5% in the group treated with cryotherapy and 56.6% in the group treated with NZCS. The average number of treatment applications required for curing warts was significantly lower in the cured group (3.28 ± 1.63) than in the group with unresolved warts (5.5 ± 1.27) (p < 0.01). Moreover, the average number of applications was lower in the cryotherapy group (3.6 ± 1.8) than in the NZCS group (4.8 ± 1.8) (p < 0.01). Based on the findings, NZCS could be considered a favorable first-line treatment option for plantar warts.

Chylothorax in newborns after cardiac surgery: a rare complication?

The aim of this study was to analyze patients diagnosed with chylothorax after congenital heart disease surgery among a cohort of neonatal patients, comparing the evolution, complications, and prognosis after surgery of patients who were and were not diagnosed with chylothorax, and to analyze possible risk factors that may predict the appearance of chylothorax in this population. Retrospective and observational study included all neonates (less than 30 days since birth) who underwent congenital heart disease surgery in a level III neonatal intensive care department. We included infants born between January 2014 and December 2019. We excluded those infants who were born before 34 weeks of gestational age or whose birth weight was less than 1800 g. We also excluded catheter lab procedures and patent ductus arteriosus closure surgeries. Included patients were divided into two groups depending on whether they were diagnosed with chylothorax or not after surgery, and both groups were compared in terms of perinatal-obstetrical information, surgical data, and NICU course after surgery. We included 149 neonates with congenital heart disease surgery. Thirty-one patients (20.8%) developed chylothorax, and in ten patients (32.3%), it was considered large volume chylothorax. Regarding the evolution of these patients, 22 infants responded to general dietetic measures, a catheter procedure was performed in 9, and 5 of them finally required pleurodesis. Cardiopulmonary bypass, median sternotomy, and delayed sternal closure were the surgical variables associated with higher risks of chylothorax. Patients with chylothorax had a longer duration of inotropic support and mechanical ventilation and took longer to reach full enteral feeds. As complications, they had higher rates of cholestasis, catheter-related sepsis, and venous thrombosis. Although there were no differences in neonatal mortality, patients with chylothorax had a higher rate of mortality after the neonatal period. In a multiple linear regression model, thrombosis and cardiopulmonary bypass multiplied by 10.0 and 5.1, respectively, the risk of chylothorax and have an umbilical vein catheter decreases risk. CONCLUSION: We have found a high incidence of chylothorax after neonatal cardiac surgery, which prolongs the average stay and causes significant morbidity and mortality. We suggested that chylothorax could be an underestimated complication of congenital heart disease surgery during the neonatal period. WHAT IS KNOWN: • Acquired chylothorax in the neonatal period usually appears as a complication of congenital heart disease surgery, being the incidence quite variable among the different patient series (2.5-16.8%). The appearance of chylothorax as a complication of a cardiac surgery increases both mortality and morbidity in these patients, which makes it a quality improvement target in the postsurgical management of this population. WHAT IS NEW: •Most of the published studies include pediatric patients of all ages, from newborns to teenagers, and there is a lack of studies focusing on neonatal populations. The main strength of our study is that it reports, to the best of our knowledge, one of the largest series of neonatal patients receiving surgery for congenital heart disease in the first 30 days after birth. We have found a high incidence of chylothorax after cardiac surgery during the neonatal period compared to other studies. We suggested that chylothorax could be an underestimated complication of congenital heart disease surgery during this period of life.

Onychomycosis associated with diabetic foot syndrome: A systematic review.

BACKGROUND: A systematic review was conducted to investigate the prevalence of onychomycosis in patients with diabetes. The association of onychomycosis with risk factors in patients with diabetic foot syndrome was also examined. METHODS: The recommendations in the preferred reporting items for systematic reviews and meta-analysis (PRISMA) checklist were applied, and the included studies were assessed using the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) method. Searches were conducted in October 2022 using PubMed (Medline) and Scopus for clinical studies, clinical trials, comparative studies, observational studies, and randomised clinical trials or controlled clinical trials addressing the prevalence and consequences of onychomycosis in patients with diabetes, diagnoses or treatments. Two authors performed the study selection and data extraction, and any discrepancies between the two reviewers were resolved through discussion with a third reviewer. RESULTS: The systematic review included ten studies that met the inclusion criteria, and these studies enrolled 5664 patients with diabetes. Among these patients, 29.18% had onychomycosis that was mainly caused by Trichophyton rubrum. A significant association was found between the occurrence of onychomycosis and the presence of diabetic neuropathy (p = .012) and elevated glycosylated haemoglobin values (p = .039). There was no significant association between onychomycosis and ulceration (p = .185). Eight studies had a grade 4 level of evidence and a grade C recommendation, and one study had a grade 1b level of evidence and a grade A recommendation. CONCLUSION: The information described in the literature is insufficient and heterogeneous regarding the association of risk factors and ulceration in patients with diabetic foot compared with developing onychomycosis. There is also a need to implement onychomycosis diagnostic testing instead of relying only on a clinical diagnosis. Additional prospective, randomised, comparative studies are needed to increase the quality of studies in the literature.

Microbiological culture combined with PCR for the diagnosis of onychomycosis: Descriptive analysis of 121 patients.

BACKGROUND: Onychomycosis is the most common nail pathology, involving various pathogens such as dermatophytes, moulds and yeasts. OBJECTIVE: The objective of this study was to observe the prevalence of onychomycosis, analyse the most appropriate diagnostic test, and assess the distribution of pathogens based on age, sex, quarter of the year, duration of symptoms and previous treatment. METHODS: Retrospectively, mycological culture and PCR data and results were collected from 121 patients. RESULTS: Of the 121 samples, 57% (69/121) tested positive when both microbiological study techniques were combined. The prevalence of onychomycosis was higher when PCR was performed (52.1%) compared to microbiological culture (33.1%). Among the 81 samples negative by microbiological culture, 31 were positive by PCR. Similarly, of the 58 samples negative by PCR, eight were positive by microbiological culture. Diagnostic accuracy data (with 95% confidence intervals) for PCR, using microbiological culture as the gold standard, were as follows: sensitivity of 0.8, specificity of 0.62, positive predictive value of 0.51 and negative predictive value of 0.86. The most frequently identified pathogen was Trichophyton rubrum, and the hallux nail plate was the most commonly affected location. However, no statistically significant associations were found between sex, age, quarter of the year and affected area with culture and PCR results. CONCLUSION: Combining microbiological culture and PCR can increase the detection rate of onychomycosis and help avoid false-negative results.

Exploring Coumarin-Based Boron Emissive Complexes as Temperature Thermometers in Polymer-Supported Materials.

Three coumarin-based boron complexes (L1, L2 and L3) were designed and successfully incorporated into polymeric matrixes for evaluation as temperature probes. The photophysical properties of the complexes were carried out in different solvents and in the solid state. In solution, compound L1 exhibited the highest fluorescence quantum yield, 33%, with a positive solvatochromism also being observed on the absorption and emission when the polarity of the solvent increased. Additionally in the presence of anions, L1 showed a colour change from yellow to pink, followed by a quenching in the emission intensity, which is due to deprotonation with the formation of a quinone base. Absorption and fluorescence spectra of L1 were calculated at different temperatures by the DFT/B3LYP method. The decrease in fluorescence of compound L1 with an increase in temperature seems to be due to the presence of pronounced torsional vibrations of the donor and acceptor fragments relative to the single bond with C(carbonyl)-C (styrene fragment). L1, L2 and L3, through their incorporation into the polymeric matrixes, became highly emissive by aggregation. These dye@doped polymers were evaluated as temperature sensors, showing an excellent fluorescent response and reversibility after 15 cycles of heating and cooling.

Collateral Sensitivity to Fosfomycin of Tobramycin-Resistant Mutants of Pseudomonas aeruginosa Is Contingent on Bacterial Genomic Background.

Understanding the consequences in bacterial physiology of the acquisition of drug resistance is needed to identify and exploit the weaknesses derived from it. One of them is collateral sensitivity, a potentially exploitable phenotype that, unfortunately, is not always conserved among different isolates. The identification of robust, conserved collateral sensitivity patterns is then relevant for the translation of this knowledge into clinical practice. We have previously identified a robust fosfomycin collateral sensitivity pattern of Pseudomonas aeruginosa that emerged in different tobramycin-resistant clones. To go one step further, here, we studied if the acquisition of resistance to tobramycin is associated with robust collateral sensitivity to fosfomycin among P. aeruginosa isolates. To that aim, we analyzed, using adaptive laboratory evolution approaches, 23 different clinical isolates of P. aeruginosa presenting diverse mutational resistomes. Nine of them showed collateral sensitivity to fosfomycin, indicating that this phenotype is contingent on the genetic background. Interestingly, collateral sensitivity to fosfomycin was linked to a larger increase in tobramycin minimal inhibitory concentration. Further, we unveiled that fosA low expression, rendering a higher intracellular accumulation of fosfomycin, and a reduction in the expression of the P. aeruginosa alternative peptidoglycan-recycling pathway enzymes, might be on the basis of the collateral sensitivity phenotype.

The Inactivation of the Putative Two-Component System Sensor PA14_27940 Increases the Susceptibility to Several Antibiotics and Reduces the Motility of Pseudomonas aeruginosa.

The identification of targets whose inactivation increases the activity of antibiotics helps to fight antibiotic resistance. Previous work showed that a transposon-insertion mutant in the gene PA14_27940 increases Pseudomonas aeruginosa susceptibility to aminoglycosides. Since polar effects may affect the phenotype, in the present work, we generated an in-frame PA14_27940 deletion mutant. A PA14_27940 deletion increased the susceptibility to aminoglycosides, tetracycline, tigecycline, erythromycin and fosfomycin. Excepting fosfomycin, the other antibiotics are inducers of the MexXY efflux pump. MexXY induction is required for P. aeruginosa resistance to these antibiotics, which is post-transcriptionally regulated by the anti-repressor ArmZ. Although mexXY is inducible by tobramycin in ΔPA14_27940, the induction level is lower than in the parental PA14 strain. Additionally, armZ is induced by tobramycin in PA14 and not in ΔPA14_27940, supporting that ΔPA14_27940 presents an ArmZ-mediated defect in mexXY induction. For its part, hypersusceptibility to fosfomycin may be due to a reduced expression of nagZ and agmK, which encode enzymes of the peptidoglycan recycling pathway. ΔPA14_27940 also presents defects in motility, an element with relevance in P. aeruginosa's virulence. Overall, our results support that PA14_27940 is a good target for the search of adjuvants that will increase the activity of antibiotics and reduce the virulence of P. aeruginosa.

Development of New Targeted Nanotherapy Combined with Magneto-Fluorescent Nanoparticles against Colorectal Cancer.

The need for non-invasive therapies capable of conserving drug efficiency and stability while having specific targetability against colorectal cancer (CRC), has made nanoparticles preferable vehicles and principal building blocks for the development of complex and multi-action anti-tumoral approaches. For that purpose, we herein report the production of a combinatory anti-tumoral nanotherapy using the production of a new targeting towards CRC lines. To do so, Magneto-fluorescent NANO3 nanoparticles were used as nanocarriers for a combination of the drugs doxorubicin (DOX) and ofloxacin (OFLO). NANO3 nanoparticles' surface was modified with two different targeting agents, a newly synthesized (anti-CA IX acetazolamide derivative (AZM-SH)) and a commercially available (anti-epidermal growth factor receptor (EGFR), Cetuximab). The cytotoxicity revealed that only DOX-containing nanosystems showed significant and even competitive cytotoxicity when compared to that of free DOX. Interestingly, surface modification with AZM-SH promoted an increased cellular uptake in the HCT116 cell line, surpassing even those functionalized with Cetuximab. The results show that the new target has high potential to be used as a nanotherapy agent for CRC cells, surpassing commercial targets. As a proof-of-concept, an oral administration form of NANO3 systems was successfully combined with Eudragit® enteric coating and studied under extreme conditions.