New drug discovery strategies for the treatment of benznidazole-resistance in Trypanosoma cruzi, the causative agent of Chagas disease.

INTRODUCTION: Benznidazole, the drug of choice for treating Chagas Disease (CD), has significant limitations, such as poor cure efficacy, mainly in the chronic phase of CD, association with side effects, and parasite resistance. Understanding parasite resistance to benznidazole is crucial for developing new drugs to treat CD. AREAS COVERED: Here, the authors review the current understanding of the molecular basis of benznidazole resistance. Furthermore, they discuss the state-of-the-art methods and critical outcomes employed to evaluate the efficacy of potential drugs against T. cruzi, aiming to select better compounds likely to succeed in the clinic. Finally, the authors describe the different strategies employed to overcome resistance to benznidazole and find effective new treatments for CD. EXPERT OPINION: Resistance to benznidazole is a complex phenomenon that occurs naturally among T. cruzi strains. The combination of compounds that inhibit different metabolic pathways of the parasite is an important strategy for developing a new chemotherapeutic protocol.

Impact of PVC microplastics in photodynamic inactivation of Staphylococcus aureus and MRSA.

Photodynamic processes have found widespread application in therapies. These processes involve photosensitizers (PSs) that, when excited by specific light wavelengths and in the presence of molecular oxygen, generate reactive oxygen species (ROS), that target cells leading to inactivation. Photodynamic action has gained notable attention in environmental applications, particularly against pathogens and antibiotic-resistant bacteria (ARB) that pose a significant challenge to public health. However, environmental matrices frequently encompass additional contaminants and interferents, including microplastics (MPs), which are pollutants of current concern. Their presence in water and effluents has been extensively documented, highlighting their impact on conventional treatment methods, but this information remains scarce in the context of photodynamic inactivation (PDI) setups. Here, we described the effects of polyvinyl chloride (PVC) microparticles in PDI targeting Staphylococcus aureus and its methicillin-resistant strain (MRSA), using curcumin as a PS under blue light. The presence of PVC microparticles does not hinder ROS formation; however, depending on its concentration, it can impact bacterial inactivation. Our results underscore that PDI remains a potent method for reducing bacterial concentrations in water and wastewater containing ARB, even in highly contaminated scenarios with MPs.

Recurrent community-acquired pneumococcal meningitis in adults with and without identified predisposing factors.

Bacterial meningitis is still a significant public health concern, with high morbidity and mortality rates. Despite this, it is still a rare event that requires the bacterial invasion of the meninges. However, some predisposing factors can trigger recurrent episodes of meningitis. This study is aimed at determining the clinical characteristics and the molecular epidemiology of episodes of recurrent community-acquired meningitis with and without predisposing factors. For this purpose, we performed a retrospective study of our laboratory database during the period of 2010 to 2020. Additionally, using molecular tools developed in our previous works, the epidemiology of the pathogens causing these episodes was analyzed using cerebrospinal fluid samples, especially in the absence of isolated strains. We observed a total of 1,779 meningitis cases and 230 were caused by Streptococcus pneumoniae. Of those, 16 were recurrent meningitis episodes (16/1,779; 0.9%) from seven patients. Pneumococcus was the main agent responsible in these recurrent episodes and only two episodes were caused by Haemophilus influenzae. The mean age of these patients was 20 years old and three had predisposing factors which could have led to contracting meningitis. The samples presented different pneumococcal serotypes. Most of them were non-vaccine-covered serotypes and antibiotic susceptible strains. Therefore, it was demonstrated how the practical employment of molecular tools, developed for research, when applied in the routine of diagnosis, can provide important information for epidemiological surveillance. Furthermore, it was shown how pneumococcus was the leading cause of recurrent community-acquired meningitis without predisposing factors, suggesting that pneumococcal vaccination may be necessary, even in those groups of individuals considered to be less susceptible.

Structure-Activity Relationship of a Pyrrole Based Series of PfPKG Inhibitors as Anti-Malarials.

Controlling malaria requires new drugs against Plasmodium falciparum. The P. falciparum cGMP-dependent protein kinase (PfPKG) is a validated target whose inhibitors could block multiple steps of the parasite's life cycle. We defined the structure-activity relationship (SAR) of a pyrrole series for PfPKG inhibition. Key pharmacophores were modified to enable full exploration of chemical diversity and to gain knowledge about an ideal core scaffold. In vitro potency against recombinant PfPKG and human PKG were used to determine compound selectivity for the parasite enzyme. P. berghei sporozoites and P. falciparum asexual blood stages were used to assay multistage antiparasitic activity. Cellular specificity of compounds was evaluated using transgenic parasites expressing PfPKG carrying a substituted "gatekeeper" residue. The structure of PfPKG bound to an inhibitor was solved, and modeling using this structure together with computational tools was utilized to understand SAR and establish a rational strategy for subsequent lead optimization.

Physical and autonomic functionality in women with breast cancer pre and post chemotherapy: a case control study.

BACKGROUND: Breast cancer (BC) is one of the most incident types of cancer among women in the world. Although chemotherapy is an effective way to treat several types of cancer, it may also cause serious complications, including cardiotoxicity. This study aimed to identify the impact of chemotherapy on functional capacity, muscle strength and autonomic function. METHODS: Ten breast cancer patients in therapeutic follow-up (TG) and ten women without comorbidities (CG) participated in the study (46±8.87 years old). Both groups were evaluated at two time points, before and 20 weeks after the start of chemotherapy. Functional capacity and muscle strength were assessed by 6-minute walk test (6MWT) and handgrip test, respectively. Autonomic function was assessed by heart rate variability analysis. RESULTS: TG presented greater reductions in the handgrip test for the non-dominant hand (TG ↓15.2%; CG: ↑1.1%, p<0.05) compared to GC. However, no significant differences were found regarding VO2max (p>0.05) and 6MWT total distance (p>0.05). Regarding the heart rate variability variables before and after follow-up period, rMSSD (CG= 39.15±37.66; TG= 14.89±8.28, p= 0.01) and SDNN (CG= 55.77±40.03; TG= 26.30±10.37, p= 0.02) showed effect in the group and time interaction, whereas the LF/HF ratio presented significant difference only in the time analysis (CG= 2.24±2.30; TG= 2.84±1.82, p= 0.04). CONCLUSION: Chemotherapy used in the treatment of breast cancer patients resulted in decreased muscle strength and autonomic imbalance. The data suggests that chemotherapy may carry the risk of developing cardiovascular disease. TRIAL REGISTRATION: Registration not required.

Discovery of Potent Antimalarial Type II Kinase Inhibitors with Selectivity over Human Kinases.

While progress has been made in the effort to eradicate malaria, the disease remains a significant threat to global health. Acquired resistance to frontline treatments is emerging in Africa, urging a need for the development of novel antimalarial agents. Repurposing human kinase inhibitors provides a potential expedited route given the availability of a diverse array of kinase-targeting drugs that are approved or in clinical trials. Phenotypic screening of a library of type II human kinase inhibitors identified compound 1 as a lead antimalarial, which was initially developed to target human ephrin type A receptor 2 (EphA2). Here, we report a structure-activity relationship study and lead optimization of compound 1, which led to compound 33, with improved antimalarial activity and selectivity.

Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase.

Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism.

Influence of temperature combined with photodynamic inactivation on the development of Aedes aegypti.

To reduce the speed of selection of populations resistant to chemical insecticides, photodynamic inactivation (PDI) against Aedes aegypti is a hot-topic and promising alternative technique to vector control. Temperature is an important factor in the survival of Ae. aegypti larvae and mosquitoes as it influences physiology, behavior, and ecology. This work aimed to evaluate parameters of the biological cycle of Ae. aegypti such as: hatching rate, larval development, adult mosquito longevity, sex ratio, weight, and lethal concentration of larval mortality (LC) through the combination of PDI with different temperatures. The number of larvae found after 48 h suggests that temperature affects hatching rate. Additionally, results showed a delay in development of surviving larvae after PDI when compared to control groups, and there was a reduction in the longevity of mosquitoes that undertook photodynamic action. PDI also led to a predominance of male insects, and observed weight indicates that the inactivation method may have also interfered in mosquito size. The results point to a satisfactory performance of PDI at all tested temperatures. Experimental conditions that were not lethal to all larvae implied that PDI impacts the mosquitoes' biological cycle. Though metabolism and development are improved at higher temperatures, so is PDI action, thus maintaining the net benefit. Therefore, it is assumed that the proposed photolarvicide can be useful in reducing arbovirus transmission, and results invite for future research in different abiotic conditions.

Structure-activity relationships of novel N-imidazoylpiperazines with potent anti-Trypanosoma cruzi activity.

Background: Chagas disease is caused by the parasite Trypanosoma cruzi, and the lack of effective and safe treatments makes identifying new classes of compounds with anti-T. cruzi activity of paramount importance. Methods: Hit-to-lead exploration of a metabolically stable N-imidazoylpiperazine was performed. Results: Compound 2, a piperazine derivative active against T. cruzi, was selected to perform the hit-to-lead exploration, which involved the design, synthesis and biological evaluation of 39 new derivatives. Conclusion: Compounds 6e and 10a were identified as optimized compounds with low micromolar in vitro activity, low cytotoxicity and suitable preliminary absorption, distribution, metabolism and excretion and physicochemical properties. Both compounds reduced parasitemia in mouse models of Chagas disease, providing a promising opportunity for further exploration of new antichagasic compounds.

Technological Trends Involving Probiotics in the Treatment of Diabetic Neuropathy: A Patent Review (2009-2022).

BACKGROUND: Diabetic neuropathy (DN) causes neuropathic pain, and current treatments are unsatisfactory. Recently studies have demonstrated an assertive correlation between gut microbiota and pain modulation. OBJECTIVE: Considering the emerging search for new therapies for the control of DN and the growing commercial interest in the probiotics market, this study aimed to provide patents on the use of probiotics in the control of DN. METHODS: This is a patent prospection performed in the Espacenet Patent database, using the association of keywords and IPC related to probiotics in medical preparations and foods, from 2009 to December 2022. RESULTS: Results have shown that in 2020, there was a boom in patent filing in the area. Asian countries accounted for more than 50% of all 48 inventions (n = 48), with Japan as the only applicant in 2021. Products being developed in recent years point to effects that may represent an advancement in DN treatment, such as reduced concentration of pro-inflammatory mediators, metabolites and neurotransmitters release, and hypoglycemic potential. All effects were more related to the Lactobacillus and Bifidobacterium genera, associated with more than one property mentioned. CONCLUSION: The mechanisms attributed to the microorganisms suggest the therapeutic potential of probiotics in the non-pharmacological treatment of pain. New applications for probiotics have resulted from great research interest by academia, but also reflect commercial interests despite the paucity of clinical trials. Thus, the present work supports the evolution of research to explore the benefits of probiotics and their clinical use in DN.

2,3,5-triphenyl tetrazolium chloride as colorimetric indicator for drug susceptibility testing against nontuberculous mycobacteria.

This study aimed to propose and evaluate a drug susceptibility testing (DST) using the 2,3,5-triphenyl tetrazolium chloride (TTC) as a colorimetric indicator against Mycobacterium abscessus complex (MABC), M. avium complex (MAC), and M. kansasii strains, main nontuberculous mycobacteria (NTM) of clinical relevance. Our results demonstrated that the assay using TTC and the broth microdilution method recommended by the Clinical and Laboratory Standards Institute had essential agreement above 91%, 92%, and 100%, for drugs tested against MABC, MAC, and M. kansasii strains, respectively. Categorical agreement above 91% was obtained for most drugs tested against MABC, except to cefoxitin (76.5%). For drugs tested against MAC and M. kansasii, categorical agreement above 92% and 100% was observed, respectively. TTC showed to be a promising colorimetric indicator of growth to be used in DST for NTM, allowing an easier reading of results.

Violência obstétrica no processo do abortamento

Objetivo: Analisar as práticas assistenciais de saúde no processo do abortamento tipificadas como violência obstétrica. Metodologia: Estudo qualitativo e descritivo, realizado em um hospital público no Brasil com 15 profissionais de saúde de nível médio e superior. Os dados foram coletados presencialmente, através de um roteiro de entrevista semiestruturada. O perfil foi analisado pela estatística descritiva simples e as questões abertas pela técnica de conteúdo temática proposta por Bardin. Resultados: Evidenciou-se que as práticas que denotam violência obstétrica relacionam-se a alocação das mulheres em processo de abortamento no mesmo ambiente que gestantes e puérperas e ao emitirem juízos de valor no momento da assistência às mulheres. Conclusão: Há necessidade de educação permanente para que as/os profissionais possam assistir de maneira humanizada e qualificada.

Objetivo: Analizar las prácticas de atención a la salud en el proceso de aborto tipificadas como violencia obstétrica. Metodología: Estudio cualitativo y descriptivo, realizado en un hospital público en Brasil con 15 profesionales de salud de nivel medio y superior. Los datos fueron recogidos presencialmente, a través de un guion de entrevista semiestructurada. El perfil fue analizado por la estadística descriptiva simple y las cuestiones abiertas por la técnica de contenido temática propuesta por Bardin. Resultados: Se evidenció que los profesionales de salud presentaron conocimiento insuficiente sobre violencia obstétrica en el momento en que la restringieron al parto o aborto, a la tipificación física/verbal e identificaron solo a los médicos y enfermeras como los principales perpetradores. Las prácticas que denotan violencia obstétrica se relacionan a la asignación de las mujeres en proceso de aborto en el mismo ambiente que gestantes y puérperas, y al emitir juicios de valor en el momento de la asistencia. Conclusión: Hay necesidad de educación permanente para que los profesionales puedan asistir de manera humanizada y cualificada.

Objective: To analyze health care practices in the abortion process typified as obstetric violence. Methodology: Qualitative and descriptive study, conducted in a public hospital in Brazil with 15 health professionals of medium and higher education. The data were collected in person, through a semi-structured interview script. The profile was analyzed by simple descriptive statistics and the questions opened by the thematic content technique proposed by Bardin. Results: It was evidenced that health professionals had insufficient knowledge about obstetric violence at the time they restricted it to childbirth or abortion, physical/verbal typing and identified only doctors and nurses as the main perpetrators. The practices that denote obstetric violence are related to the allocation of women in the process of abortion in the same environment as pregnant women and puerperal women and when issuing value judgments at the time of care. Conclusion: There is a need for permanent education so that the professionals can assist in a humanized and qualified way.

Representações sociais de mulheres no ciclo gravídico-puerperal sobre violência obstétrica

Objetivos: Traçar as características biopsicossociais das mulheres no ciclo grávido-puerperal e analisar as representações sociais dessas mulheres sobre a violência obstétrica. Metodologia: Estudo descritivo, de abordagem qualitativa, norteado pela Teoria das Representações Sociais, realizado no período de setembro de 2021 a abril de 2022, com 40 mulheres atendidas em uma maternidade de Minas Gerais, no Brasil. Os dados foram coletados por meio de um roteiro de entrevista semiestruturada e da técnica de associação livre de palavras. A caracterização foi analisada pela estatística descritiva simples, a entrevista semiestruturada pela técnica de conteúdo temática proposta por Bardin e a técnica de associação livre de palavras pelo software Iramuteq. Resultados: 82,5 % das participantes possuíam faixa de 18 e 29 anos, 77,5 % intitularam-se pardas, 25 % tinham ensino médio completo e 65 % referiram renda de 1 a 3 salários-mínimos. Quanto à história obstétrica, 52 % possuíam idade gestacional entre 37 e 41 semanas, 70 % não haviam planejado a gravidez, 42,5 % haviam sido admitidas em trabalho de parto e 87,5 % estavam acompanhadas. A violência obstétrica é representada pelas mulheres de maneira superficial com enfoque na dimensão física e emocional, sendo em alguns momentos naturalizada. Conclusão: A violência obstétrica é uma grave problemática vivenciada pelo público feminino e a falta de conhecimento pode levar à naturalização, deixando-as em posição de ampla vulnerabilidade.

Objetivos: Trazar las características biopsicosociales de mujeres en el ciclo gravídico-puerperal y analizar las representaciones sociales de estas mujeres sobre violencia obstétrica Metodología: Estudio descriptivo, de abordaje cualitativo, guiado por la teoría de las representaciones sociales, realizado en el período de septiembre de 2021 a abril de 2022, con 40 mujeres atendidas en una maternidad de Minas Gerais, en Brasil. Los datos fueron recogidos a través de un guion de entrevista semiestructurada y de la técnica de asociación libre de palabras. La caracterización fue analizada por la estadística descriptiva simple, la entrevista semiestructurada por la técnica de contenido temático propuesta por Bardin, y la técnica de asociación libre de palabras por el software Iramuteq. Resultados: 82.5 % de las participantes poseían rango de 18 y 29 años, 77.5 % se identificaron como pardas, 25 % poseían enseñanza media completa y 65 % refirieron renta de 1 a 3 salarios mínimos. En cuanto a la historia obstétrica, 52 % poseían edad gestacional entre 37 y 41 semanas, 70 % no habían planeado el embarazo, 42.5 % habían sido admitidas en trabajo de parto y 87.5 % estaban acompañadas. La violencia obstétrica es representada por las mujeres de manera superficial, con enfoque en la dimensión física y emocional, a veces naturalizada. Conclusión: La violencia obstétrica es una grave problemática vivida por el público femenino y la falta de conocimiento puede llevar a la naturalización, dejándolas en posición de amplia vulnerabilidad

Objectives: To trace the biopsychosocial characteristics of women in the pregnancy-puerperal cycle and to analyze the social representations of these women on obstetric violence. Methodology: Descriptive study, qualitative approach, guided by the Theory of Social Representations conducted in the period from September 2021 to April 2022, with 40 women assisted in a maternity hospital in Minas Gerais, Brazil. The data was collected through a script of semi-structured interview and the technique of free association of words. The characterization was analyzed by simple descriptive statistics, the semi-structured interview by the thematic content technique proposed by Bardin and the free word association technique by Iramuteq software. Results: 82.5 % of the participants had a range of 18 and 29 years, 77.5% self-identified as pardas (mixed race), 25 % had completed high school and 65 % reported income from 1 to 3 minimum wages. Regarding obstetric history, 52,0% had gestational age between 37 and 41 weeks, 70.0% had not planned pregnancy, 42.5% had been admitted for labor and 87.5% were monitored. Obstetric violence is represented by women in a superficial way with a focus on the physical and emotional dimension, being in some moments naturalized. Conclusion: Obstetric violence is a serious problem experienced by the female public and the lack of knowledge can lead to naturalization, leaving them in a position of broad vulnerability

Hydrogen peroxide preoxidation as a strategy for enhanced antimicrobial photodynamic action against methicillin-resistant Staphylococcus aureus.

Antimicrobial photodynamic treatment (aPDT) is a photooxidative process based on the excitation of a photosensitizer (PS) in the presence of molecular oxygen, under specific wavelengths of light. It is a promising method for advanced treatment of water and wastewater, particularly targeting disinfection challenges, such as antibiotic-resistant bacteria (ARB). Research in improved aPDT has been exploring new PS materials, and additives in general. Hydrogen peroxide (H2O2) a widely applied disinfectant, mostly in the food industry and clinical settings, present environmentally negligible residuals at the usually applied concentrations, making it friendly for the water and wastewater sectors. Here, we explored the effects of preoxidation with H2O2 followed by blue light-mediated (450 nm) aPDT using curcumin (a natural-based PS) against methicillin-resistant Staphylococcus aureus (MRSA). Results of the sequential treatment pointed to a slight hampering in aPDT efficiency at very low H2O2 concentrations, followed by an increasing cooperative effect up to a deleterious point (≥7 log10 inactivation in CFU mL-1), suggesting a synergistic interaction of preoxidation and aPDT. The increased performance in H2O2-pretreated aPDT encourages studies of optimal operational conditions for the assisted technology and describes potentials for using the described strategy to tackle the issue of ARB spread.

Molecular targets for Chagas disease: validation, challenges and lead compounds for widely exploited targets.

INTRODUCTION: Chagas disease (CD) imposes social and economic burdens, yet the available treatments have limited efficacy in the disease's chronic phase and cause serious adverse effects. To address this challenge, target-based approaches are a possible strategy to develop new, safe, and active treatments for both phases of the disease. AREAS COVERED: This review delves into target-based approaches applied to CD drug discovery, emphasizing the studies from the last five years. We highlight the proteins cruzain (CZ), trypanothione reductase (TR), sterol 14 α-demethylase (CPY51), iron superoxide dismutase (Fe-SOD), proteasome, cytochrome b (Cytb), and cleavage and polyadenylation specificity factor 3 (CPSF3), chosen based on their biological and chemical validation as drug targets. For each, we discuss its biological relevance and validation as a target, currently related challenges, and the status of the most promising inhibitors. EXPERT OPINION: Target-based approaches toward developing potential CD therapeutics have yielded promising leads in recent years. We expect a significant advance in this field in the next decade, fueled by the new options for Trypanosoma cruzi genetic manipulation that arose in the past decade, combined with recent advances in computational chemistry and chemical biology.

Photoantimicrobial chitosan-gelatin-pomegranate peel extract films for strawberries preservation: From microbiological analysis to in vivo safety assessment.

This study aimed to investigate the application of biopolymeric materials (chitosan, gelatin, and pomegranate peel extract as photosensitizer) and antimicrobial photodynamic therapy (aPDT) on the physicochemical and microbial safety of strawberries. The photosensitizer potential of the materials was confirmed by a light-dose-dependent photobleaching profile. The application of light (525 nm; 50 J cm-2) decreased by >2 log CFU mL-1 the survival of Staphylococcus aureus on the surface of the photoactive-biopolymeric films. Moreover, the materials did not present in vivo cytotoxicity using Danio rerio (Zebrafish) as well as cytophytotoxic, genotoxic, or mutagenic potentials against Allium cepa plant model, which points out their safety to be used as films without posing a risk to the humans and the environment. The photoactive-polymeric coatings were able to maintain the strawberries weight, and the association with green light was 100 % effective in delaying fungal contamination. These coated-strawberries presented a significant reduction in S. aureus survival after light application (5.47-4.34 log CFU mL-1). The molecular level analysis of the photoactive compound cyanidin-3-glucoside indicates absorption on UV-Vis consistent with aPDT action. Therefore, this study showed that the antimicrobial effects of aPDT combined with photoactive-biopolymeric coatings were enhanced, while the quality of the strawberries was maintained.

Photon spectra effects tested on the vegetal model Allium cepa.

The use of artificial light sources in plants is considered a type of photobiomodulation (PBM), a trend in agriculture and food industries, aiming at decontamination, pest control, and increased production yield. However, literature lacks a broader assessment to address the effects of photon light spectra on plant characteristics. Here, we aimed to describe the effects of visible light, infrared, and ultraviolet light upon Allium cepa, a known bioindicator, under various light doses. Samples irradiated under visible and infrared light did not show cytotoxicity, genotoxicity, or mutagenicity in any of the evaluated doses. Light induction at 460 and 635 nm significantly stimulated root development of the test organism. In contrast, 254 nm irradiation proved to be cytotoxic, genotoxic, and mutagenic. This work reveals and quantifies the spectral response of A. cepa seeds, suggesting that it can be proposed as a model for future research on mechanisms of PBM in plants.

Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase.

Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure activity relationship and the selectivity mechanism.

Predictive validity of the EVARUCI scale to evaluate risk for pressure injury in critical care patients.

OBJECTIVE: To compare the predictive capacity of the current risk assessment scale for pressure ulcers in intensive care (EVARUCI), translated into Brazilian Portuguese, using the Braden scale. METHOD: This cross-sectional study collected prospective data from adult patients in three intensive care units. The receiver operating characteristic (ROC) and precision-recall curve (PR curve) were used to analyse the predictive capacity for pressure injury (PI) using both predictive values and odds ratios (ORs). RESULTS: The incidence of PIs in the study sample of 324 patients was 14.2%. The area under the ROC curve was 0.807 for EVARUCI and 0.798 for the Braden scale. At a cutoff point of 10 on the EVARUCI scale, sensitivity was 69.6%; specificity 78.4%; positive predictive value 34.8%; and OR 8.3. At a cutoff point of 11 on the Braden scale, sensitivity was 76.1%; specificity 75.9%; positive predictive value 34.3%; and OR 10. The area under the PR curve was 0.396 for the EVARUCI scale and 0.348 for the Braden scale, reflecting a smaller area for both. The F1 score value was 0.476 with 37.5% precision and 65.2% recall for the EVARUCI scale, and 0.473 with 34.3% precision and 76.1% recall for the Braden scale. CONCLUSION: The EVARUCI scale predictive capacity was similar to that of the Braden scale. However, the precision of both scales was low for the accurate prediction of patients at risk of developing PIs.

Bioprospecting for Isoetes cangae Endophytes with Potential to Promote Plant Growth.

Isoetes cangae is a native plant found only in a permanent pond in Serra dos Carajás in the Amazon region. Plant-associated microbial communities are recognized to be responsible for biological processes essential for the health, growth, and even adaptation of plants to environmental stresses. In this sense, the aims of this work were to isolate, identify, and evaluate the properties of endophytic bacteria isolated from I. cangae. The bioprospecting of potentially growth-promoting endophytes required the following steps to be taken: isolation of endophytic colonies, molecular identification by 16S rDNA sequence analysis, and evaluation of the bacterial potential for nitrogen fixation, production of indole acetic acid and siderophores, as well as phosphate solubilization and mineralization. Bacillus sp., Rhizobium sp., Priestia sp., Acinetobacter sp., Rossellomorea sp., Herbaspirillum sp., Heyndrickxia sp., and Metabacillus sp., among other bacterial species, were identified. The isolates showed to be highly promising, evidencing the physiological importance for the plant and having the potential to promote plant growth.