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Pertussis (whooping cough) is a vaccine-preventable but re-emerging, highly infectious respiratory disease caused by Bordetella pertussis. There are currently no effective treatments for pertussis, complicating care for non-vaccinated individuals, especially newborns. Disease manifestations are predominantly caused by pertussis toxin (PT), a pivotal virulence factor classified as an ADP-ribosylating AB-type protein toxin. In this work, an unbiased approach using peptide libraries, bioassay-guided fractionation and mass spectrometry revealed α 1 -antitrypsin (α 1 AT) as a potent PT inhibitor. Biochemistry-, cell culture- and molecular modeling-based in vitro experimentation demonstrated that the α 1 AT mode of action is based on blocking PT-binding to the host target cell surface. In the infant mouse model of severe pertussis, α 1 AT expression was reduced upon infection. Further, systemic administration of α 1 AT significantly reduced B. pertussis-induced leukocytosis, which is a hallmark of infant infection and major risk factor for fatal pertussis. Taken together our data demonstrates that α 1 AT is a novel PT inhibitor and that further evaluation and development of α 1 AT as a therapeutic agent for pertussis is warranted. Importantly, purified α 1 AT is already in use clinically as an intravenous augmentation therapy for those with genetic α 1 AT deficiency and could be repurposed to clinical management of pertussis., Competing Interests: Conflicts of Interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Invasive candidiasis is a global public health problem as it poses a significant threat in hospital-settings. The aim of this study was to evaluate C14R, an analog derived from peptide BP100, as a potential antimicrobial peptide against the prevalent opportunistic yeast Candida albicans and the emergent multidrug-resistant yeast Candida auris ., Methods: Antifungal susceptibility testing of C14R against 99 C . albicans and 105 C . auris clinical isolates from Colombia, was determined by broth microdilution. Fluconazole was used as a control antifungal. The synergy between C14R and fluconazole was assessed in resistant isolates. Assays against fungal biofilm and growth curves were also carried out. Morphological alterations of yeast cell surface were evaluated by scanning electron microscopy. A permeability assay verified the pore-forming ability of C14R., Results: C. albicans and C. auris isolates had a geometric mean MIC against C14R of 4.42 µg/ml and 5.34 µg/ml, respectively. Notably, none of the isolates of any species exhibited growth at the highest evaluated peptide concentration (200 µg/ml). Synergistic effects were observed when combining the peptide and fluconazole. C14R affects biofilm and growth of C. albicans and C. auris . Cell membrane disruptions were observed in both species after treatment with the peptide. It was confirmed that C14R form pores in C. albicans ' membrane., Discussion: C14R has a potent antifungal activity against a large set of clinical isolates of both C. albicans and C. auris , showing its capacity to disrupt Candida membranes. This antifungal activity remains consistent across isolates regardless of their clinical source. Furthermore, the absence of correlation between MICs to C14R and resistance to fluconazole indicates the peptide's potential effectiveness against fluconazole-resistant strains. Our results suggest the potential of C14R, a pore-forming peptide, as a treatment option for fungal infections, such as invasive candidiasis, including fluconazole and amphotericin B -resistant strains., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Vélez, Argel, Kissmann, Alpízar-Pedraza, Escandón, Rosenau, Ständker and Firacative.)

Background: Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and leads to ~10,000 deaths each year. Nifurtimox and benznidazole are the only two drugs available but have significant adverse effects and limited efficacy. New chemotherapeutic agents are urgently required. Here we identified inhibitors of the acidic M17 leucyl-aminopeptidase from T. cruzi (LAPTc) that show promise as novel starting points for Chagas disease drug discovery., Methodology/principal Findings: A RapidFire-MS screen with a protease-focused compound library identified novel LAPTc inhibitors. Twenty-eight hits were progressed to the dose-response studies, from which 12 molecules inhibited LAPTc with IC50 < 34 μM. Of these, compound 4 was the most potent hit and mode of inhibition studies indicate that compound 4 is a competitive LAPTc inhibitor, with Ki 0.27 μM. Compound 4 is selective with respect to human LAP3, showing a selectivity index of >500. Compound 4 exhibited sub-micromolar activity against intracellular T. cruzi amastigotes, and while the selectivity-window against the host cells was narrow, no toxicity was observed for un-infected HepG2 cells. In silico modelling of the LAPTc-compound 4 interaction is consistent with the competitive mode of inhibition. Molecular dynamics simulations reproduce the experimental binding strength (-8.95 kcal/mol), and indicate a binding mode based mainly on hydrophobic interactions with active site residues without metal cation coordination., Conclusions/significance: Our data indicates that these new LAPTc inhibitors should be considered for further development as antiparasitic agents for the treatment of Chagas disease., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Izquierdo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

CIDEM-501 is a hybrid antimicrobial peptide rationally designed based on the structure of panusin and panulirin template peptides. The new peptide exhibits significant antibacterial activity against multidrug-resistant pathogens (MIC = 2-4 μM) while conserving no toxicity in human cell lines. We conducted molecular dynamics (MD) simulations using the CHARMM-36 force field to explore the CIDEM-501 adsorption mechanism with different membrane compositions. Several parameters that characterize these interactions were analyzed to elucidate individual residues' structural and thermodynamic contributions. The membrane models were constructed using CHARMM-GUI, mimicking the bacterial and eukaryotic phospholipid compositions. Molecular dynamics simulations were conducted over 500 ns, showing rapid and highly stable peptide adsorption to bacterial lipids components rather than the zwitterionic eucaryotic model membrane. A predominant peptide orientation was observed in all models dominated by an electric dipole. The peptide remained parallel to the membrane surface with the center loop oriented to the lipids. Our findings shed light on the antibacterial activity of CIDEM-501 on bacterial membranes and yield insights valuable for designing potent antimicrobial peptides targeting multi- and extreme drug-resistant bacteria.

Background: The "Bridge Project" is a Mexico in Alliance with St. Jude (MAS) initiative developed in 2019 to improve access, accuracy, and timeliness of specialized diagnostic studies for patients with suspected acute lymphoblastic leukemia (ALL). The project strategy relies on service centralization to improve service delivery, biological characterization, risk-group classification, and support proper treatment allocation., Methods: This is an ongoing prospective multisite intersectoral quality improvement (QI) project available to all patients 0-18 years of age presenting with suspected ALL to the 14 actively participating institutions in 12 Mexican states. Institutions send specimens to one centralized laboratory. From a clinical standpoint, the project secures access to a consensus-derived comprehensive diagnostic panel. From a service delivery standpoint, we assess equity, timeliness, effectiveness, and patient-centeredness. From an implementation science standpoint, we document feasibility, utility, and appropriateness of the diagnostic panel and centralized approach. This analysis spans from July 2019 to June 2023., Results: 612 patients have accessed the project. The median age was 6 years (IQR 3-11), and 53% were males. 94% of the specimens arrived within 48 hours, which documents the feasibility of the centralized model, and 100% of the patients received precise and timely diagnostic results, which documents the effectiveness of the approach. Of 505 (82.5%) patients with confirmed ALL, 463/505 (91.6%) had B-cell ALL, and 42/505 (8.3%) had T-cell ALL. High-hyperdiploidy was detected by DNA index in 36.6% and hypodiploidy in 1.6%. 76.6% of the patients had conclusive karyotype results. FISH studies showed t(12;21) in 15%, iAMP21 in 8.5%, t(1;19) in 7.5%, t(4;11) in 4.2%, t(9;22) in 3.2%, del(9)(p21) in 1.8%, and TRA/D (14)(q11.2) rearrangement in 2.4%. Among B-cell ALL patients, 344/403 (85.1%) had Day 15 MRD<1% and 261/305 (85.6%) Day 84 MRD<0.01. For T-cell ALL patients 20/28 (71.4%) had Day 29 MRD<0.01% and 19/22 (86.4%) Day 84 MRD<0.01%., Conclusions: By securing access to a standardized consensus-derived diagnostic panel, the Bridge Project has allowed better characterization of childhood ALL in Mexico while producing unprecedented service improvements and documenting key implementation outcomes. We are using these results to inform iterative changes to the diagnostic panel and an associated treatment guideline (MAS-ALL18)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Friedrich, Mercado, Echeandia-Abud, Guerrero-Gomez, González-Zamorano, López-Ruíz, Portillo-Zavala, García-Segura, Reynoso-Gutiérrez, López-Facundo, Cárdenas-Pedraza, Valois-Escamilla, Mera-González, Covarrubias-Zapata, Vollbrechtshausen-Castelán, Loeza-Oliva, Garay-Sánchez, Moreno-Serrano, Mendoza-Sánchez, Casillas-Toral, Sandoval-Cabrera, Gutiérrez-Martínez, Jiménez-Osorio, Arce-Cabrera, Aguilar-Escobar, González-Montalvo and Romo-Rubio.)

The diminishing portfolio of mankind's available antibiotics urges science to develop novel potent drugs. Here, we present a peptide fitting the typical blueprint of amphipathic and membrane-active antimicrobial peptides, denominated C14R. This 2 kDa peptide consists of 16 amino acid residues, with seven being either hydrophobic, aromatic, or non-polar, and nine being polar or positively charged, strictly separated on opposite sides of the predicted α-helix. The affinity of the peptide C14R to P. aeruginosa membranes and its intrinsic tendency to productively insert into membranes of such composition were analyzed by dynamic simulations. Its biological impact on the viability of two different P. aeruginosa reference strains was demonstrated by determining the minimal inhibitory concentrations (MICs), which were found to be in the range of 10-15 µg/mL. C14R's pore-forming capability was verified in a permeabilization assay based on the peptide-triggered uptake of fluorescent dyes into the bacterial cells. Finally, the peptide was used in radial diffusion assays, which are commonly used for susceptibility testing of antimicrobial peptides in clinical microbiology. In comparison to reference strains, six clinical P. aeruginosa isolates were clearly affected, thereby paving the way for further in-depth analyses of C14R as a promising new AMP drug in the future.

Context: Phytocompounds xanthatin and 8-epi-xanthatin, obtained from Xanthium chinese Mill, showed antitumoral activity in vitro related to the microtubules destabilizing properties of these phytocompounds. Five binding sites for microtubule destabilizing agents have been characterized on tubulin by high-resolution X-ray crystallography: vinca domain, colchicine, pironetin, maytansine site, and more recently, the seventh site. This work aims to develop a comprehensive computational strategy to understand and eventually predict the interaction between xanthatin and 8-epi-xanthatin with the destabilizing-antimitotic binding domain of the tubulin heterodimer. In addition, we propose a putative binding site for these phytocompounds into the microtubule destabilizing binding sites on the tubulin heterodimer. Xanthanolides showed higher stability in the colchicine and pironetin binding sites, whit a greater affinity for the former. In addition, we found that xanthanolides and non-classical colchicine binding site inhibitors share a high structural similarity., Methods: The 3D structures for xanthatin and 8-epi-xanthatin were obtained using DFT with the hybrid functional B3LYP and the base 6-31G (d,p), implemented in Gaussian 09. The 3D coordinates for tubulin proteins were downloaded from PDB. The complexes tubulin-xanthanolides were predicted using a Monte-Carlo iterated search combined with the BFGS gradient-based optimizer implemented in the AutoDock Vina. The xanthanolides-tubulin complexes were energy minimized by molecular dynamics simulations at vacuum, and their stabilities were evaluated by solvated molecular dynamics simulations during 100 ns. All molecular dynamics simulations were performed using the conjugate gradient method implemented in NAMD2 and CHARMM36 forcefield., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Mollusks have been widely investigated for antimicrobial peptides because their humoral defense against pathogens is mainly based on these small biomolecules. In this report, we describe the identification of three novel antimicrobial peptides from the marine mollusk Nerita versicolor . A pool of N. versicolor peptides was analyzed with nanoLC-ESI-MS-MS technology, and three potential antimicrobial peptides (Nv-p1, Nv-p2 and Nv-p3) were identified with bioinformatical predictions and selected for chemical synthesis and evaluation of their biological activity. Database searches showed that two of them show partial identity to histone H4 peptide fragments from other invertebrate species. Structural predictions revealed that they all adopt a random coil structure even when placed near a lipid bilayer patch. Nv-p1, Nv-p2 and Nv-p3 exhibited activity against Pseudomonas aeruginosa . The most active peptide was Nv-p3 with an inhibitory activity starting at 1.5 µg/mL in the radial diffusion assays. The peptides were ineffective against Klebsiella pneumoniae , Listeria monocytogenes and Mycobacterium tuberculosis . On the other hand, these peptides demonstrated effective antibiofilm action against Candida albicans , Candida parapsilosis and Candida auris but not against the planktonic cells. None of the peptides had significant toxicity on primary human macrophages and fetal lung fibroblasts at effective antimicrobial concentrations. Our results indicate that N. versicolor -derived peptides represent new AMP sequences and have the potential to be optimized and developed into antibiotic alternatives against bacterial and fungal infections.

Objective.: To analyze the association between the social context (demographic, socioeconomic and social support factors) and moderate-severe food and nutritional insecurity in families with children aged 0-59 months enrolled in municipal kindergartens in the state of Paraíba, Brazil., Materials and Methods.: We conducted a cross-sectional study in Brazilian municipalities prioritized for the prevention of childhood obesity. A questionnaire was used to collect information on the social context of the family (demographic profile of the child, socioeconomic situation and social support) as well as the Brazilian food insecurity scale. The association between the independent variables and moderate-severe food and nutrition insecurity was determined by applying Poisson regression to estimate crude and adjusted prevalence ratios and their respective 95% confidence intervals., Results.: We included 382 families; 27.2% had moderate-severe food and nutrition insecurity. In addition, dysfunctional families with children under 24 months, from less affluent classes, beneficiaries of the Bolsa Família Program and without social support (material, emotional/informational and interaction) were more likely to present the outcome., Conclusions.: Our results show that 27.2% of the families had moderate-severe food and nutritional insecurity, were beneficiaries of the Bolsa Família Program, dysfunctional and did not have social support. Therefore, the identification of these factors would be useful to improve family food and nutritional security.

Trust and team communication are central aspects for the achievement of both individual and common goals, which affect not only work efficiency but also the well-being of its members. In addition, organizational justice could affect these indicators, as well as the perception of collective efficacy within organizations, in this case, schools. The purpose of this study was to analyze the effect of organizational justice on teachers' subjective well-being, and how this is affected/mediated by collective efficacy. We worked with a sample of 693 teachers across Chile. Multiple mediation analysis was carried out, where the latent variables of the study were estimated (subjective well-being, organizational justice, and two dimensions of collective efficacy). The results indicate that there is full mediation of the collective efficacy dimensions between the predictor-criterion relationship. Our findings allow us to hypothesize that perceptions of collective efficacy are central to explaining well-being as an intrinsic factor.

Background: Distal segment atresia (isthmus) is an extremely rare anatomical variant of obstructive aortic arch anomalies., Case Report: We present the case of a newborn who, at 48 hours of life, presented a clinical picture of heart failure. The initial echocardiogram showed a congenital interrupted aortic arch type A, patent ductus arteriosus, and ventricular septal defect. Prostaglandins were initially indicated. Subsequently, a second echocardiogram showed the absence of ductus arteriosus; the CT angiography study confirmed this finding and revealed blood flow to the descending aorta through small intercostal blood vessels. The possibility of atresia of the distal segment (isthmus) of the aortic arch was considered and confirmed at the time of surgery., Conclusions: Aortic atresia should be considered a diagnostic possibility in the presence of type A interrupted aortic arch since the hemodynamic behavior between them is similar. Surgical medical treatment should be individualized since this condition is frequently an emergency in the neonatal period. However, this is not always the case, as other cases have been reported in schoolchildren and adults., (Copyright: © 2022 Permanyer.)

Decapod crustaceans are a very diverse group and have evolved to suit a wide variety of diets. Alpha-amylases enzymes, responsible for starch and glycogen digestion, have been more thoroughly studied in herbivore and omnivore than in carnivorous species. We used information on the α-amylase of a carnivorous lobster as a connecting thread to provide a more comprehensive view of α-amylases across decapods crustaceans. Omnivorous crustaceans such as shrimps, crabs, and crayfish present relatively high amylase activity with respect to carnivorous crustaceans. Yet, contradictory results have been obtained and relatively high activity in some carnivores has been suggested to be a remnant trait from ancestor species. Here, we provided information sustaining that high enzyme sequence and overall architecture conservation do not allow high changes in activity, and that differences among species may be more related to number of genes and isoforms, as well as transcriptional and secretion regulation. However, recent evolutionary analyses revealed that positive selection might have also occurred among distant lineages with feeding habits as a selection force. Some biochemical features of decapod α-amylases can be related with habitat or gut conditions, while less clear patterns are observed for other enzyme properties. Likewise, while molt cycle variations in α-amylase activity are rather similar among species, clear relationships between activity and diet shifts through development cannot be always observed. Regarding the adaptation of α-amylase to diet, juveniles seem to exhibit more flexibility than larvae, and it has been described variation in α-amylase activity or number of isoforms due to the source of carbohydrate and its level in diets, especially in omnivore species. In the carnivorous lobster, however, no influence of the type of carbohydrate could be observed. Moreover, lobsters were not able to fine-regulate α-amylase gene expression in spite of large changes in carbohydrate content of diet, while retaining some capacity to adapt α-amylase activity to very low carbohydrate content in the diets. In this review, we raised arguments for the need of more studies on the α-amylases of less studied decapods groups, including carnivorous species which rely more on dietary protein and lipids, to broaden our view of α-amylase in decapods crustaceans.

A common practice among clinical psychologists and other health professionals is the use of school-based sexual health promotion programs as a means for preventing sexually transmitted infections. A fundamental criterion for the designing and adaptation of these programs is the age of their target populations because limited education and language are the most relevant factors that limit the efficacy of these programs. The contribution of this paper consists of assessing both the readability of the written materials that accompany the contents of a Spanish-written school-based sexual health promotion program used in Colombia, as well as the words co-occurrence network structure of its contents. The readability of the evaluated program corresponded to its intended target population aged between 14 and 19, with the schooling of 9-13 years of education. The resulting words co-occurrence network structure of the COMPAS program also mirrored its theoretical content. These results all together are deemed as empirical evidence of the adequacy of the program., (© 2020 The Authors. Published by Elsevier Inc.)

To evaluate the impact on perinatal outcomes related with placental insufficiency, by the application of the new 2017 ACC/AHA guidelines to a group of chronic hypertensive pregnancies during their first trimester assessment. The best multivariate predictive model for p-PE included a previous PE background (OR = 15) and mean arterial pressure in mmHg (OR = 1.1). EP01.38: Perinatal outcomes of pregestational hypertension according to blood pressure range at 11-14-week scan: impact of the 2017 ACC/AHA guidelines. [Extracted from the article]

Background: Colombia has one of the highest rates of the human immunodeficiency virus (HIV) and pregnancies - both of which are influenced by lack of condom use -, among adolescent population in Latin America; however, the mechanisms underlying the inconsistent use of condoms in this population are poorly understood. This descriptive and cross-sectional study's purpose was to examine sexual behavior and its precursors using the theory of planned behavior (TPB) and considering gender-based differences. Another objective was to study the mediating effect of intention in the relationship between behavior precursors and condom use based on the TPB., Methods: We recruited 1100 adolescents aged between 14 and 19 years old (M = 15.94, SD = 1.30, 54.4% female) from Bogotá and Barranquilla, two of the cities with highest adolescent birth rates among adolescents in Colombia. Sociodemographic variables, knowledge on HIV and other sexually transmitted infections (STIs), HIV/AIDS-related attitudes, including attitudes toward the use of condoms, normative beliefs, perceived behavioral control, behavioral intention, and sexual behavior were assessed using self-reports. All analyses were run using SPSS v25. The indirect effect of intention to explain the relationship between precursors and the use of condoms during sexual intercourse was estimated using the PROCESS v3 macro., Results: Descriptive analyses suggest a high risk of contracting sexually transmitted infections and unplanned pregnancies associated to inconsistent condom use, medium-low level of knowledge about sexual health, low normative beliefs regarding peers' condom use, and a certain perceived difficulty for using condoms. Condoms are used 71% of the times they have sex, but only 22% of the participants use them consistently; girls use condoms more consistently than boys. Sexual risk characteristics differed significantly by gender. Mediation analyses indicated that condom use intention mediates the relationship between behavioral precursors and frequency of condom use, according to the TPB., Conclusions: Findings provide a better understanding of sexual risk and highlight important implications for the sexual and reproductive health of adolescents. There is a need of designing and implementing protocolized sexual health promotion programs in schools with the aim of reducing sexual risk behaviors in Colombian adolescents.

This work aims to provide an effective and novel solution for the treatment of infection by using nanovehicles loaded with antibiotics capable of penetrating the bacterial wall, thus increasing the antimicrobial effectiveness. These nanosystems, named "nanoantibiotics", are composed of mesoporous silica nanoparticles (MSNs), which act as nanocarriers of an antimicrobial agent (levofloxacin, LEVO) localized inside the mesopores. To provide the nanosystem of bacterial membrane interaction capability, a polycationic dendrimer, concretely the poly(propyleneimine) dendrimer of third generation (G3), was covalently grafted to the external surface of the LEVO-loaded MSNs. After physicochemical characterization of this nanoantibiotic, the release kinetics of LEVO and the antimicrobial efficacy of each released dosage were evaluated. Besides, internalization studies of the MSNs functionalized with the G3 dendrimer were carried out, showing a high penetrability throughout Gram-negative bacterial membranes. This work evidences that the synergistic combination of polycationic dendrimers as bacterial membrane permeabilization agents with LEVO-loaded MSNs triggers an efficient antimicrobial effect on Gram-negative bacterial biofilm. These positive results open up very promising expectations for their potential application in new infection therapies., Statement of Significance: Seeking new alternatives to current available treatments of bacterial infections represents a great challenge in nanomedicine. This work reports the design and optimization of a new class of antimicrobial agent, named "nanoantibiotic", based on mesoporous silica nanoparticles (MSNs) decorated with polypropyleneimine dendrimers of third generation (G3) and loaded with levofloxacin (LEVO) antibiotic. The covalently grafting of these G3 dendrimers to MSNs allows an effective internalization in Gram-negative bacteria. Furthermore, the LEVO loaded into the mesoporous cavities is released in a sustained manner at effective antimicrobial dosages. The novelty and originality of this manuscript relies on proving that the synergistic combination of bacteria-targeting and antimicrobial agents into a unique nanosystem provokes a remarkable antimicrobial effect against bacterial biofilm., (Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)