Domestic Dog Infection with Trypanosoma cruzi from Northern and Southern Regions of Mexico.

Background: Chagas disease or American trypanosomiasis, caused by Trypanosoma cruzi and vectored by triatomines, affects millions of people worldwide. In endemic countries including Mexico, infections in domestic animals, such as dogs, may affect the risk of human disease when they serve as a source of infection to vectors that subsequently infect humans. Materials and Methods: We conducted a cross-sectional study of 296 dogs from two cities near the northern and southern borders of Mexico: Reynosa, Tamaulipas, and Tuxtla Gutierrez, Chiapas. Infection was measured based on testing of blood using T. cruzi quantitative PCR (qPCR) and up to three antibody detection assays. The StatPak immunochromatographic assay was used to screen samples and the indirect fluorescent antibody (IFA) and multiplex microsphere immunoassay (MIA) tests were used as secondary tests on all samples that screened positive and a subset of negatives. Serologic positivity was defined based on reactivity on at least two independent tests. Results: Of the 280 samples tested for parasite DNA, two (0.7%) were positive, one of which (0.4%) was confirmed as T. cruzi discrete typing unit TcIV. Overall, 72 (24.3%) samples were reactive for T. cruzi antibodies via StatPak of which 8 were also positive using MIA and 2 were also positive using IFA (including one of the PCR-positive dogs). Overall, nine dogs (3.4%) met study criteria of positivity based on either/both serology or PCR tests. Positive dogs were found in both regions of Mexico; five (2.7%) from Reynosa and four (3.6%) from Tuxtla Gutierrez. We found no association between infection status and state of origin, sex, age group, breed group, neighborhood, and whether other pets lived in the home. Conclusion: Our results re-emphasize dogs' utility as sentinels for T. cruzi in Mexico and underscore the need for improved veterinary diagnostic tests and parasite surveillance at the household level in endemic countries.

Autoantibodies Neutralizing GM-CSF in HIV-Negative Colombian Patients Infected with Cryptococcus gattii and C. neoformans.

BACKGROUND: Cryptococcosis is a life-threatening disease caused by Cryptococcus neoformans or C. gattii. Neutralizing autoantibodies (auto-Abs) against granulocyte-macrophage colony-stimulating factor (GM-CSF) in otherwise healthy adults with cryptococcal meningitis have been described since 2013. We searched for neutralizing auto-Abs in sera collected from Colombian patients with non-HIV-associated cryptococcosis in a retrospective national cohort from 1997 to 2016. METHODS: We reviewed clinical and laboratory records and assessed the presence of neutralizing auto-Abs against GM-CSF in 30 HIV negative adults with cryptococcosis (13 caused by C. gattii and 17 caused by C. neoformans). RESULTS: We detected neutralizing auto-Abs against GM-CSF in the sera of 10 out of 13 (77%) patients infected with C. gattii and one out of 17 (6%) patients infected with C. neoformans. CONCLUSIONS: We report eleven Colombian patients diagnosed with cryptococcosis who had auto-Abs that neutralize GM-CSF. Among these patients, ten were infected with C. gattii and only one with C. neoformans.

Updating and profiling the natural product-likeness of Latin American compound libraries.

Compound databases of natural products play a crucial role in drug discovery and development projects and have implications in other areas, such as food chemical research, ecology and metabolomics. Recently, we put together the first version of the Latin American Natural Product database (LANaPDB) as a collective effort of researchers from six countries to ensemble a public and representative library of natural products in a geographical region with a large biodiversity. The present work aims to conduct a comparative and extensive profiling of the natural product-likeness of an updated version of LANaPDB and the individual ten compound databases that form part of LANaPDB. The natural product-likeness profile of the Latin American compound databases is contrasted with the profile of other major natural product databases in the public domain and a set of small-molecule drugs approved for clinical use. As part of the extensive characterization, we employed several chemoinformatics metrics of natural product likeness. The results of this study will capture the attention of the global community engaged in natural product databases, not only in Latin America but across the world.

Synthesis, biosimulation and pharmacological evaluation of benzimidazole derivatives with antihypertensive multitarget effect.

In this study, we synthesized a series of seven benzimidazole derivatives incorporating the structural acidic framework of angiotensin II (Ang II) type 1 receptor (AT1R) antagonists (ARA-II) employing a three-step reaction sequence. The chemical structures were confirmed by 1H NMR, 13C NMR and mass spectral data. Through biosimulation, compounds 1-7 were identified as computational safe hits, thus, best candidates underwent ex vivo testing against two distinct mechanisms implicated in hypertension: antagonism of the Ang II type 1 receptor and the blockade of calcium channel. Molecular docking studies helped to understand at the molecular level the dual vasorelaxant effects with the recognition sites of the AT1R and the L-type calcium channel. In an in vivo spontaneously hypertensive rat model (SHR), intraperitoneally administration of compound 1 at 20 mg/kg resulted in a 25 % reduction in systolic blood pressure, demonstrating both ex vivo vasorelaxant action and in vivo antihypertensive multitarget efficacy. ©2024 Elsevier.

Food Chemicals and Epigenetic Targets: An Epi Food Chemical Database.

There is increasing awareness of epigenetics's importance in understanding disease etiologies and developing novel therapeutics. An increasing number of publications in the past few years reflect the renewed interest in epigenetic processes and their relationship with food chemicals. However, there needs to be a recent study that accounts for the most recent advances in the area by associating the chemical structures of food and natural product components with their biological activity. Here, we analyze the status of food chemicals and their intersection with natural products in epigenetic research. Using chemoinformatics tools, we compared quantitatively the chemical contents, structural diversity, and coverage in the chemical space of food chemicals with reported epigenetic activity. As part of this work, we built and curated a compound database of food and natural product chemicals annotated with structural information, an epigenetic target activity profile, and the main source of the food chemical or natural product, among other relevant features. The compounds are cross-linked with identifiers from other major public databases such as FooDB and the collection of open natural products, COCONUT. The compound database, the "Epi Food Chemical Database", is accessible in HTML and CSV formats at https://github.com/DIFACQUIM/Epi_food_Chemical_Database.

Indeterminate pulmonary nodules and prior malignancy: survival and recurrence after surgery in newly diagnosed stage I non-small cell lung cancer.

Background: Surgical excision biopsy remains the only reliable option in most cases of indeterminate pulmonary nodules, particularly in cancer survivors for whom surgery provides local control of pulmonary metastasis and the best chance of cure for early-stage lung cancer. Nevertheless, unnecessary surgeries remain a concern and the prognosis of newly diagnosed lung cancer might be influenced by the history of previous malignancy. We aimed to analyze the outcomes of resected indeterminate pulmonary nodules in patients with and without previous malignancy, and the impact of prior cancer history on survival and recurrence in stage I non-small cell lung cancer (NSCLC) patients. Methods: We retrospectively studied 176 resected indeterminate pulmonary nodules from 169 patients (58% with and 42% without previous cancer). Recurrence and overall survival (OS) were analyzed in newly diagnosed stage I NSCLC using the Kaplan-Meier method and Cox proportional hazard models. Results: The rate of benign lesions was 15.3% (9.6% in the previous cancer group and 23.6% in the no previous cancer group). In stage I NSCLC patients (n=86), previous malignancy was associated with recurrence (P<0.001) but not OS (P=0.23). Chronic obstructive pulmonary disease and visceral pleural invasion were associated with impaired OS and recurrence. Mediastinal lymph node removal was associated with better OS. Conclusions: The rate of benign resections among indeterminate pulmonary nodules in the no-previous cancer group more than doubled that of the previous cancer group and, in newly diagnosed stage I NSCLC patients, recurrence was independently associated with prior cancer. Therefore, in this setting, a history of previous malignancy should be taken into consideration when identifying patients at risk of tumor recurrence.

Targeting Leishmania infantum Mannosyl-oligosaccharide glucosidase with natural products: potential pH-dependent inhibition explored through computer-aided drug design.

Visceral Leishmaniasis (VL) is a serious public health issue, documented in more than ninety countries, where an estimated 500,000 new cases emerge each year. Regardless of novel methodologies, advancements, and experimental interventions, therapeutic limitations, and drug resistance are still challenging. For this reason, based on previous research, we screened natural products (NP) from Nuclei of Bioassays, Ecophysiology, and Biosynthesis of Natural Products Database (NuBBEDB), Mexican Compound Database of Natural Products (BIOFACQUIM), and Peruvian Natural Products Database (PeruNPDB) databases, in addition to structural analogs of Miglitol and Acarbose, which have been suggested as treatments for VL and have shown encouraging action against parasite's N-glycan biosynthesis. Using computer-aided drug design (CADD) approaches, the potential inhibitory effect of these NP candidates was evaluated by inhibiting the Mannosyl-oligosaccharide Glucosidase Protein (MOGS) from Leishmania infantum, an enzyme essential for the protein glycosylation process, at various pH to mimic the parasite's changing environment. Also, computational analysis was used to evaluate the Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profile, while molecular dynamic simulations were used to gather information on the interactions between these ligands and the protein target. Our findings indicated that Ocotillone and Subsessiline have potential antileishmanial effects at pH 5 and 7, respectively, due to their high binding affinity to MOGS and interactions in the active center. Furthermore, these compounds were non-toxic and had the potential to be administered orally. This research indicates the promising anti-leishmanial activity of Ocotillone and Subsessiline, suggesting further validation through in vitro and in vivo experiments.

Elevated glycolytic metabolism of monocytes limits the generation of HIF1A-driven migratory dendritic cells in tuberculosis.

During tuberculosis (TB), migration of dendritic cells (DCs) from the site of infection to the draining lymph nodes is known to be impaired, hindering the rapid development of protective T-cell-mediated immunity. However, the mechanisms involved in the delayed migration of DCs during TB are still poorly defined. Here, we found that infection of DCs with Mycobacterium tuberculosis (Mtb) triggers HIF1A-mediated aerobic glycolysis in a TLR2-dependent manner, and that this metabolic profile is essential for DC migration. In particular, the lactate dehydrogenase inhibitor oxamate and the HIF1A inhibitor PX-478 abrogated Mtb-induced DC migration in vitro to the lymphoid tissue-specific chemokine CCL21, and in vivo to lymph nodes in mice. Strikingly, we found that although monocytes from TB patients are inherently biased toward glycolysis metabolism, they differentiate into poorly glycolytic and poorly migratory DCs compared with healthy subjects. Taken together, these data suggest that because of their preexisting glycolytic state, circulating monocytes from TB patients are refractory to differentiation into migratory DCs, which may explain the delayed migration of these cells during the disease and opens avenues for host-directed therapies for TB.

A critical assessment of bioactive compounds databases.

Compound databases (DBs) are essential tools for drug discovery. The number of DBs in public domain is increasing, so it is important to analyze these DBs. In this article, the main characteristics of 64 DBs will be presented. The methodological strategy used was a literature search. To analyze the characteristics obtained in the review, the DBs were categorized into two subsections: Open Access and Commercial DBs. Open access includes generalist DBs (containing compounds of diverse origins), DBs with specific applicability, DBs exclusive to natural products and those containing compounds with specific pharmacological action. The literature review showed that there are challenges to making these repositories available, such as standardizing information curation practices and funding to maintain and sustain them.

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Early Intraprosthetic Dislocation of Total Hip Arthroplasty with Double Mobility Implant: Case Report.

Total hip arthroplasty (THA) is a successful surgery in the treatment of hip pain, but there are potential complications, of which dislocation is one of the most common. Dislocation management is a challenging problem that requires a multimodal approach, and the use of dual mobility implants is an option. We present a patient with a history of femoral neck fracture who underwent THA with a double mobility implant. On the 18 th postoperative day, after a fall to the ground, she developed prosthesis dislocation and had a complication after closed reduction, a subsequent intraprosthetic dislocation. After a radiographic diagnosis, the patient presented mechanical signs of hip flexion caused by a disassociated double mobility implant. The revision surgery was indicated, but the patient chose not to perform the necessary surgical procedure. A careful postoperative study of the radiographs revealed an eccentric femoral head and evidence of disassociated implantation in the surrounding soft tissues. Radiographs after closed reduction of intraprosthetic dislocations should be examined thoroughly.

Putative mechanism of a multivitamin treatment against insulin resistance.

Insulin resistance is caused by the abnormal secretion of proinflammatory cytokines in adipose tissue, which is induced by an increase in lipid accumulation in adipocytes, hepatocytes, and myocytes. The inflammatory pathway involves multiple targets such as nuclear factor kappa B, inhibitor of nuclear factor κ-B kinase, and mitogen-activated protein kinase. Vitamins are micronutrients with anti-inflammatory activities that have unclear mechanisms. The present study aimed to describe the putative mechanisms of vitamins involved in the inflammatory pathway of insulin resistance. The strategy to achieve this goal was to integrate data mining and analysis, target prediction, and molecular docking simulation calculations to support our hypotheses. Our results suggest that the multitarget activity of vitamins A, B1, B2, B3, B5, B6, B7, B12, C, D3, and E inhibits nuclear factor kappa B and mitogen-activated protein kinase, in addition to vitamins A and B12 against inhibitor of nuclear factor κ-B kinase. The findings of this study highlight the pharmacological potential of using an anti-inflammatory and multitarget treatment based on vitamins and open new perspectives to evaluate the inhibitory activity of vitamins against nuclear factor kappa B, mitogen-activated protein kinase, and inhibitor of nuclear factor κ-B kinase in an insulin-resistant context.

BIOMX-DB: A web application for the BIOFACQUIM natural product database.

Natural product databases are an integral part of chemoinformatics and computer-aided drug design. Despite their pivotal role, a distinct scarcity of projects in Latin America, particularly in Mexico, provides accessible tools of this nature. Herein, we introduce BIOMX-DB, an open and freely accessible web-based database designed to address this gap. BIOMX-DB enhances the features of the existing Mexican natural product database, BIOFACQUIM, by incorporating advanced search, filtering, and download capabilities. The user-friendly interface of BIOMX-DB aims to provide an intuitive experience for researchers. For seamless access, BIOMX-DB is freely available at www.biomx-db.com.

Ataxia-telangiectasia in Latin America: clinical features, immunodeficiency, and mortality in a multicenter study.

Ataxia-telangiectasia (AT) is a rare genetic disorder leading to neurological defects, telangiectasias, and immunodeficiency. We aimed to study the clinical and immunological features of Latin American patients with AT and analyze factors associated with mortality. Referral centers from 9 Latin American countries participated in this retrospective cohort study, and 218 patients were included. Median (IQR) ages at symptom onset and diagnosis were 1.0 (1.0-2.0)  and 5.0 (3.0-8.0) years, respectively. Most patients presented recurrent airway infections, which was significantly associated with IgA deficiency. IgA deficiency was observed in 60.8% of patients and IgG deficiency in 28.6%. T- and B-lymphopenias were also present in most cases. Mean survival was 24.2 years, and Kaplan-Meier 20-year-survival rate was 52.6%, with higher mortality associated with female gender and low IgG levels. These findings suggest that immunologic status should be investigated in all patients with AT.

The creation of the Fundação Brasileira para a Conservação da Natureza.

This study within the field of environmental history explores the scenario amid which the Fundação Brasileira para a Conservação da Natureza (Brazilian Foundation for Nature Conservation) was founded between 1958 and 1966; this important Brazilian non-governmental organization headquartered in Rio de Janeiro worked at the local, national, and international levels. Primary documentary sources were utilized, along with research of the related literature. The conclusions demonstrate the importance of non-governmental organizations predating this foundation, and the influence of conservationists on its establishment and current work.

Toward structure-multiple activity relationships (SMARts) using computational approaches: A polypharmacological perspective.

In the current era of biological big data, which are rapidly populating the biological chemical space, in silico polypharmacology drug design approaches help to decode structure-multiple activity relationships (SMARts). Current computational methods can predict or categorize multiple properties simultaneously, which aids the generation, identification, curation, prioritization, optimization, and repurposing of molecules. Computational methods have generated opportunities and challenges in medicinal chemistry, pharmacology, food chemistry, toxicology, bioinformatics, and chemoinformatics. It is anticipated that computer-guided SMARts could contribute to the full automatization of drug design and drug repurposing campaigns, facilitating the prediction of new biological targets, side and off-target effects, and drug-drug interactions.

Do Dominant Native Ants Outcompete the Invasive Argentine Ant in Mediterranean Citrus Ecosystems? A Laboratory Test.

The invasive Argentine ant (Linepithema humile) poses a significant threat to ecosystem stability worldwide. In Mediterranean citrus ecosystems, its spread may be limited by interactions with dominant native ant species. We conducted laboratory experiments to investigate the competitive dynamics between Argentine ants and two major native species, Tapinoma nigerrimum and Lasius grandis. At the individual level, both native species exhibited superior competitive performance, attributed to their larger body sizes and potential differences in chemical defences. At the colony level, T. nigerrimum demonstrated efficiency in interference competition, successfully defending food resources from Argentine ants. However, the Argentine ant exhibited higher recruitment capacity, albeit it was density-dependent. Our findings support the hypothesis that dominant native ants can serve as barriers against Argentine ant invasion in citrus ecosystems, highlighting the importance of interspecific competition in shaping community dynamics and invasive species management. This study underscores the potential role of native ant species in mitigating the impacts of invasive ants on ecosystem functioning and biodiversity conservation in agricultural landscapes, offering valuable insights for invasive species management strategies in Mediterranean citrus ecosystems.

Is self-incompatibility a reproductive barrier for hybridization in a sympatric species?

PREMISE: Barriers at different reproductive stages contribute to reproductive isolation. Self-incompatibility (SI) systems that prevent self-pollination could also act to control interspecific pollination and contribute to reproductive isolation, preventing hybridization. Here we evaluated whether SI contributes to reproductive isolation among four co-occurring Opuntia species that flower at similar times and may hybridize with each other. METHODS: We assessed whether Opuntia cantabrigiensis, O. robusta, O. streptacantha, and O. tomentosa, were self-compatible and formed hybrid seeds in five manipulation treatments to achieve self-pollination, intraspecific cross-pollination, open pollination (control), interspecific crosses or apomixis, then recorded flowering phenology and synchrony. RESULTS: All species flowered in the spring with a degree of synchrony, so that two pairs of species were predisposed to interspecific pollination (O. cantabrigiensis with O. robusta, O. streptacantha with O. tomentosa). All species had distinct reproductive systems: Opuntia cantabrigiensis is self-incompatible and did not produce hybrid seeds as an interspecific pollen recipient; O. robusta is a dioecious species, which formed a low proportion of hybrid seeds; O. streptacantha and O. tomentosa are self-compatible and produced hybrid seeds. CONCLUSIONS: Opuntia cantabrigiensis had a strong pollen-pistil barrier, likely due to its self-incompatibility. Opuntia robusta, the dioecious species, is an obligate outcrosser and probably partially lost its ability to prevent interspecific pollen germination. Given that the self-compatible species can set hybrid seeds, we conclude that pollen-pistil interaction and high flowering synchrony represent weak barriers; whether reproductive isolation occurs later in their life cycle (e.g., germination or seedling survival) needs to be determined.

The elimination of human African trypanosomiasis: Monitoring progress towards the 2021-2030 WHO road map targets.

BACKGROUND: Human African trypanosomiasis (HAT) is a neglected tropical disease that usually occurs in rural areas in sub-Saharan Africa. It caused devastating epidemics during the 20th century. Sustained, coordinated efforts by different stakeholders working with national sleeping sickness control programmes (NSSCPs) succeeded in controlling the disease and reducing the number of cases to historically low levels. In 2012, WHO targeted the elimination of the disease as a public health problem by 2020. This goal has been reached and a new ambitious target was stated in the WHO road map for NTDs 2021-2030 and endorsed by the 73rd World Health Assembly: the elimination of gambiense HAT transmission (i.e. reducing the number of reported cases to zero). The interruption of transmission was not considered as an achievable goal for rhodesiense HAT, as it would require vast veterinary interventions rather than actions at the public health level. METHODOLOGY/PRINCIPAL FINDINGS: Data reported to WHO by NSSCPs were harmonized, verified, georeferenced and included in the atlas of HAT. A total of 802 cases were reported in 2021 and 837 in 2022. This is below the target for elimination as a public health problem at the global level (< 2000 HAT cases/year); 94% of the cases were caused by infection with T. b. gambiense. The areas reporting ≥ 1 HAT case/10 000 inhabitants/year in 2018-2022 cover a surface of 73 134 km2, with only 3013 km2 at very high or high risk. This represents a reduction of 90% from the baseline figure for 2000-2004, the target set for the elimination of HAT as a public health problem. For the surveillance of the disease, 4.5 million people were screened for gambiense HAT with serological tests in 2021-2022, 3.6 million through active screening and 0.9 million by passive screening. In 2021 and 2022 the elimination of HAT as a public health problem was validated in Benin, Uganda, Equatorial Guinea and Ghana for gambiense HAT and in Rwanda for rhodesiense HAT. To reach the next goal of elimination of transmission of gambiense HAT, countries have to report zero cases of human infection with T. b. gambiense for a period of at least 5 consecutive years. The criteria and procedures to verify elimination of transmission have been recently published by WHO. CONCLUSIONS/SIGNIFICANCE: HAT elimination as a public health problem has been reached at global level, with seven countries already validated as having reached this goal. This achievement was made possible by the work of NSSCPs, supported by different public and private partners, and coordinated by WHO. The new challenging goal now is to reach zero cases by 2030. To reach this goal is crucial to maintain the engagement and support of donors and stakeholders and to keep the involvement and coordination of all partners. Along with the focus on elimination of transmission of gambiense HAT, it is important not to neglect rhodesiense HAT, which is targeted for elimination as a public health problem in the WHO road map for NTDs 2021-2030.

Deepening biomedical research training: Community-Building Wellness Workshops for Post-Baccalaureate Research Education Program (PREP) Trainees.

Problem: All trainees, especially those from historically minoritized backgrounds, experience stresses that may reduce their continuation in science, technology, engineering, math, and medicine (STEMM) careers. The Johns Hopkins University School of Medicine is one of ~45 institutions with a National Institutes of Health funded Postbaccalaureate Research Education Program (PREP) that provides mentoring and a year of fulltime research to prepare students from historically excluded groups for graduate school. Having experienced the conflation of stresses during the COVID-19 pandemic and related shutdown, we realized our program lacked a component that explicitly helped PREP Scholars recognize and cope with non-academic stresses (financial, familial, social, mental) that might threaten their confidence and success as scientists and future in STEMM. Intervention: We developed an early-intervention program to help Scholars develop life-long skills to become successful and resilient scientists. We developed a year-long series comprised of 9 workshops focused on community, introspection, financial fitness, emotional intelligence, mental health, and soft-skills. We recruited and compensated a cohort of PhD students and postdoctoral fellows to serve as Peer Mentors, to provide a community and the safest 'space' for Scholars to discuss personal concerns. Peer Mentors were responsible for developing and facilitating these Community-Building Wellness Workshops (CBWW). Context: CBWW were created and exectued as part of the larger PREP program. Workshops included a PowerPoint presentation by Peer Mentors that featured several case studies that prompted discussion and provided time for small-group discussions between Scholars and Peer Mentors. We also included pre- and post-work for each workshop. These touch-points helped Scholars cultivate the habit of introspection. Impact: The CBWW exceeded our goals. Both Peer Mentors and Scholars experienced strong mutual support, and Scholars developed life-long skills. Notably, several Scholars who had been experiencing financial, mental or mentor-related stress immediately brought this to the attention of program leadership, allowing early and successful intervention. At the completion of CBWW, PREP Scholars reported implementing many workshop skills into practice, were reshaping their criteria for choosing future mentors, and evaluating career decisions. Strikingly, Peer Mentors found they also benefitted from the program as well, suggesting a potential larger scope for the role of CBWW in academia. Lessons Learned: Peer Mentors were essential in creating a safe supportive environment that facilitated discussions, self-reflection, and self-care. Providing fair compensation to Peer Mentors for their professional mentoring and teaching contributions was essential and contributed meaningfully to the positive energy and impact of this program.