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First steps towards the identification of a new hybrid antimalarial therapeutic agent targeting PfAQP

Malaria became a public global health priority and matter of discourse during the transition between millennia. Although most malaria variants are currently successfully treated with the existing antimalarial drugs, in 2019, this disease was still responsible for approximately 409 000 deaths globally [1]. Severe malaria in humans is mostly caused by infection with Plasmodium falciparum whose complications include severe anemia and end-organ damage, pulmonary complications, and hypoglycemia or acute kidney injury [2].

The development of hybrid antimalarial agents has been actively pursued as a promising strategy to overcome the problem of resistant parasite strains since it provides treatment for all P. falciparum that infects human red blood cells and at the same time eliminates the replicative and dormant liver forms of the parasite [3]. In this communication, we will present the first steps towards the development of a multi-target strategy based on the use of keystone antimalarial drugs coupled to inhibitors of the P. falciparum aquaporin (PfAQP). This protein acts as a constitutive water and glycerol channel [4], with a key function in the reproduction of the Plasmodium, making it a promising target for the development of antimalarial therapeutics [5]. An initial structural characterization of PfAQP along with a qualitative assessment on the dynamics and function of the protein will be presented, together with an evaluation of the effect different membrane sizes on simulation times and quality of the model. These results are of utmost importance for the next steps of the project, where the inhibitory efficiency of different glycerol derivatives will be evaluated.

Acknowledgements: FCT to projects PTDC/BIA-BFS/28419/2017 (B. L. Victor) UIDB/04046/2020−UIDP/04046/2020 (BioISI).

[1] World malaria report 2020: 20 years of global progress and challenges. geneva: World health organization; 2020.

[2] Phillips, M., Burrows, J., Manyando, C. et al. Malaria. Nat Rev Dis Primers 3, 17050 (2017).

[3] Capela, R., Cabal, G. G., Rosenthal, P. J., Gut, J., Mota, M. M., Moreira, R., Lopes, F., & Prudêncio, M. (2011).. Antimicrob Agents Chemother, 55(10), 4698–4706.

[4] Newby, Z., O'Connell III, J., Robles-Colmenares, Y. et al.. Nat Struct Mol Biol 15, 619–625 (2008).

[5] Kun, J. F., & de Carvalho, E. G. (2009).. Expert Opin Ther Targets, 13(4), 385–394.

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Towards a framework to unify in silico methods for endocrine disruptors identification: the inhibition of thyroid peroxidase
, , , ,

The recurrent daily exposure of human beings to different chemicals along with increasing evidence highlighting endocrine-related human diseases [1], has led to a growing interest in understanding how endocrine-disrupting chemicals (EDCs) can affect the human endocrine system. These EDCs can be present in the environment from different sources, e.g., plant protection products (PPPs), pharmaceuticals, or dietary components [2]. Recently, guidance to identify this class of compounds in the context of PPPs and biocidal products was issued by the European Chemical Agency (ECHA) and the European Food and Safety Agency (EFSA) [3] upon a request by the European Commission (EC). Considering this new guidance, the development of new in silico methodologies capable of identifying EDCs is of utmost importance, not only for drug discovery but also for chemical risk assessment campaigns. In this context, this project aims at maximizing the predictive performance of different in silico methodologies by combining ligand-based and structural-based techniques with machine learning algorithms, overcoming the limitation of each approach, and leveraging their individual strengths. In this communication, the initial steps of this project, which focused on thyroid pathways, more specifically on the inhibition of thyroid peroxidase (TPO), will be discussed. TPO catalyses the iodination as well as the coupling of tyrosine residues to thyroglobulin to generate T3 and T4 thyroid hormones, which are of utmost importance in the regulation of multiple physiological processes of the endocrine system. Preliminary results, highlighting the criteria for the curation of a dataset assembled from a high-throughput in vitro assay developed in the Endocrine Disruptor Screening Program by the United States Environmental Agency to predict TPO inhibition via the oxidation of Amplex UltraRed in the AUR-TPO assay [4] will be shown. These results will be compared with previously reported workflows [5,6] applied to the same dataset, and a discussion on the importance of the selected curation steps will be undertaken. These steps are of major importance not only to increase the quality of the dataset, but also to reduce the noise that non-relevant compounds could have in the performance of the predictive models that will be generated in the future.

[1] Bergman, A., et al., World Health Organization, 2013
[2] Frye, C.A., et al., J. Neuroendocrinol. 2012, 24, 144
[3] Andersson, N. et al., EFSA Journal 2018, 16, 5311
[4] Friedman, F.K., et al., Tox. Sci., 2016, 151, 160
[5] Lomana, M. G., et al., Chem. Res. Toxicol., 2021, 34, 396
[6] Gadaleta, D., et al., , Front. Pharmacol., 2021, 12, 713037

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Domination, γ-Domination Topological Indices, and φ_P-polynomial of Some Chemical Structures Applied for the Treatment of COVID-19 Patients
, , ,

In medical science, pharmacology, chemical, biological, pharmaceutical properties of molecular structure are essential for drug preparation and design. These properties can be studied by using topological indices calculation. In this research work, we establish topological properties of some chemical structures that have been applied for the treatment of COVID-19 patients, by using the domination topological indices and domination indices. We determine the φ_P-polynomial for the antiviral chemical structures. The results obtained can be helpful for studying the chemical properties of chemical structures that have been applied for the treatment of COVID-19 patients.

  • Open access
  • 43 Reads

NEURODAT'21 IBRO-PERC Lecture on Brain Networks Dynamics

Description. Welcome to Prof. PhD. David Quesada invited talk cover and tutoring channel on DeepLearning in Neurosciences. The talk is part of the NEURODAT’21 training program funded by IBRO-PERC Soft Skills Training call of the International Brain Research Organization (IBRO) and the Pan-Europe Regional Committee (PERC). NEURODAT’21 is devoted to promote soft skills on entry level medicine and also STEMS area students interested on neurosciences. On this talk the professor made an introduction to the basic concepts related to Machine Learning, Networks, and Artificial Intelligence in the study of Neuroscience. Besides that, these foundations will permit to define the methodologies behind Cognitive Neuroscience, Neuromorphic Computing, Quantum Machine Learning, and Quantum Artificial Neural Networks.

Resumen: La presente comunicación va dirigida a crear las bases teóricas en matemática y biofísica para comprender los modelos usados en el Aprendizaje de Máquina, Redes, e Inteligencia Artificial para el estudio de las Neurociencias. Además, estas bases permitirán definir las metodologías detrás de la Neurociencia del Conocimiento, Computación Neuromórfica, Aprendizaje de Máquina Cuántico y Redes Neuronales Artificiales Cuánticas

Description of channel. This channel is part of the NEURODAT’21 training program funded by IBRO-PERC Soft Skills Training call of the International Brain Research Organization (IBRO) and the Pan-Europe Regional Committee (PERC). NEURODAT’21 is a training program devoted to promote soft skills on entry level Medicine and also STEMS area students interested on Neurosciences. In this tutoring channels students will be allowed to do online public questions and comments about different topics of Deep Learning and its applications in Neurosciences. Prof. Qesada will answer all questions within his area of expertise. This professor may interact with you in English or Spanish.

Talk & Channel Topics. The emphasis is on The present communication is aimed at creating the biophysical and mathematical foundations for the understanding of the current trends in the use of Machine Learning, Networks, and Artificial Intelligence in the study of Neuroscience. Besides that, these foundations will permit to define the methodologies behind Cognitive Neuroscience, Neuromorphic Computing, Quantum Machine Learning, and Quantum Artificial Neural Networks.

Instructions for students. The steps for participation are: (1) Wait for channel starting in 2021-Dec-25, you will see a posting comments option/button, (2) Register/login with your email and password to validate your user, (3) Post your question/comment for the Prof. of the channel, (4) Wait for the email advising that professor has answered your question, (5) Make other questions related to this topic or other topics, (6) Request your attendance certificate to or directly to the email of the professor.

General notes. (1) Students are allowed to made multiple questions following the same discussion threat or open new questions. (2) Some professors may release different materials, slides, etc., that the student can use to study and/or follow the discussion, click the button bellow to see the pdf files. (3) Language note: some professors allow students to select their favorite language of interaction according to professor communications skills, accordingly materials, questions, and answers may appear in these languages. (4) The channel will be open until conference finish the post-publication stage, contact chairpersons for doubts:

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NEURODAT'21 IBRO-PERC Lecture on Computational Neuroscience

The present communication is aimed at creating the biophysical and mathematical foundations for the understanding of the current trends theory of control and networks applied to Computational Neurosciences. There are many different models of interest on this area Hodgkin – Huxley model, Fitzhugh – Nagumo model, Morris – Lecar model, Hindmarsh – Rose model, Izhikievich model, Li – Rinzel model, Wilson – Cowan model, Kuramoto model, Hopfield and Spin Glass-like models, Cellular Automata models, etc. On this presentation the focus is on this class of models and their implications/relations to computational neurosciences.

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A computational study on the catalytic mechanism of Pdx2: a glutaminase containing the Cys-His-Glu triad

Pdx2, the glutaminase subunit of the pyridoxal 5’-phosphate (PLP) synthase, is a key enzyme in the synthesis of PLP. It employs a non-canonical Cys-His-Glu triad to catalyze the deamination of glutamine to glutamate and ammonia – the source of the nitrogen of PLP. For this reason, Pdx2 is considered a novel and promising drug target against diseases such as Malaria and Tuberculosis, whose pathogens rely on this enzyme to obtain PLP. Therefore, the catalytic mechanism of Pdx2 was studied with atomic detail using the computational ONIOM QM/MM methodology with an 80/81 atoms QM region, which includes all catalytic relevant residues, treated at the DLPNO-CCSD(T)/CBS//B3LYP/6-31G(d,p):ff14SB level. The results demonstrate that the catalytic mechanism of Pdx2 occurs in six steps divided into four main stages: (i) activation of Cys87, (ii) deamination of glutamine with formation of the glutamyl-thioester intermediate, (iii) hydrolysis of the formed intermediate, and (iv) enzymatic turnover. The rate-limiting step of the complete catalytic mechanism is the hydrolysis of the glutamyl-thioester intermediate (18.2 kcal.mol-1), which closely agrees with the available kinetic data (19.1–19.5 kcal mol-1). The catalytic mechanism of Pdx2 differs from other known amidases in three main points: i) it requires the activation of the nucleophile Cys87 to a thiolate; ii) the hydrolysis occurs in a single step without formation of a second tetrahedral intermediate, and iii) Glu198 does not have a direct role in the catalytic process.

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Correlated NAAG metabolism imbalance with ‘attention switching/tolerance of change’: a biomarker in the actual triad of impairment in autism.

Background: The sensory impairment is a core diagnostic feature of autism spectrum disorder. However, the underlying mechanisms of symptoms across spectrum remain unknown. Deficits in eye contact are a hallmark of autism diagnostic [1], and figure most prominently determined by in clinical instruments knower [2]. The original triad of autism impairments in the late 1970s [3] described the behavioral manifestation (impaired communication, impaired social skills, and a restricted and repetitive way to existing), while the actual triad of impairment in autism is visual as opposed to linguistic processing, impaired abstraction, and lack of theory of mind, and it is central to all diagnoses that together makes up the autism spectrum disorders (ASD) [4]. In this sense, deficits of in "attention switching/tolerance to change" are one of autism impairments that is linked to the limbic system, according to early neuropathology studies [5]. More recently, ASD has been associated with metabolic and functional abnormalities of the posterior cingulated cortex (PCC), specifically, abnormal functional responses and reductions in functional connectivity [6, 7].

Aim: To study of neuropeptide NAAG metabolism in the cingulated cortices correlated with the AQ domain ‘attention switching /tolerance of change’ associated with the actual triad of impairment in ASD.

Methods: To examine the NAAG metabolism imbalance correlates of attentional impairment symptoms that are associated with autism spectrum disorder, we analyzed spectroscopy MRI data obtained from 65 people with either autism spectrum disorder (n = 21 autism spectrum disorder, mean age = 21.0) and 44 neurotypical controls (mean age = 23.3, range: 18–35 years) using a cases-control study design. Autism quotients (AQ) scores were assessed. Statistic one-way ANOVA and Pearson correlation coefficient was applied.

Results: The results shown there is a significant positive correlation between NAA/Cr ratio and ‘attention switching /tolerance of change’ in the node PCC (r = 0.5396; p = 0.0116), and opposite direction to negative (This means that when one variable increases, the other variable decreases) correlation in TD (see Figure 1). Despite, although positive correlation is moderate (0.40 < r < 0.60) in magnitude, its direction show there is significant, i.e., the changes in the variable influence the changes in the other variable in ASD. Besides, there is a higher significant negative correlation with NAAG/Cr (r = - 0.7924, p = 0.0109), and higher significant positive correlation with NAA/NAAG (r = 0.7775, p = 0.0137) in ASD, compared to TD. In contrast in ACC, a moderate positive correlation with NAAG/Cr (r = 0.4395, p = 0.2759) highlight in ASD. According to, other authors that reported that attention is closely related to the reward value of stimuli, activating the ACC to mediate attention [8], which supports our results.

Conclusion: The neuropeptide N-Acetyl aspartyl glutamate (NAAG) is non correlated to the 'Socio-communicative' skills ASD impairment [9], however was correlated to 'Attention switching / tolerance of change' in ASD suggesting the neuropeptide imbalance as biomarker of diagnostic to the real triad of autism.


  1. Jones, W., Carr, K., & Klin, A. (2008). Absence of preferential looking to the eyes of approaching adults predicts level of social disability in 2-year-old toddlers with autism spectrum disorder. Archives of general psychiatry, 65(8), 946-954.
  2. Lord, C., Risi, S., Lambrecht, L., Cook, E. H., Leventhal, B. L., DiLavore, P. C., ... & Rutter, M. (2000). The Autism Diagnostic Observation Schedule—Generic: A standard measure of social and communication deficits associated with the spectrum of autism. Journal of autism and developmental disorders, 30(3), 205-223.
  3. Wing, Lorna. "The diagnosis of autism." Diagnosis and treatment of autism. Springer, Boston, MA, 1989. 5-22.
  4. Cashin, Andrew, and Philip Barker. "The triad of impairment in autism revisited." Journal of Child and Adolescent Psychiatric Nursing 22.4 (2009): 189-193.
  5. Pugliese, L., Catani, M., Ameis, S., Dell'Acqua, F., de Schotten, M. T., Murphy, C., ... & Murphy, D. G. (2009). The anatomy of extended limbic pathways in Asperger syndrome: a preliminary diffusion tensor imaging tractography study. Neuroimage, 47(2), 427-434.
  6. Rudie, J.D.; Dapretto, M. (2013). Convergent Evidence of Brain Overconnectivity in Children with Autism? Cell Rep. 5, 565–566.
  7. Jiménez-Espinoza, C., Francisco Marcano, and J. Gonzalez-Mora. "Heterogeneity neurochemistry in cingulate cortex in adults with autism spectrum disorders: A proton MR spectroscopy study." Med. Health Sci. J 18 (2017): 2-13.
  8. Dawson, Geraldine, et al. "Early social attention impairments in autism: social orienting, joint attention, and attention to distress." Developmental psychology 40.2 (2004): 271.
  9. Jiménez- Espinoza, C.D. NAA-NAAG metabolism imbalance associated neuronal damage and socio-communicative impairment correlation in ASD., in Proceedings of the MOL2NET'20, Conference on Molecular, Biomedical & Computational Sciences and Engineering, 6th ed., 30 January 2020–30 January 2021, MDPI: Basel, Switzerland, doi:10.3390/mol2net-06-08816

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Clinical and preclinical development of novel and emerging CAR-T cell therapies for the treatment of solid tumors

Adoptive cell therapy with genetically modified T lymphocytes that express chimeric antigen receptors is one of the most promising advanced therapies for cancer treatment. However, CAR-T cells efficacy in the solid tumor landscape is still very unsatisfactory. The development of a next generation personalized CAR-T treatment and the identification of therapeutic targets to increase the efficacy, survival, persistence, and safety in solid tumors remains as a clinical necessity and a critical frontier in cancer immunotherapy. Here, we summarize the basic, translational and clinical results of CAR-T cell immunotherapy for solid neoplasms, from its preclinical to its clinical development.

  • Open access
  • 67 Reads
Proteomic analysis of murine tumor associated myeloid populations for myeloid cell reprogramming in cancer


Tumor microenvironment (TME) remodeling is one of the major research subjects in oncology. Several strategies can be implemented to modulate the tumor microenvironment, particularly in reprogramming myeloid cells to stimulate their anti-cancer activities. Indeed, myeloid cells constitute the major component of TME. Hence, it is important to identify the molecular signatures associated to cancer-promoting myeloid cells. Here, we defined the phenotype and proteome of tumor associated myeloid cells. Moreover, we identified the relationships between myeloid-derived suppressor cells (MDSCs) and tumor associated macrophages (TAM). The proteomic atlas of tumor-associated cells revealed important routes to reprogram cancer-associated myeloid cells.


We used an ex vivo differentiation system for MDSCs and TAM by from C57BL/6J mouse bone marrow cells in cancer-polarized conditioning medium (1). Three global experiments of quantitative mass spectrometry (shotgun proteomics) were performed. Construction of functional interactomes maps from up- or down-regulated proteins was conducted with the Ingenuity Pathway Analysis (IPA) Tool from Quiagen. Targeted proteins were evaluated using western blot. We evaluated the effect at differentiation, maturation and immunosuppressive level in MDSCs and TAMs of several compounds. Markers were evaluated by cytometry and western blot.


We confirmed morphological and phenotypic differences in ex vivo differentiated myeloid populations. High-throughput proteomics uncovered protein expression patterns characteristic of populations modelling tumor-infiltrating subsets, as a result of cancer-derived factors.

Therefore, we evaluated several compounds for reprogramming tumor-associated cells. A resemblance to activated myeloid cells and a greater rise of macrophages and DC were observed. In addition, changes in cytokine secretion were detected. Moreover, the immunosuppressive functions of MDSCs decreased which led to enhanced CD4 cells proliferation and increased CD4 ability to release more IFN-gamma and IL2.


In the present study, we identified differences in proteomic signatures between MDSCs and TAMs related to lineage, and cancer-driven polarization. Moreover, these result permit us develop strategies to reprogram myeloid cells cancer associated.

  • Open access
  • 59 Reads
Seroprevalence of Q Fever and Neosporosis: Evaluation of the cause of abortions in dairy cows

Seroprevalence of Q Fever and Neosporosis: Evaluation of the cause of abortions in dairy cows

Monica Salome Guerrero
Facultad de Ingeniería y Ciencias Aplicadas, Ingeniería en Biotecnología, Universidad de las Américas

In ruminants, abortion is considered one of the major causes of economic losses in livestock worldwide (Reichel et al., 2013). Approximately 30% of abortions are caused by pathogenic bacteria (Kirkbride, 1992) such as Coxiella burnetii (Q fever), Brucella abortus (Brucellosis), Bovine Herpes Virus type 1 (BoHV-1), Neospora caninum (Neosporosis) (Kirkbride, 1992), Leptospira spp. (Leptospirosis) (Murray, 1990), Toxoplasma gondii (Toxoplasmosis) (Bártová et al., 2009) and Trypanosoma vivax (Trypanosomiasis) (Silva et al., 1998), among others; and the cost of this reproductive disorder ranges between $ 90 and $ 1900, depending on the stage of gestation in which it occurs (Peter, 2000). Q fever and bovine neosporosis are diseases that have received attention and, currently, they are part of the list of the World Organization for Animal Health because they can have a high impact on the health of livestock and public health and that they can negatively affect conservation of wildlife. (OIE, 2018).

In this study, the prevalence of C. burnetii and N. caninum in dairy cows was determined, from two farms in Pichincha, which have suffered abortions (40 cows) and a control group (42 cows) by means of a commercial ELISA (IDvet, France ). Blood samples (4 mL) were collected by caudal venipuncture in sterile vacutainers. In Pintag Parish, samples were obtained from 38 cows and in Nanegalito from 44 cows. Serology tests were performed for all 82 samples using the commercial ELISA specifications. Of the 40 samples of bovines that have aborted, a prevalence of C. burnetii of 13% was obtained in the two farms and of N. caninum of 60%. On the other hand, the control group had a prevalence of C. burnetii of 3% and of N. caninum of 11%. In addition, the cases of coinfection of all the individuals in the study with both etiological agents studied were evaluated, obtaining a prevalence of 4.87%.

There is a strong association between dairy cow abortions and their seropositivity for Q fever and neosporosis. Therefore, it is suspected that these causative agents may cause a significant part of abortions in cattle in the country.

En rumiantes, el aborto se considera una de las mayores causas de pérdidas económicas en la ganadería a nivel mundial (Reichel et al., 2013). Aproximadamente, el 30% de los abortos son causados ​​por bacterias patógenas (Kirkbride, 1992) como Coxiella burnetii (Fiebre Q) , Brucella abortus (Brucelosis), Herpes Virus Bovino tipo 1 (BoHV-1), Neospora caninum (Neosporosis) (Kirkbride, 1992), Leptospira spp. (Leptospirosis) (Murray, 1990), Toxoplasma gondii (Toxoplasmosis) (Bártová et al., 2009) y Trypanosoma vivax (Tripanosomiasis) (Silva et al., 1998), entre otros; y el costo que este desorden reproductivo oscila entre $ 90 y $ 1900, en dependencia de la fase de gestación en la que se produce (Peter, 2000). La fiebre Q y la neosporosis bovina son enfermedades que han tomado atención y, actualmente, forman parte del listado de La Organización Mundial de Sanidad Animal debido a que pueden tener un alto impacto en la sanidad del ganado y la salud pública y que pueden afectar negativamente la conservación de la fauna silvestre. (OIE, 2018).

En este estudio, se determinó la prevalencia de C. burnetii y N. caninum en vacas lecheras, de dos haciendas de Pichincha, que han sufrido abortos (40 vacas) y un grupo control (42 vacas) mediante un ELISA comercial (IDvet, Francia). Se recogieron muestras de sangre (4 mL) por punción venosa caudal en vacutainers estériles. En la Parroquia Pintag, se obtuvieron muestras de 38 vacas y en Nanegalito de 44 vacas. Se realizaron pruebas de serología para las 82 muestras mediante las especificaciones del ELISA comercial. De las 40 muestras de bovinos que han abortado se obtuvo una prevalencia de C. burnetii de 13% en las dos fincas y de N. caninum del 60%. Por otro lado, del grupo control se obtuvo una prevalencia de C. burnetii de 3% y de N. caninum del 11%. Además, se evaluaron los casos de coinfección del total de los individuos del estudio con ambos agentes etiológicos estudiados obteniéndose una prevalencia del 4, 87%.

Existe una fuerte asociación entre los abortos de vacas lecheras y su seropositividad para fiebre Q y neosporosis. Por lo tanto, se sospecha que estos agentes causales pueden causar una parte importante de los abortos en bovinos del país.


Bártová E, Sedlák K, Literák I. Toxoplasma gondii and Neospora caninum antibodies in sheep in the Czech Republic. Vet Parasitol 2009; 161(1-2): 131-132.
Kirkbride CA. Etiologic agents detected in a 10-year study of bovine abortions and stillbirths. J Vet Diagn Invest 1992; 4(2): 175-180.
Murray RD. A field investigation of causes of abortion in dairy cattle. Vet Rec 1990; 127(22): 543-547.
OIE. Old Classification of Diseases Notifiable to the OIE – List B [Internet]. 2018. Available from:
Peter AT. Abortions in dairy cows: new insights and economic impact. Adv Dairy Technol. 2000; 12:233.
Reichel M, Alejandra Ayanegui-Alcérreca M, Gondim L, Ellis J. What is the global economic impact of Neospora caninum in cattle – the billion-dollar question. Int J Parasitol. 2013;43(2):133–42.
Silva, RAMS., Eguez, A., Morales, G., Eulert, E., Montenegro, A., Ybañez, R., et al. Bovine Trypanosomiasis in Bolivian and Brazilian Lowlands. Mem Inst Oswaldo Cruz 1998; 93(1): 29-32. PMid:9698839.