Achievement and challenges of the Cuban Science, Technology, and Innovation System: A perspective on computational science. Gulín-Gonzalez J. Int J Quantum Chem. 2021 Nov 3. DOI: https://doi.org/10.1002/qua.26837

An appropriate arranging of science, technology, and innovation systems (STIS) becomes essential for emerging countries. A good management of the system allows a more efficient use of the natural and human resources and a better answer to global challenges. Data about the Cuban Science, Technology, and Innovation System (CSTIS) and its characteristics are rare in the literature. This Perspective introduces a general landscape about the growth of the CSTIS focused on the development of computational sciences and its relation to the biotechnological and pharma technologies. General features, main results, and challenges of the CSTIS system are presented here. On the other hand, growth of computational sciences is crucial because they allow to save material and human resources, energy and time, and their progress become critical as a support of the applied research, mostly in the field of the biotechnology and pharma industry. In this paper, the most relevant Cuban groups that perform research in computational chemistry, computational physics and bioinformatics are reported. According to my opinion, the training of new professionals in transdisciplinary fields (like bioinformatics), new technological infrastructure available and the accumulated experience of the computational research groups is a good platform to think about a promising future of these sciences and their contribution to the Cuban economy and society. Cuba’s experiences in the management of the STIS may be very useful for emerging countries, especially those with low financial resources.

Acoustic Identification of Sentence Accent in Speakers with Dysarthria: Cross-Population Validation and Severity Related Patterns. Mendoza Ramos V, Lowit A, Ven den Steen L, Kairuz Hernandez-Diaz HA, Hernadez-Diaz Huici ME, De Bodt M, et al, Bran Sci. 2021 Oct;11(10):1344. Epub 2021 Oct 13 DOI: 10.3390/brainsci11101344

Dysprosody is a hallmark of dysarthria, which can affect the intelligibility and naturalness of speech. This includes sentence accent, which helps to draw listeners’ attention to important information in the message. Although some studies have investigated this feature, we currently lack properly validated automated procedures that can distinguish between subtle performance differences observed across speakers with dysarthria. This study aims for cross-population validation of a set of acoustic features that have previously been shown to correlate with sentence accent. In addition, the impact of dysarthria severity levels on sentence accent production is investigated. Two groups of adults were analysed (Dutch and English speakers). Fifty-eight participants with dysarthria and 30 healthy control participants (HCP) produced sentences with varying accent positions. All speech samples were evaluated perceptually and analysed acoustically with an algorithm that extracts ten meaningful prosodic features and allows a classification between accented and unaccented syllables based on a linear combination of these parameters. The data were statistically analysed using discriminant analysis. Within the Dutch and English dysarthric population, the algorithm correctly identified 82.8 and 91.9% of the accented target syllables, respectively, indicating that the capacity to discriminate between accented and unaccented syllables in a sentence is consistent with perceptual impressions. Moreover, different strategies for accent production across dysarthria severity levels could be demonstrated, which is an important step toward a better understanding of the nature of the deficit and the automatic classification of dysarthria severity using prosodic features.

AMaLa: Analysis of Directed Evolution Experiments via Annealed Mutational Approximated Landscape. Sesta L, Uguzzoni G, Fernández-de-Cossío-Díaz J, Pagnani A, Kolchanov N. Int J Mol Sci. 2021 Oct;22(20):10908. Epub 2021 Oct 9. DOI: 10.3390/ijms222010908

We present Annealed Mutational approximated Landscape (AMaLa), a new method to infer fitness landscapes from Directed Evolution experiments sequencing data. Such experiments typically start from a single wild-type sequence, which undergoes Darwinian in vitro evolution via multiple rounds of mutation and selection for a target phenotype. In the last years, Directed Evolution is emerging as a powerful instrument to probe fitness landscapes under controlled experimental conditions and as a relevant testing ground to develop accurate statistical models and inference algorithms (thanks to high-throughput screening and sequencing). Fitness landscape modeling either uses the enrichment et arounds or assuming the last sequenced round as being sampled from an equilibrium distribution. AMaLa aims at effectively leveraging the information encoded in the whole time evolution. To do so, while assuming statistical sampling independence between sequenced rounds, the possible trajectories in sequence space are gauged with a time-dependent statistical weight consisting of two contributions: (i) an energy term accounting for the selection process and (ii) a generalized Jukes–Cantor model for the purely mutational step. This simple scheme enables accurately describing the Directed Evolution dynamics and inferring a fitness landscape that correctly reproduces the measures of the phenotype under selection (e.g., antibiotic drug resistance), notably outperforming widely used inference strategies. In addition, we assess the reliability of AMaLa by showing how the inferred statistical model could be used to predict relevant structural properties of the wild-type sequence.

Antiplatelet therapy and outcome in COVID-19: the Health Outcome Predictive Evaluation Registry. Santoro F, Nuñez-Gil IJ, Vitale E, Vianna-Llamas MC, Reche-Martínez B, Romero-Pareja R, et al. Heart. 2021 Oct;108(2):130–6.
DOI: 10.1136/heartjnl-2021-319552

Background Standard therapy for COVID-19 is continuously evolving. Autopsy studies showed high prevalence of platelet-fibrin-rich microthrombi in several organs. The aim of the study was therefore to evaluate the safety and efficacy of antiplatelet therapy (APT) in hospitalised patients with COVID-19 and its impact on survival. Methods 7824 consecutive patients with COVID-19 were enrolled in a multicentre international prospective registry (Health Outcome Predictive Evaluation-COVID-19 Registry). Clinical data and in-hospital complications were recorded. Data on APT, including aspirin and other antiplatelet drugs, were obtained for each patient. Results During hospitalisation, 730 (9%) patients received single APT (93%, n=680) or dual APT (7%, n=50). Patients treated with APT were older (74±12 years vs 63±17 years, p<0.01), more frequently male (68% vs 57%, p<0.01) and had higher prevalence of diabetes (39% vs 16%, p<0.01). Patients treated with APT showed no differences in terms of in-hospital mortality (18% vs 19%, p=0.64), need for invasive ventilation (8.7% vs 8.5%, p=0.88), embolic events (2.9% vs 2.5% p=0.34) and bleeding (2.1% vs 2.4%, p=0.43), but had shorter duration of mechanical ventilation (8±5 days vs 11±7 days, p=0.01); however, when comparing patients with APT versus no APT and no anticoagulation therapy, APT was associated with lower mortality rates (log-rank p<0.01, relative risk 0.79, 95% CI 0.70 to 0.94). On multivariable analysis, in-hospital APT was associated with lower mortality risk (relative risk 0.39, 95% CI 0.32 to 0.48, p<0.01). Conclusions APT during hospitalisation for COVID-19 could be associated with lower mortality risk and shorter duration of mechanical ventilation, without increased risk of bleeding.

A single dose of SARS-CoV-2 FINLAY-FR-1A vaccine enhances neutralization response in COVID-19 convalescents, with a very good safety profile: An open-label phase 1 clinical trial. Chang-Monteagudo A, Ochoa-Azze R, Climent-Ruiz Y, Macías-Abraham C, Rodríguez-Noda L, Valenzuela-Silva C, et al. Lancet Reg Health Am. 2021 Dec;4:100079. Epub 2021 Sep 15. DOI: 10.1016/j.lana.2021.100079

Background As a first step towards a vaccine protecting COVID-19 convalescents from reinfection, we evaluated FINLAY-FR-1A vaccine in a clinical trial. Methods Thirty COVID-19 convalescents aged 22-57 years were studied: convalescents of mild COVID-19, asymptomatic convalescents, both with PCR-positive at the moment of diagnosis; and individuals with subclinical infection detected by viral-specific IgG. They received a single intramuscular injection of the FINLAY-FR-1A vaccine (50 µg of the recombinant dimeric receptor binding domain). The primary outcomes were safety and reactogenicity, assessed over 28 days after vaccination. The secondary outcome was vaccine immunogenicity. Humoral response at baseline and following vaccination was evaluated by ELISA and live-virus neutralization test. The effector T cellular response was also assessed. Cuban Public Registry of Clinical Trials, WHO-ICTRP: https://rpcec.sld.cu/en/trials/RPCEC00000349-En. Findings No serious adverse events were reported. Minor adverse events were found, the most common, local pain: 3 (10%) and redness: 2 (6·7%). The vaccine elicited a >21 fold increase in IgG anti-RBD antibodies 28 days after vaccination. The median of inhibitory antibody titres (94·0%) was three times greater than that of the COVID-19 convalescent panel. Virus neutralization titres higher than 1:160 were found in 24 (80%) participants. There was also an increase in RBD-specific T cells producing IFN-γ and TNF-α. Interpretation A single dose of the FINLAY-FR-1A vaccine against SARS-CoV-2 was an efficient booster of pre-existing natural immunity, with excellent safety profile.

Associations between education and dementia in the Caribbean and the United States: An international comparison. Li J, Llibre-Guerra JJ, Harrati A, Weiss J, Jiménez-Velázquez IZ, Acosta D, et al. Alzheimers Dement (N Y). 2021 Sep 5;7(1):e12204.
DOI: 10.1002/trc2.12204

Introduction Despite high dementia prevalence in Hispanic populations globally, especially Caribbean Hispanics, no study has comparatively examined the association between education and dementia among Hispanics living in the Caribbean Islands and older adults in the United States. Methods We used data on 6107 respondents aged 65 and older in the baseline wave of the population‐based and harmonized 10/66 survey from Cuba, the Dominican Republic, and Puerto Rico, collected between 2003 and 2008, and 11,032 respondents aged 65 and older from the U.S.‐based Health and Retirement Study data in 2014, a total of 17,139 individuals. We estimated multivariable logistic regression models examining the association between education and dementia, adjusted for age, income, assets, and occupation. The models were estimated separately for the Caribbean population (pooled and by setting) and the U.S. population by race/ethnicity (Hispanic, Black, and White), followed by pooled models across all populations. Results In the Caribbean population, the relative risk of dementia among low versus high educated adults was 1.45 for women (95% confidence interval [CI] 1.17, 1.74) and 1.92 (95% CI 1.35, 2.49) for men, smaller compared to those in the United States, especially among non‐Hispanic Whites (women: 2.78, 95% CI 1.94, 3.61; men: 5.98, 95% CI 4.02, 7.95). Discussion The differential associations between education and dementia across the Caribbean and US settings may be explained by greater disparities in social conditions in the United States compared to the Caribbean, such as access to health care, healthy behaviors, and social stressors, which serve as potentially important mediators.

Bioactive Essential Oils from Cuban Plants: An Inspiration to Drug Development. Monzote L, García J, Gonzalez R, Scotti MT, Setzer WN. Plants (Basel). 2021 Nov 19;10(11):2515. DOI: 10.3390/plants10112515

Aromatic plants and essential oils are important agents as complementary and alternative medicines in many cultures and geographical locations. In this review, a literature search on essential oils from Cuba, their chemical compositions, and their pharmacological properties was carried out. Out of 171 published scientific articles on essential oils of Cuban plants, a total of 31 documents, focused on both chemical composition and pharmacological properties, were considered for this review. In general, an increase in articles published in the last decade was noted, particularly in recognized international journals in English. Myrtaceae and Piperaceae were the most representative families collected in the occidental area of the country. Leaves and aerial parts were predominantly used, while a wide and variable number of components were identified, including terpenes, aliphatic derivatives, sulfur-containing compounds, phenylpropanoids, alkaloids and amine-type compounds. Finally, different biological activities were reported such as antiprotozoal, antibacterial, antifungal, cytotoxic, anthelmintic, larvicidal and insecticidal. In conclusion, we encourage further studies that would promote the use of essential oils from Cuban plants in new pharmaceutical products.

Comparing the COVID-19 Responses in Cuba and the United States. Powell MA, Erwin PC, Mas Bermejo P. Am J Public Health. 2021 Dec 8;111(12):2186–93.
DOI: https://doi.org/10.2105/AJPH.2021.306526

The purpose of this analytic essay is to contrast the COVID-19 responses in Cuba and the United States, and to understand the differences in outcomes between the 2 nations. With fundamental differences in health systems structure and organization, as well as in political philosophy and culture, it is not surprising that there are major differences in outcomes. The more coordinated, comprehensive response to COVID-19 in Cuba has resulted in significantly better outcomes compared with the United States. Through July 15, 2021, the US cumulative case rate is more than 4 times higher than Cuba’s, while the death rate and excess death rate are both approximately 12 times higher in the United States. In addition to the large differences in cumulative case and death rates between United States and Cuba, the COVID-19 pandemic has unmasked serious underlying health inequities in the United States. The vaccine rollout presents its own set of challenges for both countries, and future studies can examine the comparative successes to identify effective strategies for distribution and administration. (Am J Public Health. 2021;111(12):2186-2193. https://doi.org/10.2105/AJPH.2021.306526).

Conservative treatment of a scoliosis patient after two heart surgeries in early childhood – A case report. Weiss HR, Lay M, Best-Gittens T, Moramarco M, Jimeranez M. S Afr J Physiother. 2021 Nov 30;77(2):1588. DOI: 10.4102/sajp.v77i2.1588

Introduction This is a case report of a juvenile female patient with scoliosis following two heart surgeries for congenital heart disease (CHD). Patient presentation, management and outcome Initially, the premenarchial female was 9 years old and had a Tanner stage 2–3 with a single thoracic curve of 65° Cobb. Because of the high risk for progression, immediate brace treatment was proposed as the father declined surgery. The patient received intensive treatment according to the Schroth Best Practice® programme and a Gensingen Brace® designed for large thoracic curves. Over the 18 months following the initial visit, she received two additional braces. As a result, the progression of the main curve was prevented. The patient continues to maintain an improved cosmetic result and is currently at a Risser 2. Conclusion Surgery performed for CHD in rare cases may lead to stiff spinal deformity as a consequence of that surgery. Progression of a severe and stiff curve was prevented during the most vulnerable phase of the pubertal growth spurt with an improved clinical result. Therefore, we assume that the patient may have a normal life in adulthood with minor restrictions only. Supported by pattern-specific high correction exercises and braces, these typical single thoracic curves can be re-compensated to a more balanced appearance, less prone to progression in adulthood. Clinical implications Because of the relative high risks of spinal fusion and the long-term unknowns of such an intervention, high-impact conservative treatment should be implemented first before surgical correction is considered.

COVID-19 contagion concern scale (PRE-COVID-19): Validation in Cuban patients with type 2 diabetes. Caycho-Rodríguez, Vilca LW, Corrales-Reyes IE, Hernández-García F, Pupo Pérez A, Gonzalez-Quintana P, et al. Diabetes Metab Syndr. 2021 Sep-Oct;15(5):102245. Epub 2021 Aug 14.DOI: 10.1016/j.dsx.2021.102245

Aims It is important to have valid and reliable measures to determine the psychological impact of COVID-19 in patients with diabetes; however, few instruments have been developed and validated for this population. Therefore, the aim of this study was to validate the Scale of Worry for Contagion of COVID-19 (PRE-COVID-19) in a sample of patients with diabetes mellitus (DM). Materials and methods A total of 219 patients (66.2% female, mean age 58.5 SD = 18.2) participated, selected through non-probabilistic sampling. The PRE-COVID-19 and the Generalized Anxiety Disorder Scale-2 were applied. Reliability analysis was performed for internal consistency, structural equation modeling and item response theory modeling. Results The results show that a unidimensional 5-item model presents satisfactory goodness-of-fit indices and excellent reliability values. Likewise, convergent validity between the PRE-COVID-19 and a measure of anxiety is evident. All items present adequate discrimination parameters, allowing for discerning between those patients with critical concern about COVID-19 contagion from those with severe concern. Conclusion It is concluded that the PRE-COVID-19 is an instrument with adequate psychometric propt al.erties to measure concern about COVID-19 infection and the emotional impact in patients with DM.

Cuban history of CRF19 recombinant subtype of HIV-1. Zhukova A, Voznica J, Dávila Felipe M, To TH, Pérez L, Martínez Y, et al. PLoS Pathog. 2021 Aug;17(8):e1009786.

CRF19 is a recombinant form of HIV-1 subtypes D, A1 and G, which was first sampled in Cuba in 1999, but was already present there in 1980s. CRF19 was reported almost uniquely in Cuba, where it accounts for ∼25% of new HIV-positive patients and causes rapid progression to AIDS (∼3 years). We analyzed a large data set comprising ∼350 pol and env sequences sampled in Cuba over the last 15 years and ∼350 from Los Alamos database. This data set contained both CRF19 (∼315), and A1, D and G sequences. We performed and combined analyses for the three A1, G and D regions, using fast maximum likelihood approaches, including: (1) phylogeny reconstruction, (2) spatio-temporal analysis of the virus spread, and ancestral character reconstruction for (3) transmission mode and (4) drug resistance mutations (DRMs). We verified these results with a Bayesian approach. This allowed us to acquire new insights on the CRF19 origin and transmission patterns. We showed that CRF19 recombined between 1966 and 1977, most likely in Cuban community stationed in Congo region. We further investigated CRF19 spread on the Cuban province level, and discovered that the epidemic started in 1970s, most probably in Villa Clara, that it was at first carried by heterosexual transmissions, and then quickly spread in the 1980s within the “men having sex with men” (MSM) community, with multiple transmissions back to heterosexuals. The analysis of the transmission patterns of common DRMs found very few resistance transmission clusters. Our results show a very early introduction of CRF19 in Cuba, which could explain its local epidemiological success. Ignited by a major founder event, the epidemic then followed a similar pattern as other subtypes and CRFs in Cuba. The reason for the short time to AIDS remains to be understood and requires specific surveillance, in Cuba and elsewhere.

Current limitations to identify covid-19 using artificial intelligence with chest x-ray imaging (part ii). The shortcut learning problem. López-Cabrera JD, Orozco-Morales R, Portal-Díaz JA, Lovelle-Enríquez O, Pérez-Díaz M. Health Technol (Berl). 2021 Oct 10;1–15. DOI: 10.1007/s12553-021-00609-8

Since the outbreak of the COVID-19 pandemic, computer vision researchers have been working on automatic identification of this disease using radiological images. The results achieved by automatic classification methods far exceed those of human specialists, with sensitivity as high as 100% being reported. However, prestigious radiology societies have stated that the use of this type of imaging alone is not recommended as a diagnostic method. According to some experts the patterns presented in these images are unspecific and subtle, overlapping with other viral pneumonias. This report seeks to evaluate the analysis the robustness and generalizability of different approaches using artificial intelligence, deep learning and computer vision to identify COVID-19 using chest X-rays images. We also seek to alert researchers and reviewers to the issue of “shortcut learning”. Recommendations are presented to identify whether COVID-19 automatic classification models are being affected by shortcut learning. Firstly, papers using explainable artificial intelligence methods are reviewed. The results of applying external validation sets are evaluated to determine the generalizability of these methods. Finally, studies that apply traditional computer vision methods to perform the same task are considered. It is evident that using the whole chest X-Ray image or the bounding box of the lungs, the image regions that contribute most to the classification appear outside of the lung region, something that is not likely possible. In addition, although the investigations that evaluated their models on data sets external to the training set, the effectiveness of these models decreased significantly, it may provide a more realistic representation as how the model will perform in the clinic. The results indicate that, so far, the existing models often involve shortcut learning, which makes their use less appropriate in the clinical setting.

Defining Fluoroquinolone Resistance-Mediating Mutations from Non-Resistance Polymorphisms in Mycoplasma hominis Topoisomerases. Sharrat M, Sands K, Portal EAR, Boostrom I, Mondeja BA, Rodríguez N, et al. Antibiotics (Basel). 2021 Nov 10;10(11):1379. DOI: 10.3390/antibiotics10111379

Often dismissed as a commensal, Mycoplasma hominis is an increasingly prominent target of research due to its role in septic arthritis and organ transplant failure in immunosuppressed patients, particularly lung transplantation. As a mollicute, its highly reductive genome and structure render it refractile to most forms of treatment and growing levels of resistance to the few sources of treatment left, such as fluoroquinolones. We examined antimicrobial susceptibility (AST) to fluoroquinolones on 72 isolates and observed resistance in three (4.1%), with corresponding mutations in the quinolone resistance-determining region (QRDR) of S83L or E87G in gyrA and S81I or E85V in parC. However, there were high levels of polymorphism identified between all isolates outside of the QRDR, indicating caution for a genomics-led approach for resistance screening, particularly as we observed a further two quinolone-susceptible isolates solely containing gyrA mutation S83L. However, both isolates spontaneously developed a second spontaneous E85K parC mutation and resistance following prolonged incubation in 4 mg/L levofloxacin for an extra 24-48 h. Continued AST surveillance and investigation is required to understand how gyrA QRDR mutations predispose M. hominis to rapid spontaneous mutation and fluoroquinolone resistance, absent from other susceptible isolates. The unusually high prevalence of polymorphisms in M. hominis also warrants increased genomics’ surveillance.

Discovery, Optimization, and Clinical Application of Natural Antimicrobial Peptides. Rodríguez AA, Otero-González A, Ghattas M, Ständker L, Gentilucci L. Biomedicines. 2021 Oct;9(10):1381. Epub 2021 Oct 3. DOI: 10.3390/biomedicines9101381

Antimicrobial peptides (AMPs) are widespread in multicellular organisms. These structurally diverse molecules are produced as the first line of defense against pathogens such as bacteria, viruses, fungi, and parasites. Also known as host defense peptides in higher eukaryotic organisms, AMPs display immunomodulatory and anticancer activities. During the last 30 years, technological advances have boosted the research on antimicrobial peptides, which have also attracted great interest as an alternative to tackling the antimicrobial resistance scenario mainly provoked by some bacterial and fungal pathogens. However, the introduction of natural AMPs in clinical trials faces challenges such as proteolytic digestion, short half-lives, and cytotoxicity upon systemic and oral application. Therefore, some strategies have been implemented to improve the properties of AMPs aiming to be used as effective therapeutic agents. In the present review, we summarize the discovery path of AMPs, focusing on preclinical development, recent advances in chemical optimization and peptide delivery systems, and their introduction into the market.

DNA damage in circulating leukocytes measured with the comet assay may predict the risk of death. Bonassi S, Ceppi M, Azqueta A, Milić M, Monica N, et al. Sci Rep. 2021;11:16793. DOI: 10.1038/s41598-021-95976-7

The comet assay or single cell gel electrophoresis, is the most common method used to measure strand breaks and a variety of other DNA lesions in human populations. To estimate the risk of overall mortality, mortality by cause, and cancer incidence associated to DNA damage, a cohort of 2,403 healthy individuals (25,978 person-years) screened in 16 laboratories using the comet assay between 1996 and 2016 was followed-up. Kaplan–Meier analysis indicated a worse overall survival in the medium and high tertile of DNA damage (p < 0.001). The effect of DNA damage on survival was modelled according to Cox proportional hazard regression model. The adjusted hazard ratio (HR) was 1.42 (1.06–1.90) for overall mortality, and 1.94 (1.04–3.59) for diseases of the circulatory system in subjects with the highest tertile of DNA damage. The findings of this study provide epidemiological evidence encouraging the implementation of the comet assay in preventive strategies for non-communicable diseases.

Effect of low-speed drilling without irrigation on osseointegration: an experimental study in dogs. Fujiwara S, Botticelli D, Kaneko N, Urbizo Velez J, Tumedei M, Bengazi F. Oral Maxillofac Surg. 2021 Nov 26. DOI: 10.1007/s10006-021-01023-0

Objective To study the early phases of osseointegration at implants installed in sites prepared with either high rotational speed with irrigation or low rotational speed without irrigation. Material and methods After 3 months from tooth extraction, two implants were installed in one side of the mandible of twelve dogs. The osteotomies were prepared either at 60 rpm without irrigation or at 750 rpm with refrigeration. Biopsies were obtained after 4 and 8 weeks of healing, six animals each period for histological analyses. Results After 4 weeks of healing, new bone percentage in contact with the implant surface (BIC%) was 46.6 ± 7.3% and 43.1 ± 6.8% at the low- and high-speed sites, respectively (p = 0.345). After 8 weeks of healing, the fractions increased to 60.0 ± 11.1% and 60.2 ± 6.2%, respectively (p = 0.753). Conclusions Implants installed in sites prepared using either low-rotational drilling without irrigation or high speed with irrigation presented similar amounts of osseointegration.

Electroencephalographic and morphometric abnormalities in psychopath offenders. Calzada-Reyes A, Alvarez-Amador A, Galan-García Lídice, Valdes-Sosa M. Behav Sci Law. 2021 Nov 20. DOI: 10.1002/bsl.2548

The main goals of the present study were to replicate and extend current knowledge related to paralimbic dysfunctions associated with psychopathy. The research evaluated the quantitative electroencephalography, current density (CD) source and synchronization likelihood analysis during the rest condition and structural magnetic resonance imaging images to compare volumetric and cortical thickness, in inmates recruited from two prisons located in Havana City. The Psychopathy Checklist-Revised (PCL-R) was used as a quantitative measure of psychopathy. This study showed most beta energy and less alpha activity in male psychopath offenders. Low-resolution electromagnetic tomography signified an increase of beta activity in psychopath offender groups within paralimbic regions. The superior temporal gyrus volume was associated with the F1 factor while the fusiform, anterior cingulate and associative occipital areas were primarily associated with the F2 factor of PCL-R scale. Cortical thickness in the left dorsal anterior cingulate cortex and the temporal pole was negatively associated with PCL-R total score.

Electromagnetic Field as a Treatment for Cerebral Ischemic Stroke. Moya Gómez A, Perez Font L, Bronckaers A. Front Mol Biosci. 2021 Sep 7;8:742596.
DOI: 10.3389/fmolb.2021.742596

Cerebral stroke is a leading cause of death and adult-acquired disability worldwide. To this date, treatment options are limited; hence, the search for new therapeutic approaches continues. Electromagnetic fields (EMFs) affect a wide variety of biological processes and accumulating evidence shows their potential as a treatment for ischemic stroke. Based on their characteristics, they can be divided into stationary, pulsed, and sinusoidal EMF. The aim of this review is to provide an extensive literature overview ranging from in vitro to even clinical studies within the field of ischemic stroke of all EMF types. A thorough comparison between EMF types and their effects is provided, as well as an overview of the signal pathways activated in cell types relevant for ischemic stroke such as neurons, microglia, astrocytes, and endothelial cells. We also discuss which steps have to be taken to improve their therapeutic efficacy in the frame of the clinical translation of this promising therapy.

Evaluation of Cell-Penetrating Peptides as Mucosal Immune Enhancers for Nasal Vaccination. Lobaina Y, Urquiza D, Garay H, Perera Y, Yang K. Int J Pept Res Ther. 2021 Oct 13;1–10. DOI: 10.1007/s10989-021-10296-8

Cell-penetrating peptides (CPPs) have been evaluated as enhancers in drug delivery, their addition in medical formulations favors drug absorption allowing obtaining the pharmacological effect with lower doses. In vaccine formulations their inclusion has been also explored with interesting results. Currently mucosal vaccination constitutes a promising alternative with the main advantage of inducing both systemic and mucosal immune responses, which are crucial for control tumors and infections at mucosal tissues. In the present work the nasal immune-enhancing effect of four CPPs was evaluated in Balb/c mice. Animals were intranasally immunized with CPP and the recombinant hepatitis B surface protein (HBsAg) as model antigen. The antibody response in sera and mucosal tissue was measured by ELISA. The IFN-γ secretion response at spleen was also evaluated by ELISPOT and ELISA. Among the CPPs studied one novel peptide stand out by its ability to potentiate the humoral and cellular immune response against the co-administered antigen. Considering that the use of mucosal routes is a promising strategy in vaccination, which are gaining special relevance nowadays in the development of novel candidates against SARS-CoV-2 and other potential emerging respiratory virus, the searching and development of safe mucosal adjuvants constitute a current need.

From Naturally-Sourced Protease Inhibitors to New Treatments for Fungal Infections. Gutiérrez-Góngora D, Geddes-McAlister J, Djordjevic. J Fungi (Basel). 2021 Dec;7(12):1016. Epub 2021 Nov 27. DOI: 10.3390/jof7121016

Proteases are involved in a broad range of physiological processes, including host invasion by fungal pathogens, and enzymatic inhibition is a key molecular mechanism controlling proteolytic activity. Importantly, inhibitors from natural or synthetic sources have demonstrated applications in biochemistry, biotechnology, and biomedicine. However, the need to discover new reservoirs of these inhibitory molecules with improved efficacy and target range has been underscored by recent protease characterization related to infection and antimicrobial resistance. In this regard, naturally-sourced inhibitors show promise for application in diverse biological systems due to high stability at physiological conditions and low cytotoxicity. Moreover, natural sources (e.g., plants, invertebrates, and microbes) provide a large reservoir of undiscovered and/or uncharacterized bioactive molecules involved in host defense against predators and pathogens. In this Review, we highlight discoveries of protease inhibitors from environmental sources, propose new opportunities for assessment of antifungal activity, and discuss novel applications to combat biomedically-relevant fungal diseases with in vivo and clinical purpose.

Glycan Array Evaluation of Synthetic Epitopes between the Capsular Polysaccharides from Streptococcus pneumoniae 19F and 19A. Morelli L, Lay L, Santana-Mederos D, Valdes-Balbin Y, Verez Bencomo V, van Diepen A, et al. ACS Chem Bio. 2021 Sep 17;16(9):1671–9. Epub 2021 Sep 1. DOI: 10.1021/acschembio.1c00347

Vaccination represents the most effective way to prevent invasive pneumococcal diseases. The glycoconjugate vaccines licensed so far are obtained from capsular polysaccharides (CPSs) of the most virulent serotypes. Protection is largely limited to the specific vaccine serotypes, and the continuous need for broader coverage to control the outbreak of emerging serotypes is pushing the development of new vaccine candidates. Indeed, the development of efficacious vaccine formulation is complicated by the high number of bacterial serotypes with different CPSs. In this context, to simplify vaccine composition, we propose the design of new saccharide fragments containing chemical structures shared by different serotypes as cross-reactive and potentially cross-protective common antigens. In particular, we focused on Streptococcus pneumoniae (Sp) 19A and 19F. The CPS repeating units of Sp 19F and 19A are very similar and share a common structure, the disaccharide ManNAc-β-(1→4)-Glc (A-B). Herein, we describe the synthesis of a small library of compounds containing different combinations of the common 19F/19A disaccharide. The six new compounds were tested with a glycan array to evaluate their recognition by antibodies in reference group 19 antisera and factor reference antisera (reacting against 19F or 19A). The disaccharide A-B, phosphorylated at the upstream end, emerged as a hit from the glycan array screening because it is strongly recognized by the group 19 antisera and by the 19F and 19A factor antisera, with similar intensity compared with the CPSs used as controls. Our data give a strong indication that the phosphorylated disaccharide A-B can be considered a common epitope among different Sp 19 serotypes.

HeberNasvac, a Therapeutic Vaccine for Chronic Hepatitis B, Stimulates Local and Systemic Markers of Innate Immunity: Potential Use in SARS-CoV-2 Postexposure Prophylaxis. Fleites YA, Aguiar J, Cinza Z, Bequet M, Marrero E, Vizcaíno M, et al. Euroasian J Hepatogasroenterol. 2021 Jul–Dec;11(2):50–70.
DOI: 10.5005/jp-journals-10018-1344

Introduction More than 180 million people have been infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and more than 4 million coronavirus disease-2019 (COVID-19) patients have died in 1.5 years of the pandemic. A novel therapeutic vaccine (NASVAC) has shown to be safe and to have immunomodulating and antiviral properties against chronic hepatitis B (CHB). Materials and methods A phase I/II, open-label controlled and randomized clinical trial of NASVAC as a postexposure prophylaxis treatment was designed with the primary aim of assessing the local and systemic immunomodulatory effect of NASVAC in a cohort of suspected and SARS-CoV-2 risk-contact patients. A total of 46 patients, of both sexes, 60 years or older, presenting with symptoms of COVID-19 were enrolled in the study. Patients received NASVAC (100 μg per Ag per dose) via intranasal at days 1, 7, and 14 and sublingual, daily for 14 days. Results and discussion The present study detected an increased expression of toll-like receptors (TLR)-related genes in nasopharyngeal tonsils, a relevant property considering these are surrogate markers of SARS protection in the mice model of lethal infection. The HLA-class II increased their expression in peripheral blood mononuclear cell’s (PBMC’s) monocytes and lymphocytes, which is an attractive property taking into account the functional impairment of innate immune cells from the periphery of COVID-19-infected subjects. NASVAC was safe and well tolerated by the patients with acute respiratory infections and evidenced a preliminary reduction in the number of days with symptoms that needs to be confirmed in larger studies. Conclusions: Our data justify the use of NASVAC as preemptive therapy or pre-/postexposure prophylaxis of SARS-CoV-2 and acute respiratory infections in general. The use of NASVAC or their active principles has potential as immunomodulatory prophylactic therapies in other antiviral settings like dengue as well as in malignancies like hepatocellular carcinoma where these markers have shown relation to disease progression.

Identification of two potential aetiological agents of chronic diarrhoea in an immunocompromised patient in Cuba using conventional and molecular diagnostic techniques. Jerez Puebla LE, Núñez Fernández FA, Atencio Millán I, Pérez Ávila J, Fraga Nodarse J, Cruz Rodríguez I, et al. J Microbiol Methods. 2021 Nov 17;192:106376. DOI: 10.1016/j.mimet.2021.106376

The aetiology of diarrhoea in a patient in Cuba with HIV was investigated. Although molecular diagnostics are still not used in many under-resourced settings, here traditional methods were supported by use of PCR. This approach enabled detection of a dual infection (Cystoisospora belli and Enterocytozoon bieneusi), the latter of which was not identified by microscopy with Didier’s trichromic staining.

Inclusivity and diversity: Integrating international perspectives on stem cell challenges and potential. Fears R, Akutsu H, Alentajan-Aleta LT, Caicedo A, Campos de Carvalho AC, Čolić M, et al. Stem Cell Reports. 2021 Aug 10;16(8):1847–52. Epub 2021 Jul 29.
DOI: 10.1016/j.stemcr.2021.07.003

Regenerative medicine has great potential. The pace of scientific advance is exciting and the medical opportunities for regeneration and repair may be transformative. However, concerns continue to grow, relating to problems caused both by unscrupulous private clinics offering unregulated therapies based on little or no evidence and by premature regulatory approval on the basis of insufficient scientific rationale and clinical evidence. An initiative by the InterAcademy Partnership convened experts worldwide to identify opportunities and challenges, with a focus on stem cells. This was designed to be inclusive and consensus outputs reflected the diversity of the global research population. Among issues addressed for supporting research and innovation while protecting patients were ethical assessment; pre-clinical and clinical research; regulatory authorization and medicines access; and engagement with patients, policy makers, and the public. The InterAcademy Partnership (IAP) identified options for action for sharing good practice and building collaboration within the scientific community and with other stakeholders worldwide.

International Neurotrauma Training Based on North-South Collaborations: Results of an Inter-institutional Program in the Era of Global Neurosurgery. Rubiano AM, Griswold DP, Adelson PD, Echeverri RA, Khan AA, Morales S, et al. Front Surg. 2021;8:633774. Epub 2021 Jul 29. DOI: 10.3389/fsurg.2021.633774

Objective Shortage of general neurosurgery and specialized neurotrauma care in low resource settings is a critical setback in the national surgical plans of low and middle-income countries (LMIC). Neurotrauma fellowship programs typically exist in high-income countries (HIC), where surgeons who fulfill the requirements for positions regularly stay to practice. Due to this issue, neurosurgery residents and medical students from LMICs do not have regular access to this kind of specialized training and knowledge-hubs. The objective of this paper is to present the results of a recently established neurotrauma fellowship program for neurosurgeons of LMICs in the framework of global neurosurgery collaborations, including the involvement of specialized parallel education for neurosurgery residents and medical students. Methods The Global Neurotrauma Fellowship (GNTF) program was inaugurated in 2015 by a multi-institutional collaboration between a HIC and an LMIC. The course organizers designed it to be a 12-month program based on adapted neurotrauma international competencies with the academic support of the Barrow Neurological Institute at Phoenix Children’s Hospital and Meditech Foundation in Colombia. Since 2018, additional support from the UK, National Institute of Health Research (NIHR) Global Health Research in Neurotrauma Project from the University of Cambridge enhanced the infrastructure of the program, adding a research component in global neurosurgery and system science. Results Eight fellows from Brazil, Venezuela, Cuba, Pakistan, and Colombia have been trained and certified via the fellowship program. The integration of international competencies and exposure to different systems of care in high-income and low-income environments creates a unique environment for training within a global neurosurgery framework. Additionally, 18 residents (Venezuela, Colombia, Ecuador, Peru, Cuba, Germany, Spain, and the USA), and ten medical students (the United Kingdom, USA, Australia, and Colombia) have also participated in elective rotations of neurotrauma and critical care during the time of the fellowship program, as well as in research projects as part of an established global surgery initiative. Conclusion We have shown that it is possible to establish a neurotrauma fellowship program in an LMIC based on the structure of HIC formal training programs. Adaptation of the international competencies focusing on neurotrauma care in low resource settings and maintaining international mentoring and academic support will allow the participants to return to practice in their home-based countries.

KBE009: A Bestatin-Like Inhibitor of the Trypanosoma cruzi Acidic M17 Aminopeptidase with In Vitro Anti-Trypanosomal Activity. González-Bacerio J, Arocha I, Elisa Aguado M, Méndez Y, Marsiccobetre S, Izquierdo M, et al. Life (Basel). 2021 Oct;11(10):1037. Epub 2021 Oct 1. DOI: 10.3390/life11101037

Chagas disease, caused by the kinetoplastid parasite Trypanosoma cruzi, is a human tropical illness mainly present in Latin America. The therapies available against this disease are far from ideal. Proteases from pathogenic protozoan have been considered as good drug target candidates. T. cruzi acidic M17 leucyl-aminopeptidase (TcLAP) mediates the major parasite’s leucyl-aminopeptidase activity and is expressed in all parasite stages. Here, we report the inhibition of TcLAP (IC₅₀ = 66.0 ± 13.5 µM) by the bestatin-like peptidomimetic KBE009. This molecule also inhibited the proliferation of T. cruzi epimastigotes in vitro (EC₅₀ = 28.1 ± 1.9 µM) and showed selectivity for the parasite over human dermal fibroblasts (selectivity index: 4.9). Further insight into the specific effect of KBE009 on T. cruzi was provided by docking simulation using the crystal structure of TcLAP and a modeled human orthologous, hLAP3. The TcLAP-KBE009 complex is more stable than its hLAP3 counterpart. KBE009 adopted a better geometrical shape to fit into the active site of TcLAP than that of hLAP3. The drug-likeness and lead-likeness in silico parameters of KBE009 are satisfactory. Altogether, our results provide an initial insight into KBE009 as a promising starting point compound for the rational design of drugs through further optimization.

Measurement of total and free prostate specific antigen (PSA) in human serum samples using an ultra-microanalytical system. Cazanave Mora JM, Del Valle García R, Perez López L, Becquer Ariza DC, Zulueta Rodríguez O, Melchor Rodríguez A, et al. J Pharm Biomed Anal. 2021 Nov 11;208:114470. DOI: 10.1016/j.jpba.2021.114470

Prostate specific antigen (PSA) is a serine protease used for the screening of prostate cancer. The total portion of PSA (tPSA) can be found in its free form (fPSA), or bound to other proteins forming a stable complex. A heterogeneous sandwich-type UltraMicro Enzyme-Linked ImmunoSorbent Assay (UMELISA) has been developed for the measurement of tPSA and fPSA in human serum samples. Strips coated with a high affinity monoclonal antibody (MAb) directed against PSA are used as solid phase, to ensure the specificity of the assay. Biotinylated MAbs specific for tPSA and fPSA ensured sensitivity, given the high affinity binding to streptavidin. The assay was completed in 1.5 h, with a measuring range 0.019-20 µg/L (tPSA), and 0.009-20 µg/L (fPSA). The intra- and inter-assay CV were lower than 9%. Recovery percentages were 96-105%. High correlations were found between the values of the UMELISA PSA standards and the International Reference Standards 96/670 (R² = 0.9996) and 96/688 (R² = 0.9989). The assay did not recognize any of the interfering molecules tested. Regression analysis of serum samples showed a good correlation with Roche Elecsys total PSA (n = 631, R² = 0.986, ρc = 0.992), BioMérieux VIDAS TPSA (n = 631, R² = 0.989, ρc = 0.993) and Roche Elecsys free PSA (n = 164, R² = 0.973, ρc = 0.979), all with a relative difference below 15%, and a p < 0.001. A retrospective study of the use of UMELISA PSA in Cuba was carried out. The analytical performance characteristics of UMELISA PSA support its use for the quantification of tPSA and fPSA in human serum samples in a single kit, making it an affordable diagnostic assay available to Cuban Public Health System and developing countries. Between the years 2014-2020, more than 3 million Cuban patients have benefited from the test for free.

Multilocus Genotyping of Pneumocystis jirovecii from Deceased Cuban AIDS Patients Using Formalin-Fixed and Paraffin-Embedded Tissues. Friaza V, de Armas Y, Capó V, Morilla R, Plascencia-Hernández A, Pérez-Gómez HR, et al. J Fungi (Basel). 2021 Dec;7(12):1042. DOI: 10.3390/jof7121042

The results of the genotypic characterization of Pneumocystis jirovecii are described in lung tissue samples from 41 Cubans who died of AIDS with pneumocystosis between 1995 and 2008. Histological sections of the lung preserved as formalin-fixed and paraffin-embedded tissue were examined. PCR amplification and nucleotide sequencing of the two mitochondrial genes (large and small) of the pathogen allowed verification of a predominance of genotype 3 (85T/248C) of the large mitochondrial gene and genotype 3 (160A/196T) of the small mitochondrial gene over a period of 14 years (1995–2008). These results suggest that the 85T/248C//160A/196T genotype circulates with the highest frequency (81.3%) among AIDS patients in Cuba. Multilocus analysis indicates a limited circulation of pathogen genotypes on the island with the existence of a clonal genotype with an epidemic structure. Furthermore, it appears that circulating strains of P. jirovecii have not developed mutations related to sulfonamide resistance. Taken together, the data in this study revealed important elements about pneumocystosis in Cuban patients dying of AIDS and the usefulness of formalin-fixed and paraffin-embedded samples to carry out molecular epidemiology studies of P. jirovecii.

Multi-Tissue Transcriptomic-Informed In Silico Investigation of Drugs for the Treatment of Dengue Fever Disease. Sierra B, Magalhães AC, Soares D, Cavadas B, Perez AB, Alvarez M, et al. Viruses. 2021 Aug;13(8):1540. Epub 2021 Aug 4.
DOI: 10.3390/v13081540

Transcriptomics, proteomics and pathogen-host interactomics data are being explored for the in silico–informed selection of drugs, prior to their functional evaluation. The effectiveness of this kind of strategy has been put to the test in the current COVID-19 pandemic, and it has been paying off, leading to a few drugs being rapidly repurposed as treatment against SARS-CoV-2 infection. Several neglected tropical diseases, for which treatment remains unavailable, would benefit from informed in silico investigations of drugs, as performed in this work for Dengue fever disease. We analyzed transcriptomic data in the key tissues of liver, spleen and blood profiles and verified that despite transcriptomic differences due to tissue specialization, the common mechanisms of action, “Adrenergic receptor antagonist”, “ATPase inhibitor”, “NF-kB pathway inhibitor” and “Serotonin receptor antagonist”, were identified as druggable (e.g., oxprenolol, digoxin, auranofin and palonosetron, respectively) to oppose the effects of severe Dengue infection in these tissues. These are good candidates for future functional evaluation and clinical trials.

Murine monoclonal antibodies against RBD of the SARS-CoV-2 spike protein as useful analytical tools for subunit vaccine development and clinical trials. Blanco OR, Dorta D, Hernandez C, Abreu D, Domínguez AG, Luna Y, et al. J Immunol Methods. 2021 Nov 26;113195. DOI: 10.1016/j.jim.2021.113195

COVID-19 pandemic poses a serious threat to human health; it has completely disrupted global stability, making vaccine development an important goal to achieve. Monoclonal antibodies play an important role in subunit vaccines strategies. In this work, nine murine MAbs against the RBD of the SARS-CoV-2 spike protein were obtained by hybridoma technology. Characterization of purified antibodies demonstrated that five of them have affinities in the order of 10⁸ L/mol. Six of the eight MAbs showed specific recognition of different recombinant RBD-S antigens in solution. Studies of the additivity index of anti-RBD antibodies, by using a novel procedure to determine the additivity cut point, showed recognition of at least five different epitopes. The MAbs CBSSRBD-S.11 and CBSSRBD-S.8 revealed significant neutralizing capacity against SARS-CoV-2 in an ACE2-RBD binding inhibition assay (IC₅₀ = 85.5pM and IC₅₀ = 122.7pM, respectively) and in a virus neutralizing test with intact SARS-CoV-2 (VN₅₀ = 0.552 nM and VN₅₀ = 4.854 nM, respectively) when D614G strain was used to infect Vero cells. Also CBSSRBD-S.11 neutralized the SARS-CoV-2 strains Alpha and Beta: VN₅₀ = 0.707 nM and VN₅₀ = 0.132 nM, respectively. The high affinity CBSSRBD-S.8 and CBSSRBD-S.7 recognized different epitopes, so they are suitable for the development of a sandwich ELISA to quantitate RBD-S recombinant antigens in biomanufacturing processes, as well as in pharmacokinetic studies in clinical and preclinical trials.

Nimotuzumab for COVID-19: case series. Abdo Cuza AA, Pin Ávila J, Machado Martínez R, González JJ, Pérez Aspuro G, Gutiérrez Martínez JA, et al. Immunotherapy. 2021 Nov 22. DOI: 10.2217/imt-2021-0269

Background In COVID-19, EGFR production is upregulated in the alveolar epithelial cells. EGFR overexpression further activates STAT-3 and increases lung pathology. The EGFR pathway is also one of the major nodes in pulmonary fibrosis. Methods Nimotuzumab, a humanized anti-EGFR antibody, was used to treat three patients with severe or moderate COVID-19. The antibody was administered in combination with other drugs included in the national COVID-19 protocol. Results Nimotuzumab was well tolerated. IL-6 decreased from the first antibody infusion. Clinical symptoms significantly improved after nimotuzumab administration, and the CT scans at discharge showed major resolution of the lung lesions and no signs of fibrosis. Conclusion Safe anti-EGFR antibodies like nimotuzumab may modulate COVID-19-associated hyperinflammation and prevent fibrosis.

Prognostic factors at admission on patients with cancer and COVID-19. Analysis of HOPE registry data. Pérez-Segura P, Paz-Cabezas M, Núñez-Gil IJ, Arroyo-Espiglero R, Maroun Eid C, Romero R, et al. Med Clin (English Edition). 2021 Oct 8;157(7):318–24. DOI: https://doi.org/10.1016/j.medcle.2021.02.010

Background Previous works seem to agree in the higher mortality of cancer patients with COVID-19. Identifying potential prognostic factors upon admission could help identify patients with a poor prognosis. Methods We aimed to explore the characteristics and evolution of COVID-19 cancer patients admitted to hospital in a multicenter international registry (HOPE COVID-19). Our primary objective is to define those characteristics that allow us to identify cancer patients with a worse prognosis (mortality within 30 days after the diagnosis of COVID-19). Results 5838 patients have been collected in this registry, of whom 770 had cancer among their antecedents. In hospital mortality reached 258 patients (33.51%). The median was 75 years (65–82). Regarding the distribution by sex, 34.55% of the patients (266/770) were women.The distribution by type of cancer: genitourinary 238/745 (31.95%), digestive 124/745 (16.54%), hematologic 95/745 (12.75%). In multivariate regression analysis, factors that are independently associated with mortality at admission are: renal impairment (OR 3.45, CI 97.5% 1.85–6.58), heart disease (2.32, 1.47–3.66), liver disease (4.69, 1.94–11.62), partial dependence (2.41, 1.34–4.33), total dependence (7.21, 2.60–21.82), fatigue (1.84, 1.16–2.93), arthromialgias (0.45, 0.26–0.78), SatO2 < 92% (4.58, 2.97–7.17), elevated LDH (2.61, 1.51–4.69) and abnormal decreased Blood Pressure (3.57, 1.81–7.15). Analitical parameters are also significant altered. Conclusion In patients with cancer from the HOPE registry, 30-day mortality from any cause is high and is associated with easily identifiable clinical factors upon arrival at the hospital. Identifying these patients can help initiate more intensive treatments from the start and evaluate the prognosis of these patients.

Protective effects of Surfacen® in allergen-induced asthma mice model. Blanco O, Ramírez W, Lugones Y, Díaz E, Morejón A, Rodríguez VS, et al. Int Immunopharmacol. 2021 Nov 23;108391. DOI:https://doi.org/10.1016/j.intimp.2021.108391

Airway obstruction with increased airway resistance in asthma, commonly caused by smooth muscle constriction, mucosal edema and fluid secretion into the airway lumen, may partly be due to a poor function of pulmonary surfactant. Surfacen®, a clinical pulmonary surfactant, has anti-inflammatory action, but its effect on asthma has not been studied. This work aimed to evaluate the effect of Surfacen® in a murine allergen-induced acute asthma model, using house dust mite allergens. In a therapeutic experimental setting, mice were first sensitized by being administered with two doses (sc) of Dermatophagoides siboney allergen in aluminum hydroxide followed by one intranasal administration of the allergen. Then, sensitized mice were administered with aerosol of hypertonic 3% NaCl, Salbutamol 0.15 mg/kg, or Surfacen® 16 mg in a whole-body chamber on days 22, 23, and 24. Further, mice were subjected to aerosol allergen challenge on day 25. Surfacen® showed bronchial dilation and inhibition of Th2 inflammation (lower levels of IL-5 and IL-13 in broncoalveolar lavage) which increased IFN-γ and unchanged IL-10 in BAL. Moreover, Sufacen® administration was associated with a marked inhibition of the serum specific IgE burst upon allergen exposure, as well as, IgG2a antibody increase, suggesting potential anti-allergy effects with inclination towards Th1. These results support also the effectiveness of the aerosol administration method to deliver the drug into lungs. Surfacen® induced a favorable pharmacological effect, with a bronchodilator outcome comparable to Salbutamol, consistent with its action as a lung surfactant, and with an advantageous anti-inflammatory and anti-allergic immunomodulatory effect.

PTML modeling for peptide discovery: in silico design of non-hemolytic peptides with antihypertensive activity. Kleandrova VV, Rojas-Vargas JA, Scotti MT, Speck-Planche A. Mol Divers. 2021 Nov 21. DOI: 10.1007/s11030-021-10350-z

Hypertension is a medical condition that affects millions of people worldwide. Despite the high efficacy of the current antihypertensive drugs, they are associated with serious side effects. Peptides constitute attractive options for chemical therapy against hypertension, and computational models can accelerate the design of antihypertensive peptides. Yet, to the best of our knowledge, all the in silico models predict only the antihypertensive activity of peptides while neglecting their inherent toxic potential to red blood cells. In this work, we report the first sequence-based model that combines perturbation theory and machine learning through multilayer perceptron networks (SB-PTML-MLP) to enable the simultaneous screening of antihypertensive activity and hemotoxicity of peptides. We have interpreted the molecular descriptors present in the model from a physicochemical and structural point of view. By strictly following such interpretations as guidelines, we performed two tasks. First, we selected amino acids with favorable contributions to both the increase of the antihypertensive activity and the diminution of hemotoxicity. Then, we assembled those suitable amino acids, virtually designing peptides that were predicted by the SB-PTML-MLP model as antihypertensive agents exhibiting low hemotoxicity. The potentiality of the SB-PTML-MLP model as a tool for designing potent and safe antihypertensive peptides was confirmed by predictions performed by online computational tools reported in the scientific literature. The methodology presented here can be extended to other pharmacological applications of peptides.

Sustained Antiviral and Liver Protection by a Nasal Therapeutic Vaccine (NASVAC, Containing Both HBsAg and HBcAg) in Patients with Chronic Hepatitis B: 2-Year Follow-Up of Phase III Clinical Trial. Fazle Akbar SM, Al Mahtab M, Cesar Aguilar J, Yoshida O, Pentón E, Guillen Nieto G, et al. Pathogens. 2021 Nov 5;10(11):1440.
DOI: 10.3390/pathogens10111440

A phase III clinical trial in treatment-naïve patients with chronic hepatitis B (CHB) revealed the safety and considerable therapeutic efficacy of a vaccine containing both hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) (NASVAC) at the end of treatment (EOT) and 24 weeks after EOT. Two years after EOT, we checked HBV DNA, alanine aminotransferase (ALT), and hepatitis B e antigen (HBeAg). The data reveal that 33 of 66 NASVAC-recipient CHB patients became negative for HBV DNA in the blood two years after EOT. The ALT levels were within the upper limit of normal (ULN) in 37 patients, although all 66 CHB patients had elevated ALT (above ULN) before the start of therapy. Out of the total twelve HBeAg-positive patients, eight patients became negative for HBeAg. None of the patients developed cirrhosis of the liver within this period. NASVAC is a finite treatment regimen with sustained antiviral and liver-protecting properties. This study is the first to report follow-up data of immune therapy for CHB. NASVAC, an immune therapy of finite duration, is endowed with sustained antiviral and liver protection properties in CHB patients.

TaqI polymorphism of the VDR gene: aspects related to the clinical behavior of COVID-19 in Cuban patients. Morales Peralta E, Zúñiga Rosales Y, Collazo Mesa T, Santos GOnzalez EN, Hernandez Perez Y, Gonzalez Torres MA, et al. Egypt J Med Hum Genet. 2021 Nov 30;22(1):83. DOI: 10.1186/s43042-021-00206-4

Purpose To determine the relationship between the genotypes of the TaqI polymorphism of VDR gene and the clinical forms of COVID-19 in Cuban patients. Methods TaqI polymorphism was determined by the PCR in 104 Cuban patients, who suffered different clinical forms of COVID-19. Results There was a greater possibility of presenting symptomatic forms [OR = 2.081, 95% CI: 0.243–17.842], even severe [OR = 1.200, 95% CI: 0.217–6.638], related to the tt genotype. Conclusion There are signs of association between the risk of developing COVID-19 and the genotypes of the TaqI polymorphism of the VDR gene in the studied Cuban patients.

Targeting CK2 mediated signaling to impair/tackle SARS-CoV-2 infection: a computational biology approach. Miranda J, Bringas R, Fernández-de Cossío J, Perera-Negrin. Mol Med. 2021 Dec 20;27:161. DOI: 10.1186/s10020-021-00424-x

Background Similarities in the hijacking mechanisms used by SARS-CoV-2 and several types of cancer, suggest the repurposing of cancer drugs to treat Covid-19. CK2 kinase antagonists have been proposed for cancer treatment. A recent study in cells infected with SARS-CoV-2 found a significant CK2 kinase activity, and the use of a CK2 inhibitor showed antiviral responses. CIGB-300, originally designed as an anticancer peptide, is an antagonist of CK2 kinase activity that binds to the CK2 phospho-acceptor sites. Recent preliminary results show the antiviral activity of CIGB-300 using a surrogate model of coronavirus. Here we present a computational biology study that provides evidence, at the molecular level, of how CIGB-300 may interfere with the SARS-CoV-2 life cycle within infected human cells. Methods Sequence analyses and data from phosphorylation studies were combined to predict infection-induced molecular mechanisms that can be interfered by CIGB-300. Next, we integrated data from multi-omics studies and data focusing on the antagonistic effect on the CK2 kinase activity of CIGB-300. A combination of network and functional enrichment analyses was used. Results Firstly, from the SARS-CoV studies, we inferred the potential incidence of CIGB-300 in SARS-CoV-2 interference on the immune response. Afterwards, from the analysis of multiple omics data, we proposed the action of CIGB-300 from the early stages of viral infections perturbing the virus hijacking of RNA splicing machinery. We also predicted the interference of CIGB-300 in virus-host interactions that are responsible for the high infectivity and the particular immune response to SARS-CoV-2 infection. Furthermore, we provided evidence of how CIGB-300 may participate in the attenuation of phenotypes related to muscle, bleeding, coagulation and respiratory disorders. Conclusions Our computational analysis proposes putative molecular mechanisms that support the antiviral activity of CIGB-300.

The DNA co-vaccination using Sm antigen and IL-10 as prophylactic experimental therapy ameliorates nephritis in a model of lupus induced by pristane. Martín-Márquez BT, Satoh M, Hernández-Pando R, Martínez-García EK, Heron Petri M, Sandoval-García F, et al. PLoS One. 2021;16(10):0259114. DOI: 10.1371/journal.pone.0259114

Introduction Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies such as anti-Sm. Studies in patients with SLE and murine models of lupus reveal that the most critical anti-Sm autoantibodies are predominantly direct against D1_(83–119), D2, and B´/B epitopes. Objectives The present study aimed to analyze the induction of antigen-specific tolerance after prophylactic immunization with a DNA vaccine encoding the epitopes: D1_83-119, D2, B´/B, and B´/B_COOH in co-vaccination with IFN-γ or IL-10 in a murine model of lupus induced by pristane. Material and methods To obtain endotoxin-free DNA vaccines, direct cloning techniques using pcDNA were performed: D1_83-119, D2, B´/B, B´/B_COOH, IFN-γ, or IL-10. Lupus was induced by 0.5 mL of pristane via intraperitoneal in BALB/c female mice. Immunoprecipitation with K562 cells was metabolically labeled with ³⁵S and ELISA to detect serum antibodies or mice IgG1, IgG2a isotypes. ELISA determined IL-10 and IFN-γ from splenocytes supernatants. Proteinuria was assessed monthly, and lupus nephritis was evaluated by immunofluorescence, and electron microscopy. Results The prophylactic co-vaccination with D2/IL-10 reduced the expression of kidney damage observed by electron microscopy, direct immunofluorescence, and H & E, along with reduced level of anti-nRNP/Sm antibodies (P = 0.048). Conclusion The prophylactic co-vaccination of IL-10 with D2 in pristane-induced lupus ameliorates the renal damage maybe by acting as prophylactic DNA tolerizing therapy.

The Risk Perception COVID-19 Scale (RP-COVID19-S): Initial Validation and Its Relationship with Gender and Age in a Cuban Population Sample. Fernández-Castillo E, Fernández-Fleites Z, Broche-Pérez Y, Otero-Ramos IM, Martín-González R, Lorenzo Ruiz A. Int J Ment Health Addict. 2021 Oct 25;1–21. DOI: 10.1007/s11469-021-00672-2

Background Risk perception about COVID-19 constitutes an important variable contributing to promotion of personal protection practices. The aims of this study were to exploring the factorial structure of the risk perception COVID-19 scale (RP-COVID19-S) in a sample of Cuban adults and to identify its relationship with variables such as gender and age. Methods A cross-sectional web-based survey design was conducted. The sample comprised 394 Cuban participants. Categorical Principal Component Analysis (CATPCA) was used to explore internal factorial structure of the scale. Logistic regression was modeling to identify variables independently associated with RP about COVID-19. Results CATPCA allowed identifying a three-dimensional factorial structure into the scale: knowledge and beliefs, emotional reactions and behavioral dissonance, and motivations for change. The odds of a woman with middle RP compared to low RP was 2.17 times more than for a man. Also, the odds of a woman with high knowledge and beliefs compared to low knowledge and beliefs were 1.96 times more than for a man. The odds of a person in older group, with middle risk perception compared with low level, was 5.0 (global risk perception), 3.33 (knowledge and beliefs), and 3.13 (emotional reactions and behavioral dissonance) times more than for a person in younger group, respectively. Conclusion The Risk Perception to COVD-19 Scale (RP-COVID-19-S) showed satisfactory psychometric properties to evaluated risk perception related to COVID-19 in Cuban population sample. Middle level of global risk perception was found in the sample. High level of risk perception about COVID-19 was found on participants older than 42 years old and in woman.

Update on Dihydropteroate Synthase (DHPS) Mutations in Pneumocystis jirovecii. De la Horra C, Friaza V, Morilla R, Delgado J, Medrano FJ, Miller RF, et al. J Fungi (Basel). 2021 Oct 13;7(10):856. DOI: 10.3390/jof7100856

A Pneumocystis jirovecii is one of the most important microorganisms that cause pneumonia in immunosupressed individuals. The guideline for treatment and prophylaxis of Pneumocystis pneumonia (PcP) is the use of a combination of sulfa drug-containing trimethroprim and sulfamethoxazole. In the absence of a reliable method to culture Pneumocystis, molecular techniques have been developed to detect mutations in the dihydropteroate synthase gene, the target of sulfa drugs, where mutations are related to sulfa resistance in other microorganisms. The presence of dihydropteroate synthase (DHPS) mutations has been described at codon 55 and 57 and found almost around the world. In the current work, we analyzed the most common methods to identify these mutations, their geographical distribution around the world, and their clinical implications. In addition, we describe new emerging DHPS mutations. Other aspects, such as the possibility of transmitting Pneumocystis mutated organisms between susceptible patients is also described, as well as a brief summary of approaches to study these mutations in a heterologous expression system.

WeBrain: A web-based brainformatics platform of computational ecosystem for EEG big data analysis. Dong L, Li J,Zou Q, Zhang Y, Zhao L, Wen X, et al. Neuroimage. 2021 Nov 17;245:118713. DOI: 10.1016/j.neuroimage.2021.118713

The current evolution of ‘cloud neuroscience’ leads to more efforts with the large-scale EEG applications, by using EEG pipelines to handle the rapidly accumulating EEG data. However, there are a few specific cloud platforms that seek to address the cloud computational challenges of EEG big data analysis to benefit the EEG community. In response to the challenges, a WeBrain cloud platform (https://webrain.uestc.edu.cn/) is designed as a web-based brainformatics platform and computational ecosystem to enable large-scale EEG data storage, exploration and analysis using cloud high-performance computing (HPC) facilities. WeBrain connects researchers from different fields to EEG and multimodal tools that have become the norm in the field and the cloud processing power required to handle those large EEG datasets. This platform provides an easy-to-use system for novice users (even no computer programming skills) and provides satisfactory maintainability, sustainability and flexibility for IT administrators and tool developers. A range of resources are also available on https://webrain.uestc.edu.cn/, including documents, manuals, example datasets related to WeBrain, and collected links to open EEG datasets and tools. It is not necessary for users or administrators to install any software or system, and all that is needed is a modern web browser, which reduces the technical expertise required to use or manage WeBrain. The WeBrain platform is sponsored and driven by the China-Canada-Cuba international brain cooperation project (CCC-Axis, http://ccc-axis.org/), and we hope that WeBrain will be a promising cloud brainformatics platform for exploring brain information in large-scale EEG applications in the EEG community.