High-gamma and beta bursts in the Left Supramarginal Gyrus can accurately differentiate verbal memory states and performance.

The left supramarginal gyrus (LSMG) may mediate attention to memory, and gauge memory state and performance. We performed a secondary analysis of 142 verbal delayed free recall experiments, in patients with medically-refractory epilepsy with electrode contacts implanted in the LSMG. In 14 of 142 experiments (in 14 of 113 patients), the cross-validated convolutional neural networks (CNNs) that used 1-dimensional(1-D) pairs of convolved high-gamma and beta tensors, derived from the LSMG recordings, could label recalled words with an area under the receiver operating curve (AUROC) of greater than 60% [range: 60-90%]. These 14 patients were distinguished by: 1) higher amplitudes of high-gamma bursts; 2) distinct electrode placement within the LSMG; and 3) superior performance compared with a CNN that used a 1-D tensor of the broadband recordings in the LSMG. In a pilot study of 7 of these patients, we also cross-validated CNNs using paired 1-D convolved high-gamma and beta tensors, from the LSMG, to: a) distinguish word encoding epochs from free recall epochs [AUC 0.6-1]; and distinguish better performance from poor performance during delayed free recall [AUC 0.5-0.86]. These experiments show that bursts of high-gamma and beta generated in the LSMG are biomarkers of verbal memory state and performance.

Non-enzymatic biosensor based on F,S-doped carbon dots/copper nanoarchitecture applied in the simultaneous electrochemical determination of NADH, dopamine, and uric acid in plasma.

This work presents the synthesis and characterization of an innovative F,S-doped carbon dots/CuONPs hybrid nanostructure obtained by a direct mixture between F,S-doped carbon dots obtained electrochemically and copper nitrate alcoholic solution. The hybrid nanostructures synthesized were characterized by absorption spectroscopy in the Ultraviolet region (UV-vis), high-resolution transmission electron microscopy (HRTEM), X-ray photoelectron spectroscopy (XPS), and different electrochemical techniques. The fluoride and sulfur-doped carbon dots/CuONPs nanostructures were used to prepare a non-enzymatic biosensor on a printed carbon electrode, exhibiting excellent electrocatalytic activity for the simultaneous determination of NADH, dopamine, and uric acid in the presence of ascorbic acid with a detection limit of 20, 80, and 400 nmol L-1, respectively. The non-enzymatic biosensors were also used to determine NADH, dopamine, and uric acid in plasma, and they did not suffer significant interference from each other.

LeFort III Versus Monobloc Frontofacial Advancement: A Comparative Analysis of Soft Tissue Changes.

INTRODUCTION: The LeFort III and monobloc are commonly used midface advancement procedures for patients with syndromic craniosynostosis with well characterized postoperative skeletal changes. However, the differential effects of these procedures on facial soft tissues are less understood. The purpose of this study was to critically analyze and compare the effects of these 2 procedures on the overlying soft tissues of the face. METHODS: Frontal and lateral preoperative and postoperative photographs of patients undergoing monobloc or LeFort III were retrospectively analyzed using ImageJ to measure soft tissue landmarks. Measurements included height of facial thirds, nasal length and width, intercanthal distance, and palpebral fissure height and width. Facial convexity was quantified by calculating the angle between sellion (radix), subnasale, and pogonion on lateral photographs. RESULTS: Twenty-five patients with an average age of 6.7 years (range 4.8-14.5) undergoing monobloc (n=12) and LeFort III (n=13) were identified retrospectively and analyzed preoperatively and 6.4±3.6 months postoperatively. Patients undergoing LeFort III had a greater average postoperative increase in facial convexity angle acuity (28.2°) than patients undergoing monobloc (17.8°, P =0.021). Patients in both groups experience postoperative increases in nasal width ( P <0.001) and decreases in palpebral fissure height ( P <0.001). CONCLUSIONS: Both subcranial LeFort III advancements and monobloc frontofacial advancements resulted in significant changes in the soft tissues. Patients undergoing LeFort III procedures achieved greater acuity of the facial convexity angle, likely because the nasion is not advanced with the LeFort III segment.

The Use of Resorbable Fixation for Posterior Cranial Vault Distraction Osteogenesis.

SUMMARY: Posterior vault distraction osteogenesis (PVDO) traditionally relies on the use of cranial distractors affixed with titanium screws to the posterior cranial vault transport segment to allow for expansion of intracranial volume. We describe a novel technique using the Synthes RAPIDSORB IPS resorbable fixation system for stable fixation of the distraction hardware for PVDO. In a retrospective review of our experience with the IPS system, there was no instance of hardware or fixation failure. This off-label use of the IPS system results in a significant reduction in operative time for hardware removal while allowing for a more limited dissection, which can help reduce devascularization of the bony regenerate, bony relapse, and other complications.

Transcriptomics-Guided In Silico Drug Repurposing: Identifying New Candidates with Dual-Stage Antiplasmodial Activity.

In tropical and subtropical areas, malaria stands as a profound public health challenge, causing an estimated 247 million cases worldwide annually. Given the absence of a viable vaccine, the timely and effective treatment of malaria remains a critical priority. However, the growing resistance of parasites to currently utilized drugs underscores the critical need for the identification of new antimalarial therapies. Here, we aimed to identify potential new drug candidates against Plasmodium falciparum, the main causative agent of malaria, by analyzing the transcriptomes of different life stages of the parasite and identifying highly expressed genes. We searched for genes that were expressed in all stages of the parasite's life cycle, including the asexual blood stage, gametocyte stage, liver stage, and sexual stages in the insect vector, using transcriptomics data from publicly available databases. From this analysis, we found 674 overlapping genes, including 409 essential ones. By searching through drug target databases, we discovered 70 potential drug targets and 75 associated bioactive compounds. We sought to expand this analysis to similar compounds to known drugs. So, we found a list of 1557 similar compounds, which we predicted as actives and inactives using previously developed machine learning models against five life stages of Plasmodium spp. From this analysis, two compounds were selected, and the reactions were experimentally evaluated. The compounds HSP-990 and silvestrol aglycone showed potent inhibitory activity at nanomolar concentrations against the P. falciparum 3D7 strain asexual blood stage. Moreover, silvestrol aglycone exhibited low cytotoxicity in mammalian cells, transmission-blocking potential, and inhibitory activity comparable to those of established antimalarials. These findings warrant further investigation of silvestrol aglycone as a potential dual-acting antimalarial and transmission-blocking candidate for malaria control.

Asociación entre SARS-COV-2 y enfermedades crónicas en personal de salud. Un programa de medicina preventiva / Association between SARS-COV-2 and chronic diseases in health personnel. A preventive medicine program

RESUMEN Objetivo La infección por SARS-CoV-2 ha sido relacionada con hipertensión, obesidad y diabetes para riesgo de hospitalización y muerte. Con respecto a las enfermedades pulmonares obstructivas, la literatura es diversa; hay variación en la frecuencia de estas y por ende en su relación con la COVID-19. La evidencia disponible únicamente detalla a los pacientes hospitalizados, y es escasa la referida a trabajadores de la salud, por lo que el analizar las principales comorbilidades en este grupo resulta de ayuda para la implementación de programas preventivos. El objetivo de este estudio fue describir la prevalencia y la asociación de diversas comorbilidades con la infección por SARS-CoV-2 en trabajadores de la salud. Métodos Estudio transversal analítico, en trabajadores del principal centro de referencia nacional para enfermedades respiratorias de México, que acudieron a atención para descarte de infección por SARS-CoV-2 mediante un programa preventivo; para el tamaño de muestra se usó fórmula para cálculo de proporciones. Se analizaron medidas de resumen y asociación. Resultados La prevalencia de COVID-19 fue de 22,9 %. Las comorbilidades más frecuentes en cuanto a prevalencia fueron: sobrepeso (29,0 %), obesidad (13,2 %), tabaquismo (8,6 %), hipertensión (5,5 %), rinitis alérgica (3,9 %) y asma (2,8 %). El sobrepeso, la obesidad y la vacunación contra SARS-CoV-2 tuvieron razones de momios para prevalencia de 1,78, 1,72 y 0,43, respectivamente. Las personas vacunadas y con comorbilidades tienen menor duración de la enfermedad (p=0,001). Conclusiones La obesidad y el sobrepeso muestran asociación con SARS-CoV-2, la vacunación es un factor protector, sobre todo en aquellos pacientes con comorbilidades.

ABSTRACT Objective The SARS-CoV-2 infection has been linked to hypertension, obesity and diabetes as risks of hospitalization and death. Regarding obstructive pulmonary diseases, the scientific literature is diverse; finding variation in the frequency of these and therefore their relationship with COVID-19. The available evidence only details hospitalized patients, with insufficient information referring to health workers, so analyzing the main comorbidities in this group is helpful for the implementation and improvement of preventive programs. The objective of this study was to describe the prevalence and association of comorbidities with SARS-CoV-2 infection in health care workers. Methods Analytical cross-sectional study, in workers of the main national reference center for respiratory diseases in Mexico, who came to care to rule out SARS-CoV-2 infection through a preventive program; calculation of proportions was performed for the sample size. Summary and association measures were calculated. Results The prevalence of COVID-19 was 22.9 %. The most frequent comorbidities were: overweight obesity, smoking, hypertension, allergic rhinitis and asthma, with prevalences of 29.0 %, 13.2 %, 8.6 %, 5.5 %, 3.9%, 2.8 % respectively. Overweight, obesity and vaccination against SARS-CoV-2 had Prevalence Ratios of 1.78, 1.72 and 0.43 respectively. Conclusions Obesity and overweight show association with SARS-CoV-2; vaccination is a protective factor, especially in people with comorbidities.

Novel Transmission-Blocking Antimalarials Identified by High-Throughput Screening of Plasmodium berghei Ookluc.

Safe and effective malaria transmission-blocking chemotherapeutics would allow a community-level approach to malaria control and eradication efforts by targeting the mosquito sexual stage of the parasite life cycle. However, only a single drug, primaquine, is currently approved for use in reducing transmission, and drug toxicity limits its widespread implementation. To address this limitation in antimalarial chemotherapeutics, we used a recently developed transgenic Plasmodium berghei line, Ookluc, to perform a series of high-throughput in vitro screens for compounds that inhibit parasite fertilization, the initial step of parasite development within the mosquito. Screens of antimalarial compounds, approved drug collections, and drug-like molecule libraries identified 185 compounds that inhibit parasite maturation to the zygote form. Seven compounds were further characterized to block gametocyte activation or to be cytotoxic to formed zygotes. These were further validated in mosquito membrane-feeding assays using Plasmodium falciparum and P. vivax. This work demonstrates that high-throughput screens using the Ookluc line can identify compounds that are active against the two most relevant human Plasmodium species and provides a list of compounds that can be explored for the development of new antimalarials to block transmission.

Wolff-Parkinson-White Apresentado como QRS Alternante e Outros Diagnósticos Diferenciais em uma Grande Coorte de Triagem de ECG Pré-Participação / Wolff-Parkinson-White Presenting as QRS Alternans and Other Differential Diagnoses in a Large Pre-Participation ECG Screening Cohort

Resumo Fundamento A síndrome de Wolff-Parkinson-White (WPW) é uma condição pró-arrítmica que pode exigir restrição de atividades extenuantes e é caracterizada por sinais de ECG, incluindo ondas delta. Observamos casos de padrões intermitentes de WPW apresentando-se como QRS alternante ('WPW alternante') em uma grande coorte de triagem de ECG pré-participação de homens jovens que se candidataram ao recrutamento militar. Objetivos Nosso objetivo foi determinar o padrão de WPW alternante, as características do caso e a prevalência de outros diagnósticos diferenciais relevantes apresentando-se como alternância de QRS em um ambiente de pré-participação. Métodos Cento e vinte e cinco mil cento e cinquenta e oito recrutas militares do sexo masculino prospectivos foram revisados de janeiro de 2016 a dezembro de 2019. Uma revisão de prontuários médicos eletrônicos identificou casos de WPW alternante e padrões ou síndrome de WPW. A revisão de prontuários médicos eletrônicos identificou casos de diagnósticos diferenciais relevantes que podem causar alternância de QRS. Resultados Quatro indivíduos (2,2%) apresentaram WPW alternante em 184 indivíduos com diagnóstico final de padrão ou síndrome de WPW. Dois desses indivíduos manifestaram sintomas ou achados eletrocardiográficos compatíveis com taquicardia supraventricular. A prevalência geral de WPW alternante foi de 0,003%, e a prevalência de WPW foi de 0,147%. As WPW alternantes representaram 8,7% dos indivíduos com QRS alternantes, e QRS alternantes tiveram prevalência de 0,037% em toda a população. Conclusões A WPW alternante é uma variante da WPW intermitente, que compreendeu 2,2% dos casos de WPW em nossa coorte de triagem pré-participação. Não indica necessariamente um baixo risco de taquicardia supraventricular. Deve ser reconhecido na triagem de ECG e distinguido de outras patologias que também apresentam QRS alternantes.

Abstract Background Wolff-Parkinson-White (WPW) syndrome is a proarrhythmic condition that may require restriction from strenuous activities and is characterized by ECG signs, including delta waves. We observed cases of intermittent WPW patterns presenting as QRS alternans ('WPW alternans') in a large pre-participation ECG screening cohort of young men reporting for military conscription. Objectives We aimed to determine the WPW alternans pattern, case characteristics, and the prevalence of other relevant differential diagnoses presenting as QRS alternans in a pre-participation setting. Methods One hundred twenty-five thousand one hundred fifty-eight prospective male military recruits were reviewed from January 2016 to December 2019. A review of electronic medical records identified cases of WPW alternans and WPW patterns or syndrome. Reviewing electronic medical records identified cases of relevant differential diagnoses that might cause QRS alternans. Results Four individuals (2.2%) had WPW alternans out of 184 individuals with a final diagnosis of WPW pattern or syndrome. Two of these individuals manifested symptoms or ECG findings consistent with supraventricular tachycardia. The overall prevalence of WPW alternans was 0.003%, and the prevalence of WPW was 0.147%. WPW alternans represented 8.7% of individuals presenting with QRS alternans, and QRS alternans had a prevalence of 0.037% in the entire population. Conclusions WPW alternans is a variant of intermittent WPW, which comprised 2.2% of WPW cases in our pre-participation screening cohort. It does not necessarily indicate a low risk for supraventricular tachycardia. It must be recognized at ECG screening and distinguished from other pathologies that also present with QRS alternans.

Wolff-Parkinson-White Presenting as QRS Alternans and Other Differential Diagnoses in a Large Pre-Participation ECG Screening Cohort. / Wolff-Parkinson-White Apresentado como QRS Alternante e Outros Diagnósticos Diferenciais em uma Grande Coorte de Triagem de ECG Pré-Participação.

BACKGROUND: Wolff-Parkinson-White (WPW) syndrome is a proarrhythmic condition that may require restriction from strenuous activities and is characterized by ECG signs, including delta waves. We observed cases of intermittent WPW patterns presenting as QRS alternans ('WPW alternans') in a large pre-participation ECG screening cohort of young men reporting for military conscription. OBJECTIVES: We aimed to determine the WPW alternans pattern, case characteristics, and the prevalence of other relevant differential diagnoses presenting as QRS alternans in a pre-participation setting. METHODS: One hundred twenty-five thousand one hundred fifty-eight prospective male military recruits were reviewed from January 2016 to December 2019. A review of electronic medical records identified cases of WPW alternans and WPW patterns or syndrome. Reviewing electronic medical records identified cases of relevant differential diagnoses that might cause QRS alternans. RESULTS: Four individuals (2.2%) had WPW alternans out of 184 individuals with a final diagnosis of WPW pattern or syndrome. Two of these individuals manifested symptoms or ECG findings consistent with supraventricular tachycardia. The overall prevalence of WPW alternans was 0.003%, and the prevalence of WPW was 0.147%. WPW alternans represented 8.7% of individuals presenting with QRS alternans, and QRS alternans had a prevalence of 0.037% in the entire population. CONCLUSIONS: WPW alternans is a variant of intermittent WPW, which comprised 2.2% of WPW cases in our pre-participation screening cohort. It does not necessarily indicate a low risk for supraventricular tachycardia. It must be recognized at ECG screening and distinguished from other pathologies that also present with QRS alternans.

FUNDAMENTO: A síndrome de Wolff-Parkinson-White (WPW) é uma condição pró-arrítmica que pode exigir restrição de atividades extenuantes e é caracterizada por sinais de ECG, incluindo ondas delta. Observamos casos de padrões intermitentes de WPW apresentando-se como QRS alternante ('WPW alternante') em uma grande coorte de triagem de ECG pré-participação de homens jovens que se candidataram ao recrutamento militar. OBJETIVOS: Nosso objetivo foi determinar o padrão de WPW alternante, as características do caso e a prevalência de outros diagnósticos diferenciais relevantes apresentando-se como alternância de QRS em um ambiente de pré-participação. MÉTODOS: Cento e vinte e cinco mil cento e cinquenta e oito recrutas militares do sexo masculino prospectivos foram revisados de janeiro de 2016 a dezembro de 2019. Uma revisão de prontuários médicos eletrônicos identificou casos de WPW alternante e padrões ou síndrome de WPW. A revisão de prontuários médicos eletrônicos identificou casos de diagnósticos diferenciais relevantes que podem causar alternância de QRS. RESULTADOS: Quatro indivíduos (2,2%) apresentaram WPW alternante em 184 indivíduos com diagnóstico final de padrão ou síndrome de WPW. Dois desses indivíduos manifestaram sintomas ou achados eletrocardiográficos compatíveis com taquicardia supraventricular. A prevalência geral de WPW alternante foi de 0,003%, e a prevalência de WPW foi de 0,147%. As WPW alternantes representaram 8,7% dos indivíduos com QRS alternantes, e QRS alternantes tiveram prevalência de 0,037% em toda a população. CONCLUSÕES: A WPW alternante é uma variante da WPW intermitente, que compreendeu 2,2% dos casos de WPW em nossa coorte de triagem pré-participação. Não indica necessariamente um baixo risco de taquicardia supraventricular. Deve ser reconhecido na triagem de ECG e distinguido de outras patologias que também apresentam QRS alternantes.

The Impact of Senior Author Profile on Publication Level of Evidence in Plastic and Reconstructive Surgery.

Plastic and Reconstructive Surgery (PRS) incorporated the level of evidence (LOE) pyramid in 2011 to highlight evidence-based medicine in plastic surgery. This study aimed to assess the relationship between the profile of senior authors publishing in PRS and the LOE of publications. Methods: All accepted publications by American senior authors to PRS between January 2018 and March 2020 were classified by LOE. Demographic, educational, and career data on all senior authors were collected using publicly available online resources. Results: A total of 1030 articles were screened' of which 266 (25.8%) were eligible for LOE classification with the following distribution: I, 0.8%; II, 14.3%; III, 45.1%; IV, 33.1%; and V, 7.1%. Senior author demographic factors, including gender and race/ethnicity, did not significantly impact LOE (P > 0.05 for all). An advanced degree was associated with more publications per year, and only a PhD (P = 0.022) and board certification (P = 0.012) were associated with a higher LOE of publications (P = 0.022). Physicians working in an academic setting were significantly more likely to publish level III evidence than their private/community-based counterparts (P = 0.006). Breast papers constituted the highest proportion of level III evidence (41.4%; P < 0.001). Conclusions: Most publications in PRS contain level III-IV evidence. Senior author gender, race, and ethnicity did not impact LOE of publications. Plastic surgery board certification, possession of a PhD, and academic practice setting were associated with higher LOE of publications.

Síndrome de burnout en cirujanos generales en tiempos de la pandemia COVID-19 / Burnout syndrome in general surgeons in time of the COVID-19 pandemic

Objetivo: Evaluar el síndrome de burnout (SB) en cirujanos generales. Material y Método: Se realizó un estudio de corte transversal en nuestro centro hospitalario, en agosto de 2021. La muestra estuvo formada por 56 profesionales de la salud que incluyeron a residentes y especialistas en cirugia general quienes prestaron servicio en el contexto de la COVID-19. Resultados: La prevalencia del burnout fue del 71%, la edad media fue de 34 años y los residentes fueron los más afectados (62,5%). La distribución por sexo fue de 82,5% en masculinos y 17,5% en el sexo femenino. Del total de evaluados, 23 son casados y 17 solteros, predominando los cirujanos con hijos (60%). Discusión: Entre los pocos estudios publicados sobre el SB en trabajadores de la salud en tiempos de COVID-19 se ubican como posibles factores predisponentes: a las privaciones de sueño, el riesgo biológico ocupacional intrínseco, la cuarentena obligada a la que tienen que someterse los trabajadores de la salud fuera de casa y los dilemas éticos en la toma de decisiones de atención a pacientes. Sin embargo, un estudio ha mostrado que los estresores vinculados al SB más importantes son la falta de equipo de protección personal, el miedo al contagio de COVID-19 y el miedo de contagiar a los familiares. Conclusión: Existe una alta prevalencia del SB en cirujanos generales en el contexto de la pandemia COVID-19. Los más afectados fueron residentes jóvenes de sexo masculino, casados, con hijos y con bajos ingresos económicos.

Objective: To evaluate the burnout syndrome (BS) in general surgeons. Material and Method: A cross-sectional study was carried out in our hospital in August 2021. The sample consisted of 56 health professionals that included residents and specialists in general surgery who provided service in the context of COVID-19 Results: The prevalence of burnout was 71%, the mean age was 34 years and the residents were the most affected (62.5%). Sex was 82.5% in males and 17.5% in females. Of the total evaluated, 23 are married and 17 are single, with a predominance of surgeons with children (60%). Discussion: Among the few studies published on BS in health workers in times of COVID-19, the following are located as possible predisposing factors: sleep deprivation, intrinsic occupational biological risk, the forced quarantine that patients have to undergo. out-of-home health workers and ethical dilemmas in patient care decision-making. However, a study has shown that the most important stressors linked to BS are the lack of personal protective equipment, the fear of contagion of COVID-19 and the fear of infecting family members. Conclusion: There is a high prevalence of BS in general surgeons in the context of the COVID-19 pandemic. The most affected were young male residents, married, with children and with low income.

Degree of Sagittal Suture Fusion, Cephalic Index, and Head Shape in Nonsyndromic Sagittal Craniosynostosis.

BACKGROUND: Sagittal craniosynostosis may present with complete or partial fusion of the sagittal suture, but relationships between degree of sagittal suture fusion and head shape are currently poorly described. The aim of this study was to characterize sagittal suture fusion patterns and determine associations with head shape in a cohort of patients with nonsyndromic sagittal craniosynostosis. METHODS: Patients with nonsyndromic sagittal craniosynostosis at a tertiary care center with available computed tomography imaging were included in this study. The anterior and posterior distances of sagittal suture patency were measured along 3-dimensional parietal bones. Degree of sagittal suture fusion was compared to head shape characteristics, including cephalic index (CI), frontal bossing, and occipital bulleting. RESULTS: Ninety patients (69 male) were included in this retrospective study. The sagittal suture was on average 85.6±20.1% fused, and 45 (50.0%) patients demonstrated complete fusion of the sagittal suture. CI was associated with increased degree of fusion for the anterior one-half (ρ=0.26, P =0.033) and anterior one-third (ρ=0.30, P =0.012) of the sagittal suture. Complete fusion of the anterior one-third of the sagittal suture predicted higher CI (ß=13.86, SE=6.99, z =-0.25, P =0.047). Total degree of sagittal suture fusion was not predictive of CI or head shape in any analysis. CONCLUSIONS: Decreased fusion of the anterior one-third of the sagittal suture, but not total suture, may paradoxically predict increased severity of scaphocephaly as quantified by CI in nonsyndromic sagittal craniosynostosis.

Cadaveric Bone Allografting for Severe Mandibular Hypoplasia With Alleviation of Upper Airway Obstruction in Goldenhar Syndrome.

ABSTRACT: Severe congenital mandibular hypoplasia may cause significant upper airway obstruction, often necessitating immediate tracheostomy. Recent surgical advances have demonstrated early intervention with mandibular distraction osteogenesis over tracheostomy may yield desirable aesthetic and functional outcomes. Here we present a case of bilateral mandibular hypoplasia, severe on the right and mild on the left, secondary to Goldenhar syndrome yielding significant tongue-based upper airway obstruction that was surgically corrected with mandibular bone allograft reconstruction of the right condyle, ramus, and posterior half of the mandibular body. Postoperative polysomnography revealed significantly improved obstructive apnea and computed tomography demonstrated adequate placement of the bone allograft to overcorrect the affected hemi-mandible. To the authors' knowledge, this is the first report of immediate mandibular allografting alleviating tongue-based upper airway obstruction secondary to mandibular hypoplasia in an infant. Mandibular bone allografting may be a favorable alternative to immediate tracheostomy with delayed surgical intervention, though long-term follow up is needed to assess graft durability and maintenance of airway patency.

Artificial Intelligence Applied to the Rapid Identification of New Antimalarial Candidates with Dual-Stage Activity.

Increasing reports of multidrug-resistant malaria parasites urge the discovery of new effective drugs with different chemical scaffolds. Protein kinases play a key role in many cellular processes such as signal transduction and cell division, making them interesting targets in many diseases. Protein kinase 7 (PK7) is an orphan kinase from the Plasmodium genus, essential for the sporogonic cycle of these parasites. Here, we applied a robust and integrative artificial intelligence-assisted virtual-screening (VS) approach using shape-based and machine learning models to identify new potential PK7 inhibitors with in vitro antiplasmodial activity. Eight virtual hits were experimentally evaluated, and compound LabMol-167 inhibited ookinete conversion of Plasmodium berghei and blood stages of Plasmodium falciparum at nanomolar concentrations with low cytotoxicity in mammalian cells. As PK7 does not have an essential role in the Plasmodium blood stage and our virtual screening strategy aimed for both PK7 and blood-stage inhibition, we conducted an in silico target fishing approach and propose that this compound might also inhibit P. falciparum PK5, acting as a possible dual-target inhibitor. Finally, docking studies of LabMol-167 with P. falciparum PK7 and PK5 proteins highlighted key interactions for further hit-to lead optimization.

São Paulo School of Advanced Sciences on Vaccines: an overview.

Two years ago, we held an exciting event entitled the São Paulo School of Advanced Sciences on Vaccines (SPSASV). Sixty-eight Ph.D. students, postdoctoral fellows and independent researchers from 37 different countries met at the Mendes Plaza Hotel located in the city of Santos, SP - Brazil to discuss the challenges and the new frontiers of vaccinology. The SPSASV provided a critical and comprehensive view of vaccine research from basics to the current state-of-the-art techniques performed worldwide. For 10 days, we discussed all the aspects of vaccine development in 36 lectures, 53 oral presentations and 2 poster sessions. At the end of the course, participants were further encouraged to present a model of a grant proposal related to vaccine development against individual pathogens. Among the targeted pathogens were viruses (Chikungunya, HIV, RSV, and Influenza), bacteria (Mycobacterium tuberculosis and Streptococcus pyogenes), parasites (Plasmodium falciparum or Plasmodium vivax), and the worm Strongyloides stercoralis. This report highlights some of the knowledge shared at the SPSASV.

São Paulo School of Advanced Sciences on Vaccines: an overview

Two years ago, we held an exciting event entitled the São Paulo School of Advanced Sciences on Vaccines (SPSASV). Sixty-eight Ph.D. students, postdoctoral fellows and independent researchers from 37 different countries met at the Mendes Plaza Hotel located in the city of Santos, SP - Brazil to discuss the challenges and the new frontiers of vaccinology. The SPSASV provided a critical and comprehensive view of vaccine research from basics to the current state-of-the-art techniques performed worldwide. For 10 days, we discussed all the aspects of vaccine development in 36 lectures, 53 oral presentations and 2 poster sessions. At the end of the course, participants were further encouraged to present a model of a grant proposal related to vaccine development against individual pathogens. Among the targeted pathogens were viruses (Chikungunya, HIV, RSV, and Influenza), bacteria (Mycobacterium tuberculosis and Streptococcus pyogenes), parasites (Plasmodium falciparum or Plasmodium vivax), and the worm Strongyloides stercoralis. This report highlights some of the knowledge shared at the SPSASV.(AU)

São Paulo School of Advanced Sciences on Vaccines: an overview

Two years ago, we held an exciting event entitled the São Paulo School of Advanced Sciences on Vaccines (SPSASV). Sixty-eight Ph.D. students, postdoctoral fellows and independent researchers from 37 different countries met at the Mendes Plaza Hotel located in the city of Santos, SP - Brazil to discuss the challenges and the new frontiers of vaccinology. The SPSASV provided a critical and comprehensive view of vaccine research from basics to the current state-of-the-art techniques performed worldwide. For 10 days, we discussed all the aspects of vaccine development in 36 lectures, 53 oral presentations and 2 poster sessions. At the end of the course, participants were further encouraged to present a model of a grant proposal related to vaccine development against individual pathogens. Among the targeted pathogens were viruses (Chikungunya, HIV, RSV, and Influenza), bacteria (Mycobacterium tuberculosis and Streptococcus pyogenes), parasites (Plasmodium falciparum or Plasmodium vivax), and the worm Strongyloides stercoralis. This report highlights some of the knowledge shared at the SPSASV.(AU)

Integrative Multi-Kinase Approach for the Identification of Potent Antiplasmodial Hits.

Malaria is a tropical infectious disease that affects over 219 million people worldwide. Due to the constant emergence of parasitic resistance to the current antimalarial drugs, the discovery of new antimalarial drugs is a global health priority. Multi-target drug discovery is a promising and innovative strategy for drug discovery and it is currently regarded as one of the best strategies to face drug resistance. Aiming to identify new multi-target antimalarial drug candidates, we developed an integrative computational approach to select multi-kinase inhibitors for Plasmodium falciparum calcium-dependent protein kinases 1 and 4 (CDPK1 and CDPK4) and protein kinase 6 (PK6). For this purpose, we developed and validated shape-based and machine learning models to prioritize compounds for experimental evaluation. Then, we applied the best models for virtual screening of a large commercial database of drug-like molecules. Ten computational hits were experimentally evaluated against asexual blood stages of both sensitive and multi-drug resistant P. falciparum strains. Among them, LabMol-171, LabMol-172, and LabMol-181 showed potent antiplasmodial activity at nanomolar concentrations (EC50 ≤ 700 nM) and selectivity indices >15 folds. In addition, LabMol-171 and LabMol-181 showed good in vitro inhibition of P. berghei ookinete formation and therefore represent promising transmission-blocking scaffolds. Finally, docking studies with protein kinases CDPK1, CDPK4, and PK6 showed structural insights for further hit-to-lead optimization studies.