Effect of a thiohydantoin salt derived from l-Arginine on Leishmania amazonensis and infected cells: Insights from biological effects to molecular docking interactions.

Leishmaniasis is a neglected tropical disease caused by parasites of the genus Leishmania and is responsible for more than 1 million new cases and 70,000 deaths annually worldwide. Treatment has high costs, toxicity, complex and long administration time, several adverse effects, and drug-resistant strains, therefore new therapies are urgently needed. Synthetic compounds have been highlighted in the medicinal chemistry field as a strong option for drug development against different diseases. Organic salts (OS) have multiple biological activities, including activity against protozoa such as Leishmania spp. This study aimed to investigate the in vitro leishmanicidal activity and death mechanisms of a thiohydantoin salt derived from l-arginine (ThS) against Leishmania amazonensis. We observed that ThS treatment inhibited promastigote proliferation, increased ROS production, phosphatidylserine exposure and plasma membrane permeabilization, loss of mitochondrial membrane potential, lipid body accumulation, autophagic vacuole formation, cell cycle alteration, and morphological and ultrastructural changes, showing parasites death. Additionally, ThS presents low cytotoxicity in murine macrophages (J774A.1), human monocytes (THP-1), and sheep erythrocytes. ThS in vitro cell treatment reduced the percentage of infected macrophages and the number of amastigotes per macrophage by increasing ROS production and reducing TNF-α levels. These results highlight the potential of ThS among thiohydantoins, mainly related to the arginine portion, as a leishmanicidal drug for future drug strategies for leishmaniasis treatment. Notably, in silico investigation of key targets from L. amazonensis, revealed that a ThS compound from the l-arginine amino acid strongly interacts with arginase (ARG) and TNF-α converting enzyme (TACE), suggesting its potential as a Leishmania inhibitor.

Understanding the effects of lithium exposure on castor bean (Ricinus communis) plants, a potential bioindicator of lithium-contaminated areas.

As lithium (Li) stands out as a crucial component of batteries, the inappropriate disposal of electronic gadgets might drive Li pollution in environmentally sensitive environments, such as dumps, where castor bean (Ricinus communis) plant communities are usually found. The exposure to high Li concentration is potentially harmful to the environment and humans. Therefore, it is opportune to evaluate the potential of bioindicator species to monitor Li contamination. In this scenario, the present study assessed the effects of Li exposure on the development of castor bean plants exposed to lithium chloride at five Li dosages (0, 5, 10, 20, and 30 mg dm-3). Significant symptoms of phytotoxicity were observed at all doses. Li dosage exhibited increasing impairment effects on plant biometrics, such as stem diameter and the number of leaves, as well as on the SPAD index, nutritional balance, and biomass production. Our findings suggest castor bean as a potential model species for biomonitoring Li-contaminated areas.

Prognostic factors for endoscopic third ventriculostomy success in hydrocephalus with myelomeningocele.

PURPOSE: Myelomeningocele (MMC) is a prevalent neural tube closure defect often associated with hydrocephalus, necessitating surgical intervention in a significant proportion of cases. While ventriculoperitoneal shunting (VPS) has been a standard treatment approach, endoscopic third ventriculostomy (ETV) has emerged as a promising alternative. However, factors influencing the success of ETV in MMC patients remain uncertain. This retrospective observational study aimed to identify clinical and radiological factors correlating with a higher success rate of ETV in MMC patients. METHODS: Medical records of MMC patients who underwent ETV at a tertiary care center between 2015 and 2021 were reviewed. Demographic, clinical, and radiological data were analyzed. ETV success was defined as the absence of further hydrocephalus treatment during follow-up. RESULTS: Of 131 MMC patients, 21 met inclusion criteria and underwent ETV. The overall success rate of ETV was 57.1%, with a six-month success rate of 61.9%. Age ≤ 6 months was significantly associated with lower ETV success (25%) compared to older patients (76.9%) (OR: 0.1; 95% CI 0.005-2.006; p = 0.019). Radiological factors, including posterior fossa dimensions and linear indices, did not exhibit statistically significant associations with ETV success. CONCLUSION: Age emerged as a significant factor affecting ETV success in MMC patients, with younger patients exhibiting lower success rates. Radiological variables did not significantly influence ETV outcomes in this study. Identifying predictors of ETV success in MMC patients is crucial for optimizing treatment strategies and improving patient outcomes.

Zika, chikungunya and co-occurrence in Brazil: space-time clusters and associated environmental-socioeconomic factors.

Chikungunya and Zika have been neglected as emerging diseases. This study aimed to analyze the space-time patterns of their occurrence and co-occurrence and their associated environmental and socioeconomic factors. Univariate (individually) and multivariate (co-occurrence) scans were analyzed for 608,388 and 162,992 cases of chikungunya and Zika, respectively. These occurred more frequently in the summer and autumn. The clusters with the highest risk were initially located in the northeast, dispersed to the central-west and coastal areas of São Paulo and Rio de Janeiro (2018-2021), and then increased in the northeast (2019-2021). Chikungunya and Zika demonstrated decreasing trends of 13% and 40%, respectively, whereas clusters showed an increasing trend of 85% and 57%, respectively. Clusters with a high co-occurrence risk have been identified in some regions of Brazil. High temperatures are associated with areas at a greater risk of these diseases. Chikungunya was associated with low precipitation levels, more urbanized environments, and places with greater social inequalities, whereas Zika was associated with high precipitation levels and low sewage network coverage. In conclusion, to optimize the surveillance and control of chikungunya and Zika, this study's results revealed high-risk areas with increasing trends and priority months and the role of socioeconomic and environmental factors.

Bilateral Synchronous Olecranon Apophyseal Fracture in a Teenager: A Case Report.

Introduction: While elbow fractures are frequently observed in children, isolated apophyseal detachments of the olecranon are rare, accounting for just 1.7% of all elbow fractures in healthy children. These fractures have been found to have a large positive likelihood ratio for osteogenesis imperfecta (OI). Within the population of patients with OI, the incidence is 13.5%, with 6% sustaining bilateral fractures. There are, however, very few reports of synchronous bilateral fractures. Case Report: A 15-year-old boy sustained a bilateral olecranon apophyse fracture, AO/OTA 21u-M/7 (displaced on the right side and minimal displacement on the left) after a low-energy fall. The patient was submitted on the same day to surgical treatment (open reduction and internal fixation with AO tension band wiring technique) on the right elbow and nonoperative treatment with a cast on the left side. Exome sequencing excluded mutations related to OI. Conclusion: Apophyseal avulsion fractures of the olecranon may not be pathognomonic of OI, However, orthopedists should exercise caution and remain alert to the potential occurrence in patients who experience displaced, isolated olecranon fractures due to low-energy mechanisms, particularly if they have a history of previous fractures. The clinical genetic evaluation was recommended because of clinical suspicion of OI and because patient management can be significantly influenced by genetic testing, particularly when a genetic syndrome is identified.

Antiprotozoal Activity of Benzoylthiourea Derivatives against Trypanosoma cruzi: Insights into Mechanism of Action.

For decades, only two nitroheterocyclic drugs have been used as therapeutic agents for Chagas disease. However, these drugs present limited effectiveness during the chronic phase, possess unfavorable pharmacokinetic properties, and induce severe adverse effects, resulting in low treatment adherence. A previous study reported that N-(cyclohexylcarbamothioyl) benzamide (BTU-1), N-(tert-butylcarbamothioyl) benzamide (BTU-2), and (4-bromo-N-(3-nitrophenyl) carbamothioyl benzamide (BTU-3) present selective antiprotozoal activity against all developmental forms of Trypanosoma cruzi Y strain. In this study, we investigated the mechanism of action of these compounds through microscopy and biochemical analyses. Transmission electron microscopy analysis showed nuclear disorganization, changes in the plasma membrane with the appearance of blebs and extracellular arrangements, intense vacuolization, mitochondrial swelling, and formation of myelin-like structures. Biochemical results showed changes in the mitochondrial membrane potential, reactive oxygen species content, lipid peroxidation, and plasma membrane fluidity. In addition, the formation of autophagic vacuoles was observed. These findings indicate that BTU-1, BTU-2, and BTU-3 induced profound morphological, ultrastructural, and biochemical alterations in epimastigote forms, triggering an autophagic-dependent cell death pathway.

The influence of N-alkyl chains in benzoyl-thiourea derivatives on urease inhibition: Soil studies and biophysical and theoretical investigations on the mechanism of interaction.

Ureases are enzymes produced by fungi, plants, and bacteria associated with agricultural and clinical problems. The urea hydrolysis in NH3 and CO2 leads to the loss of N-urea fertilizers in soils and changes the human stomach microenvironment, favoring the colonization of H. pylori. In this sense, it is necessary to evaluate potential enzyme inhibitors to mitigate the effects of their activities and respond to scientific and market demands to produce fertilizers with enhanced efficiency. Thus, biophysical and theoretical studies were carried out to evaluate the influence of the N-alkyl chain in benzoyl-thiourea derivatives on urease enzyme inhibition. A screening based on IC50, binding constants, and theoretical studies demonstrated that BTU1 without the N-alkyl chain (R = H) was more active than other compounds, so the magnitude of the interaction was determined as BTU1 > BTU2 > BTU3 > BTU4 > BTU5, corresponding to progressively increased chain length. Thus, BTU1 was selected for interaction and soil application essays. The binding constants (Kb) for the supramolecular urease-BTU1 complex ranged from 7.95 to 5.71 × 103 M-1 at different temperatures (22, 30, and 38 °C), indicating that the preferential forces responsible for the stabilization of the complex are hydrogen bonds and van der Waals forces (ΔH = -15.84 kJ mol-1 and ΔS = -36.61 J mol-1 K-1). Theoretical and experimental results (thermodynamics, synchronous fluorescence, and competition assay) agree and indicate that BTU1 is a mixed inhibitor. Finally, urease inhibition was evaluated in the four soil samples, where BTU1 was as efficient as NBPT (based on ANOVA two-way and Tukey test with 95% confidence), with an average inhibition of 20% of urease activity. Thus, the biophysics and theoretical studies are strategies for evaluating potential inhibitors and showed that increasing the N-alkyl chain in benzoyl-thiourea derivatives did not favor urease inhibition.

Synergistic antifungal interaction of N-(butylcarbamothioyl) benzamide and amphotericin B against Cryptococcus neoformans.

Introduction: Cryptococcus neoformans is one of the leading causes of invasive fungal infections worldwide. Cryptococcal meningoencephalitis is the main challenge of antifungal therapy due to high morbidity and mortality rates, especially in low- and middle-income countries. This can be partly attributed to the lack of specific diagnosis difficulty accessing treatment, antifungal resistance and antifungal toxicity. Methods: In the present study, the effect of the synthetic thiourea derivative N-(butylcarbamothioyl) benzamide (BTU-01), alone and combined with amphotericin B (AmB), was evaluated in planktonic and sessile (biofilm) cells of C. neoformans. Results: BTU-01 alone exhibited a fungistatic activity with minimal inhibitory concentrations (MICs) ranging from 31.25 to 62.5 µg/mL for planktonic cells; and sessile MICs ranging from 125.0 to 1000.0 µg/mL. BTU-01 caused a concentration-dependent inhibitory activity on cryptococcal urease and did not interfere with plasma membrane fluidity. Molecular docking was performed on Canavalia ensiformis urease, and BTU-01 showed relevant interactions with the enzyme. The combination of BTU-01 and AmB exhibited synergistic fungicidal activity against planktonic and sessile cells of C. neoformans. Microscopic analysis of C. neoformans treated with BTU-01, alone or combined with AmB, revealed a reduction in cell and capsule sizes, changes in the morphology of planktonic cells; a significant decrease in the number of cells within the biofilm; and absence of exopolymeric matrix surrounding the sessile cells. Neither hemolytic activity nor cytotoxicity to mammalian cells was detected for BTU-01, alone or combined with AmB, at concentrations that exhibited antifungal activity. BTU-01 also displayed drug-likeness properties. Conclusion: These results indicate the potential of BTU-01, for the development of new strategies for controlling C. neoformans infections.

Thiohydantoins and hydantoins derived from amino acids as potent urease inhibitors: Inhibitory activity and ligand-target interactions.

We report the investigation of hydantoins and thiohydantoins derived from L and d-amino acids as inhibitors against the Canavalia ensiformis urease (CEU). The biochemical in vitro assay against CEU revealed a promising inhibitory potential for most thiohydantoins with six of them showing %I higher than the reference inhibitor thiourea (56.5%). In addition, thiohydantoin derived from l-valine, 1b, as well as the hydantoin 2d, derived from l-methionine, were identified as the most potent inhibitors with %I = 90.5 and 85.9 respectively. Enzyme kinetic studies demonstrated a mixed and uncompetitive inhibition profile for these compounds with Ki values of 0.42 mM for 1b and 0.99 mM for 2d. These kinetic parameters, obtained from traditional colorimetric assay, were strictly related to the KD values measured spectroscopically by the Saturation Transfer Difference (STD) technique for the urease complex. STD was also used to evince the moieties of the ligands responsible for the binding with the enzyme. Molecular docking studies showed that the thiohydantoin and hydantoin rings can act as a pharmacophoric group due to their binding affinity by hydrogen bonding interactions with critical amino acid residues in the enzyme active and/or allosteric site. These findings agreed with the experimental alpha values, demonstrating that 1b has affinity by free enzyme, and 2d derivative, an uncompetitive inhibitor, has great binding affinity at the allosteric site. The results for the thiohydantoin 1a, derived from d-valine, demonstrated a drastic stereochemical influence on inhibition, kinetics, and binding parameters in comparison to its enantiomer 1b.

Thiohydantoins as anti-leishmanial agents: n vitro biological evaluation and multi-target investigation by molecular docking studies.

Leishmaniasis is a neglected tropical disease caused by protozoa of the genus Leishmania. The first-line treatment of this disease is still based on pentavalent antimonial drugs that have a high toxicity profile, which could induce parasitic resistance. Therefore, there is a critical need to discover more effective and selective novel anti-leishmanial agents. In this context, thiohydantoins are a versatile class of substances due to their simple synthesis and several biological activities. In this work, thiohydantoins 1a-l were evaluated in vitro for antileishmania activity. Among them, four derivatives (1c, 1e, 1h and 1l) showed promising IC50 values around 10 µM against promastigotes forms of Leishmania amazonensis and low cytotoxicity profile for peritoneal macrophages cells. Besides, these compounds induce oxidative stress through an increase in ROS production and the labeling of annexin-V and propidium iodide, indicating that promastigotes were undergoing a late apoptosis-like process. Additionally, molecular consensual docking analysis was carried out against two important targets to L. amazonensis: arginase and trypanothione reductase enzymes. Docking results suggest that thiohydantoin ring could be a pharmacophoric group due to its binding affinity by hydrogens bond interactions with important amino acid residues at the active site of both enzymes. These results demonstrate that compounds 1c, 1e, 1h and 1l may are promising in future advance studies.Communicated by Ramaswamy H. Sarma.

Investigation of the antileishmanial activity and mechanisms of action of acetyl-thiohydantoins.

The currently available treatment options for leishmaniasis are associated with high costs, severe side effects, and high toxicity. In previous studies, thiohydantoins demonstrated some pharmacological activities and were shown to be potential hit compounds with antileishmanial properties. The present study further explored the antileishmanial effect of acetyl-thiohydantoins against Leishmania amazonensis and determined the main processes involved in parasite death. We observed that compared to thiohydantoin nuclei, acetyl-thiohydantoin treatment inhibited the proliferation of promastigotes. This treatment caused alterations in cell cycle progression and parasite size and caused morphological and ultrastructural changes. We then investigated the mechanisms involved in the death of the protozoan; there was an increase in ROS production, phosphatidylserine exposure, and plasma membrane permeabilization and a loss of mitochondrial membrane potential, resulting in an accumulation of lipid bodies and the formation of autophagic vacuoles on these parasites and confirming an apoptosis-like process. In intracellular amastigotes, selected acetyl-thiohydantoins reduced the percentage of infected macrophages and the number of amastigotes/macrophages by increasing ROS production and reducing TNF-α levels. Moreover, thiohydantoins did not induce cytotoxicity in murine macrophages (J774A.1), human monocytes (THP-1), or sheep erythrocytes. In silico and in vitro analyses showed that acetyl-thiohydantoins exerted in vitro antileishmanial effects on L. amazonensis promastigotes in apoptosis-like and amastigote forms by inducing ROS production and reducing TNF-α levels, indicating that they are good candidates for drug discovery studies in leishmaniasis treatment. Additionally, we carried out molecular docking analyses of acetyl-thiohydantoins on two important targets of Leishmania amazonensis: arginase and TNF-alpha converting enzyme. The results suggested that the acetyl groups in the N1-position of the thiohydantoin ring and the ring itself could be pharmacophoric groups due to their affinity for binding amino acid residues at the active site of both enzymes via hydrogen bond interactions. These results demonstrate that thiohydantoins are promising hit compounds that could be used as antileishmanial agents.

Antimicrobial activity of sophorolipids produced by Starmerella bombicola against phytopathogens from cherry tomato.

BACKGROUND: Phytopathogenic microorganisms are the main cause of plant diseases, generating significant economic losses for the agricultural and food supply chain. Cherry tomatoes (Solanum lycopersicum var. cerasiforme) are very perishable plants and highly demanding in the use of pesticides; therefore, alternative solutions such as biosurfactants have aroused as a potent substituent. The main objective of the present study was to investigate the antimicrobial activity of sophorolipids against the phytopathogens Botrytis cinerea, Sclerotium rolfsii, Rhizoctonia solani and Pythium ultimum. RESULTS: The biosurfactant inhibited the mycelial growth in vitro with a minimum concentration of 2 mg mL-1 . The application of sophorolipids at 1, 2 and 4 mg mL-1 in detached leaves of tomato before the inoculation of the fungus B. cinerea was the best treatment, reducing leaf necrosis by up to 76.90%. The use of sophorolipids for washing tomato fruits before the inoculation of B. cinerea was able to inhibit the development of gray mold by up to 96.27%. CONCLUSION: The results for tomato leaves and fruits revealed that the biosurfactant acts more effectively when used preventively. Sophorolipids are stable molecules that show promising action for the potential replacement of pesticides in the field and the post-harvest process against the main tomato phytopathogens. © 2021 Society of Chemical Industry.

Exploring the antileishmanial activity of N1,N2-disubstituted-benzoylguanidines: synthesis and molecular modeling studies.

In this report, we describe the synthesis and evaluation of nine N1,N2-disubstituted-benzoylguanidines against promastigotes and amastigotes forms of Leishmania amazonensis. The derivatives 2g and 2i showed low IC50 values against promastigote form (90.8 ± 0.05 µM and 68.4 ± 0.03 µM, respectively), low cytotoxicity profile (CC50 396 ± 0.02 µM and 857.9 ± 0.06 µM) for peritoneal macrophages cells and SI of 5.5 and 12.5, respectively. Investigations about the mechanism of action of 2g and 2i showed that both compounds cause mitochondrial depolarization, increase in ROS levels, and generation of autophagic vacuoles on free promastigotes forms. These compounds were also capable of reducing the number of infected macrophages with amastigotes forms (59.5% ± 0.08% and 98.1% ± 0.46%) and the number of amastigotes/macrophages (79.80% ± 0.05% and 96.0% ± 0.16%), through increasing induction of microbicide molecule NO. Additionally, ADMET-Tox in silico predictions showed drug-like features and free of toxicological risks. The molecular docking studies with arginase and gp63 showed that relevant intermolecular interactions could explain the experimental results. Therefore, these results reinforce that benzoylguanidines could be a starting scaffold for the search for new antileishmanial drugs.Communicated by Ramaswamy H. Sarma.

Avaliação dos fatores relacionados ao sucesso da terceiro ventriculostomia endoscópica na hidrocefalia associada à mielomeningocele / Evaluation of factors related to the success of endoscopic third ventriculostomy in hydrocephalus associated with myelomeningocele

Introdução: A mielomeningocele (MMC) é o defeito do tubo neural compatível com a vida mais comum, e uma de suas complicações mais frequentes é a ocorrência de hidrocefalia, principalmente em pacientes cuja correção do defeito se deu no período pós-natal. O tratamento padrão para esta população ainda é a inserção de uma derivação ventrículo-peritoneal (DVP), associada a complicações e maior morbimortalidade. Alternativamente à DVP, destaca-se a terceiro ventriculostomia endoscópica (TVE), procedimento sem a necessidade de dispositivo implantável, mas que apresenta uma taxa de sucesso muito variável na literatura médica. Objetivos: Avaliar a taxa de sucesso da TVE no tratamento da hidrocefalia associada à MMC, identificar possíveis fatores clínicos e/ou radiológicos relacionados ao sucesso do procedimento e identificar se o sucesso estimado pelo Endoscopic Third Ventriculostomy Success Score (ETVSS) foi comparável à real taxa de sucesso. Método: Vinte e um pacientes com o diagnóstico de MMC, nascidos entre 2015 e 2021 e submetidos a TVE para o tratamento da hidrocefalia foram incluídos nesse estudo. Pacientes com correção fetal da MMC foram excluídos. Dados clínicos como o perímetro cefálico ao nascimento e no pré-operatório prematuridade, presença de DVP, número de revisões e presença de infecção prévias, idade no momento da TVE, além de fatores radiológicos como o índice de Evans, ângulo clivo-occipital, volume estimado da fossa posterior e volume estimado do compartimento supratentorial foram analisados. Resultados: A taxa de sucesso em seis meses foi de 61,9%, a taxa geral de sucesso foi de 57,1% e o ETVSS médio calculado foi de 46,7%. O único fator com aparente relevância para o sucesso da TVE foi a idade, pacientes com mais de 6 meses completos apresentaram uma taxa de sucesso de 76,9% enquanto os mais novos apresentaram uma taxa de sucesso de 25% (OR: 0,03; IC 95% 0,01-0,35; p = 0,013). Não foi identificado nenhum fator radiológico associado ao sucesso do procedimento. Conclusões: O único fator de relevância estatística com o sucesso da TVE foi a idade, sendo que pacientes com idade inferior a 6 meses completos apresentaram uma probabilidade maior de falha. Já o ETVSS subestimou a taxa de sucesso do procedimento em 6 meses ­ o que demonstra a necessidade de modificações para seu aprimoramento em pacientes mais jovens.

Introduction: Myelomeningocele (MMC) is the most common neural tube defect compatible with life, and one of its most frequent complications is the occurrence of hydrocephalus (HCF), especially in patients whose defect correction took place in the postnatal period. The standard treatment for this population is still the insertion of a ventriculoperitoneal shunt (VPS), but it is associated with complications and higher morbidity and mortality. As an alternative to DVP, endoscopic third ventriculostomy (ETV) stands out, it is a procedure without the need for an implantable device, but its success rate is inconsistent in the medical literature. Objectives: To evaluate the success rate of EVT in the treatment of hydrocephalus associated with MMC and to identify possible clinical and/or radiological features associated with ETV success. Methods: Twenty-one patients with myelomeningocele, born between 2015 and 2021, that underwent EVT for hydrocephalus were included in this study. Patients with fetal MMC correction were excluded. Clinical data such as head circumference at birth and preoperatively, prematurity, presence of previous VPS, number of previous revisions, presence of a previous infection, age at the time of ETV, in addition to radiological factors such as the Evans index, clivo-occipital angle, the estimated volume of the posterior fossa and estimated volume of the supratentorial compartment were analyzed. Results: The six-month success rate was 61.9%, the overall success rate was 57.1%, and the mean calculated ETVSS was 46.7%. The only factor with apparent relevance to the success of ETV was age: the patients older than six full months had a success rate of 76.9%, while the younger ones had a success rate of 25% (OR: 0.03; 95% CI 0.01-0.35; p = 0.013). No radiological features were identified as associated with the procedure's success. Conclusions: The only factor of statistical relevance with the success of TVE was age, with patients younger than six full months of age having a higher probability of failure. The ETVSS, on the other hand, underestimated the procedure's success rate at six months, which shows a need for modifications to improve its results when applied in younger patients.

Selection and drift reduce genetic variation for milk yield in Manech Tête Rousse dairy sheep.

Decreases in genetic variance over generations reduce future genetic gain. We studied the evolution of genetic variance in the dairy sheep breed Manech Tête Rousse, which has been selected for increasingly complex objectives, including, in this order, milk yield, milk contents, scrapie resistance, and somatic cell score. We estimated base population genetic variance and genetic variance by sex and per year of birth from 1981 to 2014. The data consisted of 1,842,295 milk yield records (from 1978 to 2017) and a pedigree including 530,572 females (96% of them with records) and 3,798 artificial insemination males. As a measure of drift, we computed average relationships for each cohort from which we derived expected reduction of variance due to increased relationships. The difference between observed and expected reductions in genetic variances is the reduction in genetic variance due to selection. Average relationships increased steadily but slowly in both sexes. For females, genetic variance reduced with time until a plateau was reached at around 90% of the initial genetic variance. The reduction due to relationships (roughly 3% cumulated in 30 yr) was smaller than that due to selection (roughly 10% across the last years). A smaller loss due to selection was seen in recent years, possibly due to a change in selection objectives. These results agree well with theoretical expectations. The pattern of the evolution of genetic variance in males was similar to that for females but with a stronger reduction because of strong selection of AI males at birth. We conclude that the reductions in genetic variation due to selection and drift agree with expectations, and none of the reductions are very strong in this population because of control of inbreeding and smooth changes in selection objectives over time.

In vitro evaluation of antitrypanosomal activity and molecular docking of benzoylthioureas.

A series of sixteen benzoylthioureas derivatives were initially evaluated in vitro against the epimastigote form of Trypanosoma cruzi. All of the tested compounds inhibited the growth of this form of the parasite, and due to the promising anti-epimastigote activity from three of these compounds, they were also assayed against the trypomastigote and amastigote forms. ADMET-Tox in silico predictions and molecular docking studies with two main enzymatic targets (cruzain and CYP-51) were performed for the three compounds with the highest activity. The docking studies showed that these compounds can interact with the active site of cruzain by hydrogen bonds and can be coordinated with Fe-heme through the carbonyl oxygen atom of the CYP51. These findings can be considered an important starting point for the proposal of the benzoylthioureas as potent, selective, and multi-target antitrypanosomal agents.

Nicolau syndrome due to a traumatic finger injury with a needle : a case report with an exclusive photographic documentation.

INTRODUCTION: Nicolau syndrome, also known as livedo-like dermatitis or embolia cutis medicamentosa, is a rare complication usually after intra-muscular or intra-articular injection of various drugs. It is difficult to find photographic documentation of this syndrome from the initial stages due to its rarity and unpredictable evolution. CASE PRESENTATION: We report the case of a 54-year-old Portuguese woman who developed Nicolau Syndrome after a traumatic finger injury with a sewing needle. She developed an ulcer and cutaneous necrosis. She was treated with surgical debridement, antibiotic, analgesics and sterile dressings. The ulcer healed completely within 18 weeks with scarring. CONCLUSIONS: Although Nicolau syndrome develops very rarely, it is an important cause for morbidity. It is an iatrogenic condition. The Nicolau Syndrome following a traumatic injury with a needle without drugs, as far as we know, has never been reported in the published literature especially with photographic records from the beginning of the process.

Bias and accuracy of dairy sheep evaluations using BLUP and SSGBLUP with metafounders and unknown parent groups.

BACKGROUND: Bias has been reported in genetic or genomic evaluations of several species. Common biases are systematic differences between averages of estimated and true breeding values, and their over- or under-dispersion. In addition, comparing accuracies of pedigree versus genomic predictions is a difficult task. This work proposes to analyse biases and accuracies in the genetic evaluation of milk yield in Manech Tête Rousse dairy sheep, over several years, by testing five models and using the estimators of the linear regression method. We tested models with and without genomic information [best linear unbiased prediction (BLUP) and single-step genomic BLUP (SSGBLUP)] and using three strategies to handle missing pedigree [unknown parent groups (UPG), UPG with QP transformation in the [Formula: see text] matrix (EUPG) and metafounders (MF)]. METHODS: We compared estimated breeding values (EBV) of selected rams at birth with the EBV of the same rams obtained each year from the first daughters with phenotypes up to 2017. We compared within and across models. Finally, we compared EBV at birth of the rams with and without genomic information. RESULTS: Within models, bias and over-dispersion were small (bias: 0.20 to 0.40 genetic standard deviations; slope of the dispersion: 0.95 to 0.99) except for model SSGBLUP-EUPG that presented an important over-dispersion (0.87). The estimates of accuracies confirm that the addition of genomic information increases the accuracy of EBV in young rams. The smallest bias was observed with BLUP-MF and SSGBLUP-MF. When we estimated dispersion by comparing a model with no markers to models with markers, SSGBLUP-MF showed a value close to 1, indicating that there was no problem in dispersion, whereas SSGBLUP-EUPG and SSGBLUP-UPG showed a significant under-dispersion. Another important observation was the heterogeneous behaviour of the estimates over time, which suggests that a single check could be insufficient to make a good analysis of genetic/genomic evaluations. CONCLUSIONS: The addition of genomic information increases the accuracy of EBV of young rams in Manech Tête Rousse. In this population that has missing pedigrees, the use of UPG and EUPG in SSGBLUP produced bias, whereas MF yielded unbiased estimates, and we recommend its use. We also recommend assessing biases and accuracies using multiple truncation points, since these statistics are subject to random variation across years.

Genomic Surveillance of Yellow Fever Virus Epizootic in São Paulo, Brazil, 2016 - 2018.

São Paulo, a densely inhabited state in southeast Brazil that contains the fourth most populated city in the world, recently experienced its largest yellow fever virus (YFV) outbreak in decades. YFV does not normally circulate extensively in São Paulo, so most people were unvaccinated when the outbreak began. Surveillance in non-human primates (NHPs) is important for determining the magnitude and geographic extent of an epizootic, thereby helping to evaluate the risk of YFV spillover to humans. Data from infected NHPs can give more accurate insights into YFV spread than when using data from human cases alone. To contextualise human cases, identify epizootic foci and uncover the rate and direction of YFV spread in São Paulo, we generated and analysed virus genomic data and epizootic case data from NHPs in São Paulo. We report the occurrence of three spatiotemporally distinct phases of the outbreak in São Paulo prior to February 2018. We generated 51 new virus genomes from YFV positive cases identified in 23 different municipalities in São Paulo, mostly sampled from NHPs between October 2016 and January 2018. Although we observe substantial heterogeneity in lineage dispersal velocities between phylogenetic branches, continuous phylogeographic analyses of generated YFV genomes suggest that YFV lineages spread in São Paulo at a mean rate of approximately 1km per day during all phases of the outbreak. Viral lineages from the first epizootic phase in northern São Paulo subsequently dispersed towards the south of the state to cause the second and third epizootic phases there. This alters our understanding of how YFV was introduced into the densely populated south of São Paulo state. Our results shed light on the sylvatic transmission of YFV in highly fragmented forested regions in São Paulo state and highlight the importance of continued surveillance of zoonotic pathogens in sentinel species.