Design of N-11-Azaartemisinins Potentially Active against Plasmodium falciparum by Combined Molecular Electrostatic Potential, Ligand-Receptor Interaction and Models Built with Supervised Machine Learning Methods

N-11-azaartemisinins potentially active against Plasmodium falciparum are designed by combining molecular electrostatic potential (MEP), ligand-receptor interaction, and models built with supervised machine learning methods (PCA, HCA, KNN, SIMCA, and SDA). The optimization of molecular structures was performed using the B3LYP/6-31G* approach. MEP maps and ligand-receptor interactions were used to investigate key structural features required for biological activities and likely interactions between N-11-azaartemisinins and heme, respectively. The supervised machine learning methods allowed the separation of the investigated compounds into two classes: cha and cla, with the properties εLUMO+1 (one level above lowest unoccupied molecular orbital energy), d(C6-C5) (distance between C6 and C5 atoms in ligands), and TSA (total surface area) responsible for the classification. The insights extracted from the investigation developed and the chemical intuition enabled the design of sixteen new N-11-azaartemisinins (prediction set), moreover, models built with supervised machine learning methods were applied to this prediction set. The result of this application showed twelve new promising N-11-azaartemisinins for synthesis and biological evaluation.

Gangliosides in nervous system development,regeneration,and pathologies

Gangliosides,sialic acid-containing sphingolipids,are major constituents of neuronal membranes.According to the number of sialic acids and the structure of the oligosaccharide chain,gangliosides can be classified as simple or complex and grouped in different ganglio-series.Hundreds of gangliosides have been identified in vertebrate cells,with different expression patterns during development and related to several physiological processes,especially in the nervous system.While GD3 and its O-acetylated form,9acGD3,are highly expressed in early developmental stages,GM1,GD1a,GD1b,and GT1b are the most abundant ganglioside species in the mature nervous system.Mutations in enzymes involved in ganglioside metabolism can lead to the accumulation of specific species,a condition termed gangliosidosis and usually marked by severe neurological impairment.Changes in ganglioside levels have also been described in several neurodegenerative diseases,such as Alzheimer’s and Parkinson’s.In this review,we summarized recent information about the roles of GD3,9acGD3,GM1,GD1a,GD1b,GT1b,and other ganglioside species in nervous system development and regeneration,as well as clinical trials evaluating possible therapeutic applications of these molecules.

Mesenchymal stem cell-and extracellular vesicle-based therapies for Alzheimer's disease:progress,advantages,and challenges

Alzheimer's disease is a severe, highly disabling neurodegenerative disease, clinically characterized by a progressive decline in cognitive functions, and is the most common form of dementia in the elderly. For decades, the search for disease-modifying therapies has focused on the two main Alzheimer's disease histopathological hallmarks, seeking to prevent, mitigate, or clear the formation of extracellular aggregates of β-amyloid peptide and intracellular neurofibrillary tangles of tau protein, although without clinical success. Mesenchymal stem cell-based therapy has emerged as a promising alternative for the treatment of Alzheimer's disease, especially because it also targets other crucial players in the pathogenesis of the disease, such as neuroinflammation, synaptic dysfunction/loss, oxidative stress, and impaired neurogenesis. Herein, we review current knowledge of the therapeutic potential of mesenchymal stem cells and their extracellular vesicles for Alzheimer's disease, discussing the most recent findings in both preclinical and clinical trials as well as how advanced technologies have helped to overcome some limitations and contributed to stimulate the development of more effective treatments.

In vitro 3D malignant melanoma model for the evaluation of hypericin-loaded oil-in-water microemulsion in photodynamic therapy

Advances in biomimetic three-dimensional(3D) melanoma models have brought new prospects of drug screening and disease modeling, since their physiological relevancy for recapitulating in vivo tumor architectures is more accurate than traditional two-dimensional(2D) cell culture. Gelatin methacryloyl(GelMA) is widely used as a tissue-engineered scaffold hydrogel for 3D cell culture. In the present study, an in vitro 3D malignant melanoma model based on Gel MA was fabricated to evaluate the efficiency of hypericin(Hy)-loaded microemulsion(ME) in photodynamic therapy against melanoma. The ME was produced by the spontaneous emulsification method to enhance the bioavailability of Hy at tumor sites. Hy-loaded MEs were applied to a 3D malignant melanoma model made using 6% Gel MA and the co-culture of B16F10 and Balb/c 3T3 cells,followed by crosslinking using violet light(403 nm). The observation revealed excellent cell viability and the presence of F-actin cytoskeleton network. Hy-loaded MEs exhibited higher phototoxicity and cell accumulation(about threefold) than free Hy, and the cells cultured in the 3D system displayed lower susceptibility(about 2.5-fold) than those in 2D culture.These findings indicate that the developed MEs are potential delivery carriers for Hy;furthermore, Gel MA hydrogel-based modeling in polydimethylsiloxane(PDMS) molds is a user-friendly and cost-effective in vitro platform to investigate drug penetration and provide a basis for evaluating nanocarrier efficiency for skin cancer and other skin-related diseases.

Opportunities for Remote Collaboration in a Social Web Search Model That Integrates Parents and Children

Traditionally, search engines are designed to support a single user working alone. However, the construction of knowledge is enriched when one adds collaboration to search tasks. We identified opportunities for remote collaboration in a Social Web search model that integrates parents and children guided by 5W + 1H (who, what, where, when, why, how) dimensions. Our social search model aims at improving the search process for children. We found 7 opportunities for remote collaboration on the search process, based on implicit-explicit interactions.

First Record in Brazil of Epistylis sp. (Ciliophora) Adhered to Argulus sp. (Argulidae), a Parasite of Hoplias aimara (Eritrhinidae)

This paper records the first occurrence of Epistylis sp. on the body surface of Argulus sp. parasitizing Hoplias aimara from the upper Araguari River, in the eastern Amazon region, in the north of Brazil. Of the 16 specimens of H. aimara examined, 93.7% had their pelvic, caudal and pectoral fins and tegument infested by Argulus sp. (n = 73), which in turn were infested by Epistylis sp. The specimens of Epistylis sp. from the body surface of Argulus sp. were analyzed using Scanning Electron Microscopy (SEM). The present study also identified a widening of the geographic distribution of these two species of ectoparasites to the eastern Amazon region of Brazil.

A Bibliometric Analysis of the“NetZero”Process in the Energy Knowledge Domain

This work aimed to elucidate the key research findings within the realm of NetZero,specifically within the energy field.Employing advanced data visualization tools,particularly VOSviewer,scientific maps were meticulously crafted to explain the evolving landscape of research in this domain.The results showed that the nations that most vigorously committed to the NetZero endeavor are the United Kingdom,United States,China,Australia,and Canada,signaling a global consensus on the urgency of addressing climate change.Furthermore,this study reveals pivotal trends in the field and keywords such as“renewable energy”,“decarbonization”,“netzero”,and“sustainability”have gained remarkable prominence,especially in recent research.In conclusion,this work offers a comprehensive overview of the NetZero landscape within the energy field,emphasizing the urgency of international collaboration,and identifies key trends that will likely shape the future of sustainable energy research and policymaking.

Heme as an inducer of cerebral damage in hemorrhagic stroke:potential therapeutic implications

Intracerebral hemorrhage(ICH)consists of the rupture of a cerebral artery leading to bleeding into the surrounding parenchyma.This event has a primary phase of brain injury consisting of mechanical tissue damage due to the mass effect,followed by a secondary phase of brain injury triggered by the presence of blood components released at the site of bleeding(Bulters et al.,2018).Despite the high rates of mortality and morbidity from ICH,no effective treatment is available so far.

Isolation of Filamentous Fungi from the Caatinga Region and Production of Amylolytic Enzymes of Great Industrial Interest

The industrial importance and the high cost of the commercial amylase require the study of microorganisms that produce these enzymes. For this reason, the objective of this work was to isolate filamentous fungi from a region of the caatinga and evaluate their potential for the production of amylase. Four soil samples were collected from a deactivated dump located in the city of Diamantina, MG, in a region of the caatinga. The analysis of amylolytic production in a submerged medium at the ideal temperature of each microorganism was performed using the saccharification method, and the reducing sugars formed were quantified by DNS. Fourteen filamentous fungi were isolated, which had different morphological aspects. Regarding amylase production, a mean activity of 0.477 U·mL-1 was obtained with the isolates I 1.2.1 and I 4.4.1. These results bring important information regarding the biodiversity of the caatinga, in addition to the isolation of microorganisms that can be used as biological machinery to obtain metabolites with high biotechnological and industrial potential.

Tritrichomonas foetus:New structures by high-resolution scanning helium ion microscopy

Helium ion scanning microscopy(HIM)is a novel high-resolution scanning microscopy technique that uses helium ions instead of electrons to form images of the highest quality and resolution,providing a sub-nanometer resolution sputter uncoated biological cell.Here,we took advantage of HIM to explore the cell surface of Tritrichomonas foetus,a protist parasite of cattle that provokes hard infection and abortion in cows.We describe thin protrusions,like nanotubes described in other cells,with different sizes(27 nm to 81 nm in thickness)and various lengths(from 73 nm to 2μm),as well bulbous structures either budding from the cell surface or present in the extremities of some protrusions.The flagella also presented these thin protrusions and different protein decoration,similar to those previously described using freeze-fracture techniques.Nanotubes between two cells were also seen,and their role in infection is discussed.The cell surface was also examined and showed several pits indicative of endocytic activity and other types of arrays of particles.These observations were confirmed using Scanning Electron Microscopy(SEM),negative staining,and conventional thin sectioning for observation by transmission electron microscopy.Our findings provide new and relevant information that may contribute to a better understanding of protozoan biology and its interaction with mammalian cells.

Trypanosoma cruzi invasion in non-phagocytic cells:an ultrastructural study

Trypanosoma cruzi is the causative agent of Chagas disease.This parasite requires the intracellular niche in order to proliferate and disseminate the infection.After invasion,T.cruzi resides temporarily in an acidic vacuole which is lysed by a not well-understood mechanism.Transmission electron microscopy was used to describe the process of T.cruzi escape from the parasitophorous vacuole over the time.Using HeLa(non-professional phagocytic cells)as host cell,we observed that recently internalized parasites reside in a membrane-bounded vacuole.A few hours later,the first sign of vacuole disruption appeared as membrane discontinuities.This observation was followed by a progressive vacuole swelling as evidenced by an electron-lucent halo between the parasite and the vacuole membrane.Apparently,the vacuole membrane remnants reorganized as small vesicles that eventually disappeared from the vicinity of the parasites.Finally,parasites reach the host cell cytosol where replication takes place.The thorough ultrastructural description of this process set the base for a comprehensive understanding of the parasite-host cell interaction and,thus open the possibility of new therapeutic intervention strategies.

Analysis of the Lipolytic Potential of Filamentous Fungi Isolated from Some Plants and Soil Samples in Minas Gerais, Brazil

Microorganisms have the ability to produce several metabolites, which are widely used in biotechnological processes, including the biological catalysts called enzymes. Among these enzymes, lipases are favored because they perform various catalytic reactions such as hydrolysis, esterification, interesterification and transesterification. This work sought to isolate filamentous fungi from samples collected in Diamantina, Minas Gerais, Brazil, analyze their macroscopic morphological characteristics, determine the effect of temperature on their growth, and verify which organisms are potential lipase producers. From four collection sites, nine fungi were isolated from the leaves and soil of the jabuticaba (Plinia cauliflora) tree and three fungi from the Andu bean leaves (Cajanus cajan). The macroscopic morphological characteristics of the microorganisms were analyzed. For thermophilic analysis, the twelve isolated fungi and eight obtained from the laboratory bank were cultivated in a solid Potato-Dextrose-Agar medium from 30°C to 50°C, with intervals of 5°C. The growth rate per hour after 48 hours of development was calculated. For the selection of filamentous lipase-producing fungi, the 20 fungi were cultivated in solid BDA medium at 30°C for 96 hours, and the enzyme index was calculated. It was found that, of the 20 microorganisms, 95% developed at 30°C, and the highest growth rates were those of fungi 3.2TA, PJ8 and PJ7. At 35°C, 70% of the fungi developed, and the highest growth rates were those of fungi 3.2TA, MB2.2 and P3. At 40°C, 40% of the fungi developed, and the highest growth rates were those of fungi 3.2TA, PJ6 and PJ8. At 45°C, only the PJ6 and PJ12 fungi grew, and no organism grew at 50°C. In the screening for lipase production, the largest growth halo was observed for the 3.2TA fungus from the bank.

Microbiological Contamination and Disinfection Procedures of Kitchen Sponges used in Food Services

Kitchen sponges continue to be heavily used in Brazilian food services, even though they may be very contaminated. The objective of this study was to evaluate the microbiological contamination and the efficacy of two procedures for the disinfection of kitchen sponges used in Brazilian food services. Eighty sponges were collected from food services and then analyzed for the quantification heterotrophic microorganisms (HM), fecal coliforms (CF), Staphylococcus coagulase-positive (SA) microorganisms and to the investigation of the presence of Salmonella sp. (SAM). After that, the sponges were disinfected, separately, by either boiling water for five minutes or immersed in 200ppm sodium hypochlorite, for 10 minutes, added to a rinse with potable water. The results showed that sponges presented HM counts between 3.4 and 10.4 log CFU/sponge, with an average of 9.1 log CFU/sponge, and 76.25% of them presented CF with average counts of 8.4 log CFU/sponge. SA and SAM were found in 2.5% of samples. Both disinfection procedures were able to significantly reduce the bacterial counts, but the boiling method showed a greater reduction (99.9999%) than the method of disinfection by 200 ppm sodium hypochlorite (99.9%). Based on the results it was possible to conclude that kitchen sponges can be very contaminated, but simple disinfection procedure can be applied to significantly reduce the microbial contamination.

Foodborne outbreaks in Brazil associated with fruits and vegetables:2008 through 2014

Objectives:Foodborne disease outbreaks linked to fruits and vegetables have been increasing in occurrence worldwide;therefore,the aim of this study was to identify the reported foodborne outbreaks associated with fruit and vegetable consumption in Brazil from 2008 to 2014.Results And Limitations:Thirty produce related outbreaks resulted in 2926 illnesses,347 hospitalizations,and no deaths.Only bacterial pathogens were identified as etiological agents.Among these,Salmonella was the most frequent(30 per cent of outbreaks)followed by Staphylococcus aureus(23.3 per cent),Escherichia coli(10 per cent),Bacillus cereus(6.6 per cent),and thermotolerant coliforms(3.3 per cent),whereas etiological agents could not be determined for 26.6 per cent of outbreaks.The most common food vehicles implicated in outbreaks were generically named as fruits and vegetables(46.6 per cent of outbreaks).The term salad was used generically and specifically like salads(two outbreaks),raw/cooked salads(four outbreaks),vegetable salad,tropical salad,Caesar salad,and raw salad of cabbage and tomato.Only one outbreak was related exclusively to fruit(fruit pulp),whereas other outbreaks were related to cooked carrot,lettuce,cucumber,watermelon/cabbage,and chard/beet.Contamination sources and issues related to the future control of produce-related foodborne disease outbreaks are discussed.

eIF3 subunit M regulates blood meal digestion in Rhodnius prolixus affecting ecdysis, reproduction, and survival

In triatomines,blood-feeding triggers many physiological processes including post embryonic development and reproduction.Different feeding habits,such as hematophagy,can shape gene functions to meet the challenges of each type of diet.The gut of blood-sucking insects faces particular challenges after feeding due to the quantity and the quality of the food ingested.A comparison of transcriptomic and proteomic data indicates that post transcriptional regulation of gene expression is crucial in the triatomine gut.It was proposed that eukaryotic translation initiation factor 3 subunit m(eIF3m)and eIF3e define 2 different eIF3 complexes with a distinct affinity for the different mRNAs,thus selecting the set of mRNAs to be translated and constituting a post transcriptional mode of regulation of gene expression.Because the eIF3m is mainly expressed in the gut,we evaluated its relevance in Rhodnius prolixus physiology through RNA interference-mediated gene silencing.The knockdown of eIF3m reduced the digestion rate,affecting the processes triggered by a blood meal.Its silencing inhibited molting and caused premature death in nymphs while impaired ovary development,oviposition and increased resistance to starvation in adult females.The survival of males after feeding(resistance to starvation)was not affected by eIF3m knockdown.The information regarding the eIF3m function in insects is scarce and the phenotypes observed in R.prolixus upon eIF3m silencing are different and more severe than those previously described in Drosophila melanogaster,indicating a pleiotropic role of this gene in triatomines.

Control of inherited structural fabric on the development and exhumation of passive margins-Insights from the AraçuaíOrogen(Brazil)

The AraçuaíOrogen,in eastern Brazil,was formed during the Neoproterozoic–Cambrian amalgamation of West Gondwana.During the Mesozoic–Cenozoic opening of the South Atlantic Ocean,and the associated divergent tectonics,the orogen developed as basement to the passive margin of South America and was progressively covered by thick offshore sedimentary basins,particularly the Espírito Santo,Mucuri,and Cumuruxatiba basins,in which hydrocarbon systems have been exploited.Our understanding of the AraçuaíOrogen’s passive margin evolution,erosion,and sediment transfer to these basins ultimately depends on constraining the onshore exhumation in response to Mesozoic–Cenozoic events.Here,new and previously published data from apatite fission-track(AFT)analyses and inverse thermal history modelling of(Pre)Cambrian basement rocks from the AraçuaíOrogen resolve three discrete basement cooling and associated erosional exhumation episodes.In the Pre-Rift phase,Jurassic–Hauterivian erosion of the AraçuaíOrogen is most likely related to the adjoining intra-continental West Gondwana flexural subsidence,which increased hillslope and river erosion power.In the Rift and Transitional phases,Barremian–Albian accelerated phase of erosion is associated with the uplift of the Atlantic rift shoulders and the establishment of an oceanic base-level.In the Drift phase,reactivations in response to far-field stresses likely triggered a Late Cretaceous–Paleocene rapid erosion event.The rates at which these events unfolded vary spatially and are controlled by inherited structures.The AraçuaíOrogen experienced slower denudation rates in areas closer to the São Francisco Craton,which suggests that the tectonic reactivation and related surface uplift during the Mesozoic–Cenozoic is in first-order controlled by lithospheric rigidity.Furthermore,the structural framework of the Paramirim and Pirapora aulacogens and NE-oriented shear zones in the orogen’s southeast facilitated later reactivations.From the spatial pattern of denudation/exhumation of the AraçuaíOrogen during the Mesozoic–Cenozoic,we draw inferences on the tectonic development of the offshore basins regarding their hydrocarbon potentials.

The influence of innate and adaptative immune responses on the differential clinical outcomes of leprosy

Leprosy is a chronic infectious disease caused by Mycobacterium leprae.According to official reports from 121 countries across five WHO regions,there were 213899 newly diagnosed cases in 2014.Although leprosy affects the skin and peripheral nerves,it can present across a spectrum of clinical and histopathological forms that are strongly influenced by the immune response of the infected individuals.These forms comprise the extremes of tuberculoid leprosy(TT),with a M.leprae-specific Th1,but also a Th17,response that limits M.leprae multiplication,through to lepromatous leprosy(LL),with M.leprae-specific Th2 and T regulatory responses that do not control M.leprae replication but rather allow bacterial dissemination.The interpolar borderline clinical forms present with similar,but less extreme,immune biases.Acute inflammatory episodes,known as leprosy reactions,are complications that may occur before,during or after treatment,and cause further neurological damages that can cause irreversible chronic disabilities.This review discusses the innate and adaptive immune responses,and their interactions,that are known to affect pathogenesis and influence the clinical outcome of leprosy.

High chromosomal evolutionary dynamics in sleeper gobies(Eleotridae)and notes on disruptive biological factors in Gobiiformes karyotypes(Osteichthyes,Teleostei)

The order Gobiiformes is made up of more than 2200 species,representing one of the most diverse groups among teleost fishes.The biological causes for the tachytelic karyotype evolution of the gobies have not yet been fully studied.Here we expanded cytogenetic data for the Eleotridae family,analyzing the neotropical species Dormitator maculatus,Eleotris pisonis,Erotelis smaragdus,and Guavina guavina.In addition,a meta-analytical approach was followed for elucidating the karyotype diversification versus biological aspects(habitat and egg type)of the Gobiiformes.The species E.smaragdus and E.pisonis present 2n=46 acrocentric chromosomes(NF=46),D.maculatus 2n=46(36sm+4st+6a;NF=86),and G.guavina,the most divergent karyotype,with 2n=52 acrocentric chromosomes(NF=52).Besides numeric and structural diversification in the karyotypes,the mapping of rDNAs and microsatellites also showed noticeable numerical and positional variation,supporting the high chromosomal evolutionary dynamism of these species.In Gobiiformes,karyotype patterns which are more divergent from the basal karyotype(2n=46a)are associated with characteristics less effective to dispersion,such as the benthic habit.These adaptive characteristics,connected with the organization of the repetitive DNA content in the chromosomes,likely play a synergistic role in the remarkable karyotype diversification of this group.