Mutant p53 tends to form aggregates with amyloid properties, especially amyloid oligomers inside the nucleus, which are believed to cause oncogenic gain-of-function (GoF). The mechanism of the ...formation of the aggregates in the nucleus remains uncertain. The present study demonstrated that the DNA-binding domain of p53 (p53C) underwent phase separation (PS) on the pathway to aggregation under various conditions. p53C phase separated in the presence of the crowding agent polyethylene glycol (PEG). Similarly, mutant p53C (M237I and R249S) underwent PS; however, the process evolved to a solid-like phase transition faster than that in the case of wild-type p53C. The data obtained by microscopy of live cells indicated that transfection of mutant full-length p53 into the cells tended to result in PS and phase transition (PT) in the nuclear compartments, which are likely the cause of the GoF effects. Fluorescence recovery after photobleaching (FRAP) experiments revealed liquid characteristics of the condensates in the nucleus. Mutant p53 tended to undergo gel- and solid-like phase transitions in the nucleus and in nuclear bodies demonstrated by slow and incomplete recovery of fluorescence after photobleaching. Polyanions, such as heparin and RNA, were able to modulate PS and PT
in vitro
. Heparin apparently stabilized the condensates in a gel-like state, and RNA apparently induced a solid-like state of the protein even in the absence of PEG. Conditions that destabilize p53C into a molten globule conformation also produced liquid droplets in the absence of crowding. The disordered transactivation domain (TAD) modulated both phase separation and amyloid aggregation. In summary, our data provide mechanistic insight into the formation of p53 condensates and conditions that may result in the formation of aggregated structures, such as mutant amyloid oligomers, in cancer. The pathway of mutant p53 from liquid droplets to gel-like and solid-like (amyloid) species may be a suitable target for anticancer therapy.
Mutant p53 tends to form aggregates with amyloid properties, especially amyloid oligomers inside the nucleus, which are believed to cause oncogenic gain-of-function (GoF).
p53 is a tumor suppressor protein that is mutated in more than 50% of cancer cases. When mutated, it frequently results in p53 oncogenic gain of function (GOF), resulting in a greater tendency to ...aggregate in the phase separation and phase transition pathway. GOFs related to p53 aggregation include chemoresistance, which makes therapy even more difficult. The therapies available for the treatment of cancer are still quite limited, so the study of new molecules and therapeutic targets focusing on p53 aggregates is a promising strategy against cancer. In this review, we classify anticancer molecules with antiaggregation properties into four categories: thiol alkylating agents, designed peptides, agents with chaperone-based mechanisms that inhibit p53 aggregation, and miscellaneous compounds with anti-protein aggregation properties that have been studied in neurodegenerative diseases. Furthermore, we highlight autophagy as a possible degradation pathway for aggregated p53. Here, considering cancer as a protein aggregation disease, we review strategies that have been used to disrupt p53 aggregates, leading to cancer regression.
Requirements determine the correct construction of software and are frequently represented explicitly in the accompanying documentation in ways that vary according to the adopted software process. ...The documentation is typically written in natural language and can contain elements such as figures, tables or a more formal description. The quality assurance of artifacts written in natural language has advanced significantly since the mid-70s. SIGEPE makes use of checklists with criteria weighted by both form and content. The quality assurance team conducts periodic and individual checks on strategically selected projects. In little over a year, there was a noticeable improvement in the quality of the documentation and it was possible to identify the most common points of success and failure. This paper describes a Case Study to verify the quality of the elements of SIGEPE documentation.
O trabalho teve o objetivo de investigar a variabilidade climática no município de Santa Inês nos anos de 2011 e 2012, suas causas e efeitos na precipitação. Os estudos foram realizados a partir de ...levantamentos de dados primários na estação pluviométrica de Santa Inês e correlacionados com a dinâmica atmosférica em macro e mesoescalas, através de análises dos boletins quinzenais e mensais do INMET. Os resultados mostram que no ano de 2011 a precipitação anual esteve 90,5mm abaixo das normais climatológicas, contudo no período historicamente úmido as chuvas foram superiores à média. O desvio negativo, por conseguinte, se deu nos meses secos, o que agravou os problemas relacionados à seca. O ano de 2012 foi mais seco que o de 2011, apresentando índices pluviométricos de regiões consideradas desérticas. As precipitações de 2012 apresentaram um desvio negativo de 337,4mm e a diminuição dos totais ocorreu em praticamente todos os meses do ano, exceto em agosto. Embora a fase fria do fenômeno Enos-Oscilação Sul estivesse ativa em vários dos meses analisados, fenômenos oceano-atmosféricos, como as águas superficiais mais frias que o normal no Atlântico Tropical Sul contribuíram para a escassez de chuvas no semiárido nordestino e em Santa Inês.
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Os minerais pesados podem ser utilizados como indicadores pedogênicos, em alguns casos pode solucionar problemas importantes. Nos Tabuleiros Costeiros do Litoral Norte da Bahia materiais de origem sedimentar têm sido comumente confundidos como duripãs e fragipãs, por isso foram realizadas análises de minerais pesados em litofácies e solos do Grupo Barreiras com o intuito de contribuir para a resolução do problema. O estudo mostra que os minerais pesados presentes em estruturas associadas e em diferentes fácies do Grupo Barreiras são praticamente os mesmos, indicando o elo mineralógico. Além disso, a presença de minerais pesados instáveis e pouco estáveis, como a biotita compondo a assembléia de estruturas associadas tipo fragipãs e duripãs indica que não são de origem pedogenética, uma vez que são incompatíveis com ambiente teórico de formação, os quais exigem condições de hidromorfia temporária, dissolução intensa de minerais e precipitação em subsuperfície de compostos silicoaluminosos ou aluminosilicosos
ABSTRACT - The heavy minerals can be used as indicators pedogenic and solve important problems. In the Coastal Plains of North Bahia Coast sedimentary materials have been commonly mistaken fragipans and duripans, therefore analyzes of heavy in order to contribute to solving the problem minerals were performed. The study shows that heavy minerals in soils and different facies of the Group Barriers are the same, indicating mineralogical link. The presence of unstable heavy minerals such as biotite composing the assembly similar structures to fragipans and duripans indicates that they are not pedogenetic origin, since they are incompatible with theoretical training environment, which require temporary waterlogging conditions, intense mineral dissolution and subsurface precipitation of siliceous or aluminous compounds.
The spleen is a secondary lymphoid organ responsible for immune surveillance against blood-circulating pathogens. Absence of the spleen is associated with increased susceptibility to systemic spread ...and fatal infection by different pathogens. Severe forms of visceral leishmaniasis are associated with disorganization of spleen compartments where cell interactions essential for splenic immunological function take place. White pulp atrophies, secondary lymphoid follicles and marginal zones vanish, and the boundaries separating white and red pulp blur. Leukocyte populations are reduced or disappear or are replaced by plasma cells. In this paper, we review the published data on spleen disorganization in severe forms of visceral leishmaniasis and propose a histological classification to help the exchange of information among research groups.
Domestic dogs are the main reservoir of Leishmania infantum, a causative agent of visceral leishmaniasis (VL). The number of human disease cases is associated with the rate of canine infection. ...Currently available drugs are not efficient at treating canine leishmaniasis (CanL) and months after the treatment most dogs show disease relapse, therefore the development of new drugs or new therapeutic strategies should be sought. In CanL, dogs lack the ability to mount a specific cellular immune response suitable for combating the parasite and manipulation of cytokine signaling pathway has the potential to form part of effective immunotherapeutic methods. In this study, recombinant canine cytokines (rcaIL-12, rcaIL-2, rcaIL-15 and rcaIL-7) and soluble receptor IL-10R1 (rcasIL-10R1), with antagonistic activity, were evaluated for the first time in combination (rcaIL-12/rcaIL-2, rcaIL-12/rcaIL-15, rcaIL-12/rcasIL-10R1, rcaIL-15/rcaIL-7) or alone (rcasIL-10R1) to evaluate their immunomodulatory capacity in peripheral blood mononuclear cells (PBMCs) from dogs with leishmaniasis. All the combinations of recombinant proteins tested were shown to improve lymphoproliferative response. Further, the combinations rcaIL-12/rcaIL-2 and rcaIL-12/rcaIL-15 promoted a decrease in programmed cell death protein 1 (PD-1) expression in lymphocytes. These same combinations of cytokines and rcaIL-12/rcasIL-10R1 induced IFN-γ and TNF-α production in PBMCs. Furthermore, the combination IL-12/IL-15 led to an increased in T-bet expression in lymphocytes. These findings are encouraging and indicate the use of rcaIL-12 and rcaIL-15 in future in vivo studies aimed at achieving polarization of cellular immune responses in dogs with leishmaniasis, which may contribute to the development of an effective treatment against CanL.
Host tissues affected by Leishmania infantum have differing degrees of parasitism. Previously, the use of different biological tissues to detect L. infantum DNA in dogs has provided variable results. ...The present study was conducted to evaluate the accuracy of molecular diagnostic testing (qPCR) in dogs from an endemic area for canine visceral leishmaniasis (CVL) by determining which tissue type provided the highest rate of parasite DNA detection. Fifty-one symptomatic dogs were tested for CVL using serological, parasitological and molecular methods. Latent class analysis (LCA) was performed for accuracy evaluation of these methods. qPCR detected parasite DNA in 100% of these animals from at least one of the following tissues: splenic and bone marrow aspirates, lymph node and skin fragments, blood and conjunctival swabs. Using latent variable as gold standard, the qPCR achieved a sensitivity of 95.8% (CI 90.4-100) in splenic aspirate; 79.2% (CI 68-90.3) in lymph nodes; 77.3% (CI 64.5-90.1) in skin; 75% (CI 63.1-86.9) in blood; 50% (CI 30-70) in bone marrow; 37.5% (CI 24.2-50.8) in left-eye; and 29.2% (CI 16.7-41.6) in right-eye conjunctival swabs. The accuracy of qPCR using splenic aspirates was further evaluated in a random larger sample (n = 800), collected from dogs during a prevalence study. The specificity achieved by qPCR was 76.7% (CI 73.7-79.6) for splenic aspirates obtained from the greater sample. The sensitivity accomplished by this technique was 95% (CI 93.5-96.5) that was higher than those obtained for the other diagnostic tests and was similar to that observed in the smaller sampling study. This confirms that the splenic aspirate is the most effective type of tissue for detecting L. infantum infection. Additionally, we demonstrated that LCA could be used to generate a suitable gold standard for comparative CVL testing.
Two alleles (G1 and G2) of the apolipoprotein 1 gene (APOL1) predispose people of African descent to developing or accelerating the course of certain types of kidney disease. Population studies to ...determine the frequency of the G1 and G2 alleles are important to inform resource allocation by public health authorities. Traditionally, APOL1 genotyping is carried out in blood samples. However, sample collection, transport, and storage is cumbersome. Here we compared APOL1 genotyping in blood and buccal mucosa cell samples obtained from 23 individuals. Alleles G0 (wild), G1, and G2, as well as genotypes G0/G0, G0/G1, G1/G1, G0/G2, G1/G2, and G2/G2 were detected using both blood and buccal mucosa cells with 100% coincidence. Our data indicate that buccal mucosa cell samples may represent a suitable alternative to blood samples for APOL1 genotyping in the field.
Urban waste (UW) has caused a series of problems regarding its management. UW comprises domestic, hospital and industrial residues, which makes the destination of this waste a matter of concern, as ...it may contain a variety of highly toxic environmental polluters. Deactivated dumps can represent sources of contamination of the environment that surround these deposits, harming rivers and inhabiting organisms. Knowledge of the microbial profile of water bodies that can be affected by these toxic residues is essential for the development of alternatives and improvements in treatments applied in rivers and streams. In this sense, this work aimed to analyze the microbial community present in sediments of the Arroio Dourado stream in the municipality of Foz do Iguaçu, a stream located near a deactivated open-air dump. 16S rDNA metabarcoding suggested the dominance of acidogenic bacteria belonging to Acidobacteriota phylum, followed by less abundant phyla Actinobacteriota, Myxococcota, Chloroflexi and a small community of sulfate reducers (Desulfobacteriota). However, more than 50% of amplicon sequence variants (ASVs) were not taxonomically classified. In addition, an expressive abundance was attributed to the genus
Anaeromyxobacter
, a metabolically versatile group, which can thrive in the presence of polluting compounds present in the deactivated landfill. Thus, a possible stream treatment process can be developed. In addition, culture media can be developed for the recovery of taxonomic groups identified involved in the biodegradation of organic compounds. The results presented expand the knowledge of bacterial diversity in sediment samples recovered from the Arroio Dourado stream.
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