Differential metabolic reprogramming in developing soybean embryos in response to nutritional conditions and abscisic acid.

Seed storage compound deposition is influenced by both maternal and filial tissues. Within this framework, we analyzed strategies that operate during the development and filling of soybean embryos, using in vitro culture systems combined with metabolomics and proteomics approaches. The carbon:nitrogen ratio (C:N) of the maternal supply and the hormone abscisic acid (ABA) are specific and interacting signals inducing differential metabolic reprogrammings linked to changes in the accumulation of storage macromolecules like proteins or oils. Differences in the abundance of sugars, amino acids, enzymes, transporters, transcription factors, and proteins involved in signaling were detected. Embryos adapted to the nutritional status by enhancing the metabolism of both carbon and nitrogen under lower C:N ratio condition or only carbon under higher C:N ratio condition. ABA turned off multiple pathways especially in high availability of amino acids, prioritizing the storage compounds biosynthesis. Common responses induced by ABA involved increased sucrose uptake (to increase the sink force) and oleosin (oil body structural component) accumulation. In turn, ABA differentially promoted protein degradation under lower nitrogen supply in order to sustain the metabolic demands. Further, the operation of a citrate shuttle was suggested by transcript quantification and enzymatic activity measurements. The results obtained are useful to help define biotechnological tools and technological approaches to improve oil and protein yields, with direct impact on human and animal nutrition as well as in green chemistry.

Improved Sugarcane-Based Fermentation Processes by an Industrial Fuel-Ethanol Yeast Strain.

In Brazil, sucrose-rich broths (cane juice and/or molasses) are used to produce billions of liters of both fuel ethanol and cachaça per year using selected Saccharomyces cerevisiae industrial strains. Considering the important role of feedstock (sugar) prices in the overall process economics, to improve sucrose fermentation the genetic characteristics of a group of eight fuel-ethanol and five cachaça industrial yeasts that tend to dominate the fermentors during the production season were determined by array comparative genomic hybridization. The widespread presence of genes encoding invertase at multiple telomeres has been shown to be a common feature of both baker's and distillers' yeast strains, and is postulated to be an adaptation to sucrose-rich broths. Our results show that only two strains (one fuel-ethanol and one cachaça yeast) have amplification of genes encoding invertase, with high specific activity. The other industrial yeast strains had a single locus (SUC2) in their genome, with different patterns of invertase activity. These results indicate that invertase activity probably does not limit sucrose fermentation during fuel-ethanol and cachaça production by these industrial strains. Using this knowledge, we changed the mode of sucrose metabolism of an industrial strain by avoiding extracellular invertase activity, overexpressing the intracellular invertase, and increasing its transport through the AGT1 permease. This approach allowed the direct consumption of the disaccharide by the cells, without releasing glucose or fructose into the medium, and a 11% higher ethanol production from sucrose by the modified industrial yeast, when compared to its parental strain.

Genome Sequence of Clinical Acinetobacter baumannii Strain V15.

Acinetobacter baumannii is recognized as a critical human pathogen by the World Health Organization, and therefore there is increasing interest in studying its biology and pathophysiology. Among other strains, A. baumannii V15 has been extensively used for these purposes. Here, the genome sequence of A. baumannii V15 is presented.

Light regulation in critical human pathogens of clinical relevance such as Acinetobacter baumannii, Staphylococcus aureus and Pseudomonas aeruginosa.

It is now clearly recognized that light modulates the physiology of many bacterial chemotrophs, either directly or indirectly. An interesting case are bacterial pathogens of clinical relevance. This work summarizes, discusses, and provides novel complementary information to what is currently known about light sensing and responses in critical human pathogens such as Acinetobacter baumannii, Pseudomonas aeruginosa and Staphylococcus aureus. These pathogens are associated with severe hospital and community infections difficult to treat due to resistance to multiple drugs. Moreover, light responses in Brucella abortus, an important animal and human pathogen, are also compiled. Evidence recovered so far indicates that light modulates aspects related to pathogenesis, persistence, and antibiotic susceptibility in these pathogens; such as motility, biofilm formation, iron uptake, tolerance to antibiotics, hemolysis and virulence. The pathogens elicit differential responses to light depending likely on their pathophysiology, ability to cause disease and characteristics of the host. The response to light is not restricted to discrete physiological traits but is global. In higher organisms, light provides spatial and temporal information. Then, it is crucial to understand what information light is providing in these bacterial pathogens. Our current hypothesis postulates that light serves as a signal that allows these pathogens to synchronize their behavior to the circadian rhythm of the host, to optimize infection. Advances on the molecular mechanism of light signal transduction and physiological responses to light, as well as in the relation between light and bacterial infection, would not only enlarge our understanding of bacterial pathogenesis but also could potentially provide alternative treatment options for infectious illnesses.

Effects of gamma irradiation on the sensory and metabolic profiles of two peach cultivars.

BACKGROUND: The suitability of commercial peaches for minimal processing (MP) is limited, mainly due to shortened shelf-life. Gamma irradiation has emerged in MP fruits as a promising technology. This study aimed to investigate the effects of gamma irradiation on the sensory and metabolic profiles of MP peaches from two cultivars - 'Forastero' (FT) and 'Ruby Prince' (RP) - and evaluate the relationship between both profiles. MP peaches were packaged and divided into two groups: one without additional treatment (K) and the other subjected to gamma irradiation (1.0 kGy, I- irradiation treatment), making a total of four samples (FTK, FTI, RPK and RPI). The sensory profile was carried out by an assessor panel. Metabolite analysis was accomplished by gas chromatography-mass spectrometry. RESULTS: Irradiation significantly affected color, homogeneity, peach aroma, total flavor intensity, peach flavor, sweetness and juiciness in FT, increasing their intensities. In the RP cultivar, irradiation increased brightness, total aroma intensity, peach aroma, and flavor and texture descriptors. Regarding metabolites, only malic acid and sucrose increased their concentrations in the irradiated samples. Partial least squares showed that sucrose was mainly correlated with sweet, total aroma intensity and peach flavors, and linked with FTI sample. Bitter along with peach aroma and total intensity flavor were associated with RPI sample. CONCLUSION: The applied dose accelerated the ripening process of the peach. The study highlights the importance of complementing sensory analysis with metabolomics tools to optimize fruit quality in minimally processed peaches. © 2023 Society of Chemical Industry.

Towards a leptospirosis early warning system in northeastern Argentina.

Leptospirosis is a zoonotic disease with a high burden in Latin America, including northeastern Argentina, where flooding events linked to El Niño are associated with leptospirosis outbreaks. The aim of this study was to evaluate the value of using hydrometeorological indicators to predict leptospirosis outbreaks in this region. We quantified the effects of El Niño, precipitation, and river height on leptospirosis risk in Santa Fe and Entre Ríos provinces between 2009 and 2020, using a Bayesian modelling framework. Based on several goodness of fit statistics, we selected candidate models using a long-lead El Niño 3.4 index and shorter lead local climate variables. We then tested predictive performance to detect leptospirosis outbreaks using a two-stage early warning approach. Three-month lagged Niño 3.4 index and one-month lagged precipitation and river height were positively associated with an increase in leptospirosis cases in both provinces. El Niño models correctly detected 89% of outbreaks, while short-lead local models gave similar detection rates with a lower number of false positives. Our results show that climatic events are strong drivers of leptospirosis incidence in northeastern Argentina. Therefore, a leptospirosis outbreak prediction tool driven by hydrometeorological indicators could form part of an early warning and response system in the region.

Relationship between Climate Variables and Dengue Incidence in Argentina.

BACKGROUND: Climate change is an important driver of the increased spread of dengue from tropical and subtropical regions to temperate areas around the world. Climate variables such as temperature and precipitation influence the dengue vector's biology, physiology, abundance, and life cycle. Thus, an analysis is needed of changes in climate change and their possible relationships with dengue incidence and the growing occurrence of epidemics recorded in recent decades. OBJECTIVES: This study aimed to assess the increasing incidence of dengue driven by climate change at the southern limits of dengue virus transmission in South America. METHODS: We analyzed the evolution of climatological, epidemiological, and biological variables by comparing a period of time without the presence of dengue cases (1976-1997) to a more recent period of time in which dengue cases and important outbreaks occurred (1998-2020). In our analysis, we consider climate variables associated with temperature and precipitation, epidemiological variables such as the number of reported dengue cases and incidence of dengue, and biological variables such as the optimal temperature ranges for transmission of dengue vector. RESULTS: The presence of dengue cases and epidemic outbreaks are observed to be consistent with positive trends in temperature and anomalies from long-term means. Dengue cases do not seem to be associated with precipitation trends and anomalies. The number of days with optimal temperatures for dengue transmission increased from the period without dengue cases to the period with occurrences of dengue cases. The number of months with optimal transmission temperatures also increased between periods but to a lesser extent. CONCLUSIONS: The higher incidence of dengue virus and its expansion to different regions of Argentina seem to be associated with temperature increases in the country during the past two decades. The active surveillance of both the vector and associated arboviruses, together with continued meteorological data collection, will facilitate the assessment and prediction of future epidemics that use trends in the accelerated changes in climate. Such surveillance should go hand in hand with efforts to improve the understanding of the mechanisms driving the geographic expansion of dengue and other arboviruses beyond the current limits. https://doi.org/10.1289/EHP11616.

BfmRS encodes a regulatory system involved in light signal transduction modulating motility and desiccation tolerance in the human pathogen Acinetobacter baumannii.

We have previously shown that Acinetobacter baumannii as well as other relevant clinical bacterial pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa, perceive and respond to light at 37 °C, the normal temperature in mammal hosts. In this work, we present evidence indicating that the two-component system BfmRS transduces a light signal in A. baumannii at this temperature, showing selective involvement of the BfmR and BfmS components depending on the specific cellular process. In fact, both BfmR and BfmS participate in modulation of motility by light, while only BfmR is involved in light regulation of desiccation tolerance in this microorganism. Neither BfmR nor BfmS contain a photoreceptor domain and then most likely, the system is sensing light indirectly. Intriguingly, this system inhibits blsA expression at 37 °C, suggesting antagonistic functioning of both signaling systems. Furthermore, we present evidence indicating that the phosphorylatable form of BfmR represses motility. Overall, we provide experimental evidence on a new biological function of this multifaceted system that broadens our understanding of A. baumannii's physiology and responses to light.

Prediction of leptospirosis outbreaks by hydroclimatic covariates: a comparative study of statistical models.

Leptospirosis, the infectious disease caused by a spirochete bacteria, is a major public health problem worldwide. In Argentina, some regions have climatic and geographical characteristics that favor the habitat of bacteria of the Leptospira genus, whose survival strongly depends on climatic factors, enhanced by climate change, which increase the problems associated with people's health. In order to have a method to predict leptospirosis cases, in this paper, five time series forecasting methods are compared: two parametric (autoregressive integrated moving average and an alternative one that allows covariates, ARIMA and ARIMAX, respectively), two nonparametric (Nadaraya-Watson Kernel estimator, one and two kernels versions, NW-1 K and NW-2 K), and one semiparametric (semi-functional partial linear regression, SFPLR) method. For this, the number of cases of leptospirosis registered from 2009 to 2020 in three important cities of northeastern Argentina is used, as well as hydroclimatic covariates related to the presence of cases. According to the obtained results, there is no method that improves considerably the rest and can be recommended as a unique tool for leptospirosis prediction. However, in general, the NW-2 K method gets a better performance. This work, in addition to using a long-term high-quality time series, enriches the area of applications of statistical models to epidemiological leptospirosis data by the incorporation of hydroclimatic variables, and it is recommended directing further efforts in this line of research, under the context of current climate change.

Modeling of leptospirosis outbreaks in relation to hydroclimatic variables in the northeast of Argentina.

The transmission of leptospirosis is conditioned by climatic variables. In northeastern Argentina leptospirosis outbreaks occur mainly in coincidence with periods of abundant precipitation and high hydrometric level. A Susceptible-Infectious-Recovered Epidemiological Model (SIR) is proposed, which incorporates hydroclimatic variables for the three most populated cities in the area (Santa Fe, Paraná and Rosario), during the 2009-2018 period. Results obtained by solving the proposed SIR model for the 2010 outbreak are in good agreement with the actual data, capturing the dynamics of the leptospirosis outbreak wave. However, the model does not perform very well in the last months of the year when isolated cases appear outside the outbreak periods, probably due to non- climatic factors not explicitly considered in the present version of the model. Nevertheless, the dynamic modeling of infectious diseases considering hydroclimatic variables constitutes a climatic service for the public health system, not yet available in Argentina.

Characterization of BLUF-photoreceptors present in Acinetobacter nosocomialis.

Acinetobacter nosocomialis is a Gram-negative opportunistic pathogen, whose ability to cause disease in humans is well recognized. Blue light has been shown to modulate important physiological traits related to persistence and virulence in this microorganism. In this work, we characterized the three Blue Light sensing Using FAD (BLUF) domain-containing proteins encoded in the A. nosocomialis genome, which account for the only canonical light sensors present in this microorganism. By focusing on a light-modulated bacterial process such as motility, the temperature dependence of light regulation was studied, as well as the expression pattern and spectroscopic characteristics of the different A. nosocomialis BLUFs. Our results show that the BLUF-containing proteins AnBLUF65 and AnBLUF46 encode active photoreceptors in the light-regulatory temperature range when expressed recombinantly. In fact, AnBLUF65 is an active photoreceptor in the temperature range from 15°C to 37°C, while AnBLUF46 between 15°C to 32°C, in vitro. In vivo, only the Acinetobacter baumannii BlsA's ortholog AnBLUF65 was expressed in A. nosocomialis cells recovered from motility plates. Moreover, complementation assays showed that AnBLUF65 is able to mediate light regulation of motility in A. baumannii ΔblsA strain at 30°C, confirming its role as photoreceptor and in modulation of motility by light. Intra-protein interactions analyzed using 3D models built based on A. baumannii´s BlsA photoreceptor, show that hydrophobic/aromatic intra-protein interactions may contribute to the stability of dark/light- adapted states of the studied proteins, reinforcing the previous notion on the importance of these interactions in BLUF photoreceptors. Overall, the results presented here reveal the presence of BLUF photoreceptors in A. nosocomialis with idiosyncratic characteristics respect to the previously characterized A. baumannii's BlsA, both regarding the photoactivity temperature-dependency as well as expression patterns, contributing thus to broaden our knowledge on the BLUF family.

Enhanced ammonia detoxification to urea in hepatocytes transduced with human aquaporin-8 gene.

Hepatic ammonia detoxification to urea is critical for the prevention of hyperammonemia and neurological damage. Hepatocyte mitochondrial aquaporin-8 (AQP8) channels have been involved in ammonia-derived ureagenesis. Herein, we studied whether the adenoviral gene transfer of human AQP8 (hAQP8) to hepatocyte mitochondria enhances ammonia conversion to urea. Using primary cultured rat hepatocytes, we first confirmed the mitochondrial expression of hAQP8 and then, using unlabeled or 15 N-labeled ammonia, we demonstrated that the urea synthesis was significantly enhanced in hAQP8-transduced hepatocytes. Studies using isolated hAQP8-expressing mitochondria also showed an increased ammonia metabolism. hAQP8 transduction was able to recover the impaired ammonia-derived ureagenesis in hepatotoxin-treated hepatocytes. Our data suggest that mitochondrially-expressed hAQP8 enhances and improves hepatocyte ammonia conversion to urea, a finding with potential therapeutic implications for liver disease with impaired ammonia detoxification.

Blue light directly modulates the quorum network in the human pathogen Acinetobacter baumannii.

Quorum sensing modulates bacterial collective behaviors including biofilm formation, motility and virulence in the important human pathogen Acinetobacter baumannii. Disruption of quorum sensing has emerged as a promising strategy with important therapeutic potential. In this work, we show that light modulates the production of acyl-homoserine lactones (AHLs), which were produced in higher levels in the dark than under blue light at environmental temperatures, a response that depends on the AHL synthase, AbaI, and on the photoreceptor BlsA. BlsA interacts with the transcriptional regulator AbaR in the dark at environmental temperatures, inducing abaI expression. Under blue light, BlsA does not interact with AbaR, but induces expression of the lactonase aidA and quorum quenching, consistently with lack of motility at this condition. At temperatures found in warm-blooded hosts, the production of AHLs, quorum quenching as well as abaI and aidA expression were also modulated by light, though in this case higher levels of AHLs were detected under blue light than in the dark, in a BlsA-independent manner. Finally, AbaI reduces A. baumannii's ability to kill C. albicans only in the dark both at environmental as well as at temperatures found in warm-blooded hosts. The overall data indicate that light directly modulates quorum network in A. baumannii.

Dengue emergence in the temperate Argentinian province of Santa Fe, 2009-2020.

Dengue virus (DENV) transmission occurs primarily in tropical and subtropical climates, but within the last decade it has extended to temperate regions. Santa Fe, a temperate province in Argentina, has experienced an increase in dengue cases and virus circulation since 2009, with the recent 2020 outbreak being the largest in the province to date. The aim of this work is to describe spatio-temporal fluctuations of dengue cases from 2009 to 2020 in Santa Fe Province. The data presented in this work provide a detailed description of DENV transmission for Santa Fe Province by department. These data are useful to assist in investigating drivers of dengue emergence in Santa Fe Province and for developing a better understanding of the drivers and the impacts of ongoing dengue emergence in temperate regions across the world. This work provides data useful for future studies including those investigating socio-ecological, climatic, and environmental factors associated with DENV transmission, as well as those investigating other variables related to the biology and the ecology of vector-borne diseases.

Climate change communication by the local digital press in northeastern Argentina: An ethical analysis.

News articles about Climate Change (CC) represent the level of knowledge of the phenomenon by journalists and the public, as well as the value assigned to problems of ethical and transgenerational nature in a given society. Digital articles related to CC released by media from northeast Argentina were reviewed to study how the local digital press addresses the CC in this region as well as the social representation of the news. An analysis of the content of news articles released in the period January 2016-March 2018 was carried out to identify components that explain their social representation. This study shows that local digital media publish articles about regionally important topics. However, news about CC appear mainly when hydroclimatic events occur. Many of the digital media that release CC information are connected to important social sectors in the region, such as agriculture and economics. A difference between national and local media is that the first ones focus on international events while the latter show the regional reality. Our results also show that no exchange or reciprocity mechanism exists among CC stakeholders, such as journalists, academics and decision-makers. Consequently, building new ways to communicate CC remains a challenge. The media together with scientists, and policy-makers, have a fundamental role in showing the ethical value and importance of caring for Nature and our environment, so to leave the best possible world for future generations.

Spatio-temporal analysis of leptospirosis incidence and its relationship with hydroclimatic indicators in northeastern Argentina.

Leptospirosis is considered the most globally widespread zoonotic illness; it has been classified as an emerging or reemerging infectious disease by the World Health Organization. Leptospirosis is a disease caused by a pathogenic spirochete of the genus Leptospira. The infection occurs by contacting with the urine of animal reservoirs or contaminated environments. Leptospirosis can be controlled by vaccines used mainly in animals, antibiotics given to exposed humans, and flood-affected people moved to a safe place. Northeastern Argentina accounts for the highest annual number of cases and deaths due to leptospirosis of the country. This interdisciplinary study aims to analyze the spatial and temporal distribution of leptospirosis, and assesses the hydroclimatic factors that give rise to the outbreaks in northeastern Argentina. The main goal is to detect the hydroclimatic indicators that can influence leptospirosis outbreaks occurrence in the northeastern Argentina. We perform a spatio-temporal analysis of the leptospirosis in the provinces of Santa Fe and Entre Ríos to distinguish the regions, years and seasons with the highest incidence of this disease. This study analyzes confirmed cases of leptospirosis between 2009 and 2018 years. Hydroclimatic indicators (monthly total precipitation, monthly river hydrometric level and Oceanic Niño Index) associated with outbreaks of leptospirosis vary in different spatial scales (provincial, departmental and cities). In the last outbreak of leptospirosis in 2015-2016 the number of cases was lower than expected. This could have been a consequence of increased prophylaxis in that flood event. Therefore, this is a variable that should be incorporated in future studies.

Quorum and Light Signals Modulate Acetoin/Butanediol Catabolism in Acinetobacter spp.

Acinetobacter spp. are found in all environments on Earth due to their extraordinary capacity to survive in the presence of physical and chemical stressors. In this study, we analyzed global gene expression in airborne Acinetobacter sp. strain 5-2Ac02 isolated from hospital environment in response to quorum network modulators and found that they induced the expression of genes of the acetoin/butanediol catabolism, volatile compounds shown to mediate interkingdom interactions. Interestingly, the acoN gene, annotated as a putative transcriptional regulator, was truncated in the downstream regulatory region of the induced acetoin/butanediol cluster in Acinetobacter sp. strain 5-2Ac02, and its functioning as a negative regulator of this cluster integrating quorum signals was confirmed in Acinetobacter baumannii ATCC 17978. Moreover, we show that the acetoin catabolism is also induced by light and provide insights into the light transduction mechanism by showing that the photoreceptor BlsA interacts with and antagonizes the functioning of AcoN in A. baumannii, integrating also a temperature signal. The data support a model in which BlsA interacts with and likely sequesters AcoN at this condition, relieving acetoin catabolic genes from repression, and leading to better growth under blue light. This photoregulation depends on temperature, occurring at 23°C but not at 30°C. BlsA is thus a dual regulator, modulating different transcriptional regulators in the dark but also under blue light, representing thus a novel concept. The overall data show that quorum modulators as well as light regulate the acetoin catabolic cluster, providing a better understanding of environmental as well as clinical bacteria.

Peach Fruit Development: A Comparative Proteomic Study Between Endocarp and Mesocarp at Very Early Stages Underpins the Main Differential Biochemical Processes Between These Tissues.

Peach (Prunus persica) is an important economically temperate fruit. The development follows double sigmoid curve with four phases (S1-S4). We centered our work in the early development. In addition to S1, we studied the very early stage (E) characterized by the lag zone of the exponential growing phase S1, and the second stage (S2) when the pit starts hardening. "Dixiland" peach fruit were collected at 9 (E), 29 (S1), and 53 (S2) days after flowering (DAF) and endocarp and mesocarp were separated. There was a pronounced decrease in total protein content along development in both tissues. Quantitative proteomic allowed the identification of changes in protein profiles across development and revealed the main biochemical pathways sustaining tissue differentiation. Protein metabolism was the category most represented among differentially proteins in all tissues and stages. The decrease in protein synthesis machinery observed during development would be responsible of the protein fall, rather than a proteolytic process; and reduced protein synthesis during early development would reroute cell resources to lignin biosynthesis. These changes were accompanied by net decrease in total amino acids in E1-S1 and increase in S1-S2 transitions. Amino acid profiling, showed Asn parallels this trend. Concerted changes in Asn and in enzymes involved in its metabolism reveal that increased synthesis and decreased catabolism of Asn may conduct to an Asn increase during very early development and that the ß-Cyano-Alanine synthase/ß-Cyano-Alanine hydratase could be the pathway for Asn synthesis in "Dixiland" peach fruit. Additionally, photosynthetic machinery decays during early development in mesocarp and endocarp. Proteins related to photosynthesis are found to a higher extent in mesocarp than in endocarp. We conclude mesocarpic photosynthesis is possible to occur early on the development, first providing both carbon and reductive power and latter only reductive power. Together with proteomic, histological tests and anatomical analysis help to provide information about changes and differences in cells and cell-walls in both tissues. Collectively, this work represents the first approach in building protein databases during peach fruit development focusing on endocarp and mesocarp tissues and provides novel insights into the biology of peach fruit development preceding pit hardening.

Avaliação técnico-regulatória dos requisitos de qualidade para registro de medicamentos biológicos e biossimilares humanos: perspectivas e desafios no Brasil / Technical and regulatory evaluation of quality requirements for the registration of human biological and biosimilar drugs: perspectives and challenges in Brazil

Medicamentos biológicos são obtidos a partir de fluidos biológicos ou tecidos de origem animal por procedimentos biotecnológicos e, a partir do vencimento das suas patentes, surge a possibilidade da produção de suas cópias, os chamados biossimilares. Este tema, além de polêmico, por ainda apresentar divergências de entendimento da classe científica, também engloba 4 das 5 classes terapêuticas de medicamentos mais vendidas, e apresenta evolução crescente no mercado farmacêutico. Com o aumento da demanda, cresce o interesse na produção de medicamentos biológicos de alta qualidade, com a mesma eficácia, porém a preços mais baixos. Dessa forma, é possível entender a responsabilidade das regulamentações, principalmente no que diz respeito aos biossimilares, a fim de que eles respeitem os requisitos mínimos necessários para serem comparáveis ao seu medicamento biológico novo. Assim, este trabalho teve como objetivo avaliar questões técnico-regulatórias e os requisitos de qualidade para registro de medicamentos biológicos e biossimilares humanos frente a diferentes Autoridades Sanitárias mundiais. A análise foi baseada em três moléculas biológicas, sendo a clássica heparina e moléculas novas, filgrastim e infliximabe. Foi constatado que na teoria, a legislação brasileira é baseada em regulamentos internacionais, especialmente da Federal and Drug Administration (FDA) e European Medicines Agency (EMA), e que na prática, o Brasil tem se mostrado mais conservador na extrapolação de indicação e na aprovação dos biossimilares. Ainda, foi possível notar que independente do país, as Farmacopeias ainda necessitam de aprimoramento com relação a este tema, pois em sua maioria, não existe padronização dos parâmetros e testes a serem realizados. Pesquisa demonstrou que o conhecimento sobre biossimilares ainda não está consolidado entre profissionais médicos e que, portanto, há necessidade de programas para esclarecimentos, com a finalidade de estimular seu uso, quando possível e com custos mais interessantes

Biological drugs are obtained from biological fluids or animals tissues by biotechnological procedures and, from the expiration of their patents, the possibility of producing their "copies", the so-called biosimilars, arises. In addition to being a controversial subject, as it still presents divergences of understanding by the scientific class, it also encompasses 4 of the 5 therapeutic classes of best-selling drugs, and it presents an increasing evolution in the pharmaceutical market. As demand increases, interest in the production of high-quality biological drugs with the same effectiveness, but at lower prices, also increases. In this way, it is possible to understand the responsibility of regulations, especially with regard to biosimilars, so that they comply with the minimum requirements needed to be comparable to their reference biological medicine. Thus, the objective of this project was to evaluate technical and regulatory topics, as well as quality requirements for the registration of human biological and biosimilar medicines under the perspective of different Health Authorities around the world. The analysis was based on three biological molecules, being the classic heparin and new molecules, filgrastim and infliximab. It was found that in theory, Brazilian regulation is based on international regulations, especially the Federal and Drug Administration (FDA) and the European Medicines Agency (EMA), and that in practice, Brazil has been more conservative in the extrapolation of indication and approval of biosimilars. Also, it was possible to note that, regardless the country, Pharmacopoeias still need to be improved for this topic, since in general, there is no standardization of the parameters and tests to be performed. Research showed that the knowledge about biosimilars is not yet consolidated among doctors and that, therefore, there is a need for clarification programs, with the purpose of stimulating their use, when possible and at lower costs