Promoting advanced medical services in the framework of 3PM-a proof-of-concept by the "Centro" Region of Portugal.

Multidisciplinary team from three universities based in the "Centro" Region of Portugal developed diverse approaches as parts of a project dedicated to enhancing and expanding Predictive, Preventive, and Personalized Medicine (3PM) in the Region. In a sense, outcomes acted as a proof-of-concept, in that they demonstrated the feasibility, but also the relevance of the approaches. The accomplishments comprise defining a new regional strategy for implementing 3PM within the Region, training of human resources in genomic sequencing, and generating good practices handbooks dedicated to diagnostic testing via next-generation sequencing, to legal and ethical concerns, and to knowledge transfer and entrepreneurship, aimed at increasing literacy on 3PM approaches. Further approaches also included support for entrepreneurship development and start-ups, and diverse and relevant initiatives aimed at increasing literacy relevant to 3PM. Efforts to enhance literacy encompassed citizens across the board, from patients and high school students to health professionals and health students. This focus on empowerment through literacy involved a variety of initiatives, including the creation of an illustrated book on genomics and the production of two theater plays centered on genetics. Additionally, authors stressed that genomic tools are relevant, but they are not the only resources 3PM is based on. Thus, they defend that other initiatives intended to enable citizens to take 3PM should include multi-omics and, having in mind the socio-economic burden of chronic diseases, suboptimal health status approaches in the 3PM framework should also be considered, in order to anticipate medical intervention in the subclinical phase. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-024-00353-9.

miRNAs in Heart Development and Disease.

Cardiovascular diseases (CVD) are a group of disorders that affect the heart and blood vessels. They include conditions such as myocardial infarction, coronary artery disease, heart failure, arrhythmia, and congenital heart defects. CVDs are the leading cause of death worldwide. Therefore, new medical interventions that aim to prevent, treat, or manage CVDs are of prime importance. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the posttranscriptional level and play important roles in various biological processes, including cardiac development, function, and disease. Moreover, miRNAs can also act as biomarkers and therapeutic targets. In order to identify and characterize miRNAs and their target genes, scientists take advantage of computational tools such as bioinformatic algorithms, which can also assist in analyzing miRNA expression profiles, functions, and interactions in different cardiac conditions. Indeed, the combination of miRNA research and bioinformatic algorithms has opened new avenues for understanding and treating CVDs. In this review, we summarize the current knowledge on the roles of miRNAs in cardiac development and CVDs, discuss the challenges and opportunities, and provide some examples of recent bioinformatics for miRNA research in cardiovascular biology and medicine.

Daphnia magna Multigeneration Exposure to Carbendazim: Gene Transcription Responses.

The world population is experiencing colossal growth and thus demand for food, leading to an increase in the use of pesticides. Persistent pesticide contamination, such as carbendazim, remains a pressing environmental concern, with potentially long-term impacts on aquatic ecosystems. In the present study, Daphnia magna was exposed to carbendazim (5 µg L-1) for 12 generations, with the aim of assessing gene transcription alterations induced by carbendazim (using a D. magna custom microarray). The results showed that carbendazim caused changes in genes involved in the response to stress, DNA replication/repair, neurotransmission, ATP production, and lipid and carbohydrate metabolism at concentrations already found in the environment. These outcomes support the results of previous studies, in which carbendazim induced genotoxic effects and reproduction impairment (increasing the number of aborted eggs with the decreasing number of neonates produced). The exposure of daphnids to carbendazim did not cause a stable change in gene transcription between generations, with more genes being differentially expressed in the F0 generation than in the F12 generation. This could show some possible daphnid acclimation after 12 generations and is aligned with previous multigenerational studies where few ecotoxicological effects at the individual and populational levels and other subcellular level effects (e.g., biochemical biomarkers) were found.

Myocardial RNA Sequencing Reveals New Potential Therapeutic Targets in Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) represents a global health challenge, with limited therapies proven to enhance patient outcomes. This makes the elucidation of disease mechanisms and the identification of novel potential therapeutic targets a priority. Here, we performed RNA sequencing on ventricular myocardial biopsies from patients with HFpEF, prospecting to discover distinctive transcriptomic signatures. A total of 306 differentially expressed mRNAs (DEG) and 152 differentially expressed microRNAs (DEM) were identified and enriched in several biological processes involved in HF. Moreover, by integrating mRNA and microRNA expression data, we identified five potentially novel miRNA-mRNA relationships in HFpEF: the upregulated hsa-miR-25-3p, hsa-miR-26a-5p, and has-miR4429, targeting HAPLN1; and NPPB mRNA, targeted by hsa-miR-26a-5p and miR-140-3p. Exploring the predicted miRNA-mRNA interactions experimentally, we demonstrated that overexpression of the distinct miRNAs leads to the downregulation of their target genes. Interestingly, we also observed that microRNA signatures display a higher discriminative power to distinguish HFpEF sub-groups over mRNA signatures. Our results offer new mechanistic clues, which can potentially translate into new HFpEF therapies.

Biodiversity is overlooked in the diets of different social groups in Brazil.

Food biodiversity is essential for improving nutrition and reducing hunger in populations worldwide. However, in middle and low-income countries, the biodiversity of food production does not necessarily represent food consumption patterns by population. We used Brazil, one of the world's megabiodiverse countries, as a case study to investigate the following questions: what is the prevalence of consumption of biodiverse foods in Brazil, and what are the socioeconomic factors that influence their consumption throughout the country? We used data from a Brazilian representative national dietary survey to estimate the frequency of food consumption of unconventional food plants, edible mushrooms, and wild meat, in according to socioeconomic variables. Thus, we investigated the socioeconomic predictors of Unconventional Food Plants consumption using methods of Machine Learning (ML) and multiple zero-inflated Poisson (ZIP) regression. We showed that biodiverse food consumption in Brazil is low, just related by 1.3% of the population, varying in according to area, ethnicity, age, food insecurity, sex, and educational level. Our findings of low utilization of biodiversity suggest an important mismatch between the rich biodiversity of the country and its representation in the human diet.

Occurrence of Apicomplexa protozoa in wild birds in the Northeast region of Brazil.

Protozoa of the Apicomplexa phylum are worldwide distributed with capacity to infect endothermic animals. The study of these protozoa in wild birds in Brazil is scarce. This study aimed to evaluate the occurrence of apicomplexan protozoa in wild birds in the Northeast of Brazil. From October to December 2019, brain tissue samples were collected from 71 captive birds from the Wild Animal Screening Center of the Pernambuco State (CETRAS-Tangara) and 25 free-living birds from the Caatinga biome in Rio Grande do Norte, totaling 96 animals (41 species). Brain fragments were subjected to molecular diagnosis by nested PCR for the 18s rDNA gene of Apicomplexa parasites, followed by DNA sequencing. This gene was detected in 25% (24/96) of the samples, and it was possible to perform DNA sequencing of 14 samples, confirming three genera: Isospora, Sarcocystis and Toxoplasma from eight bird species (Amazona aestiva, Coereba flaveola, Egretta thula, Paroaria dominicana, Sporophila nigricollis, Cariama cristata, Columbina talpacoti, Crypturellus parvirostris). The occurrence these coccidia in wild birds provides important epidemiological information for the adoption of preventive measures for its conservation. Future studies are needed to better understand the consequence of Apicomplexa infection in birds in Caatinga and Atlantic Forest biomes.

Milk and Dairy Consumption and Its Relationship With Abundance of Lactobacillus crispatus in the Vaginal Microbiota: Milk Intake and Vaginal Lactobacillus.

OBJECTIVES: Diet habits, such as low milk and dairy intake, have been associated with bacterial vaginosis. Thus, the authors compared vaginal Lactobacillus crispatus abundances in women with different molecularly defined community state types (CSTs) according to the consumption of milk and/or dairy products. METHODS: A total of 516 women from the 5 geographic regions of Brazil were included. Participants were interviewed with a structured questionnaire for assessment of milk and/or dairy intake. Vaginal samples were used for sequencing of V3-V4 regions of the 16S ribosomal RNA gene for further determination of L. crispatus relative abundance (RA) and clustering into 1 of the 5 CSTs (CSTI-CSTV), as firstly described by Ravel et al. (2011). The nonparametric Mann-Whitney test was used to compare L. crispatus RA within the most representative CSTs ( L. crispatus -dominant CSTI, Lactobacillus iners -dominant CSTIII, and Lactobacillus -depleted CSTIV) in this population, according to the frequency of milk and/or dairy intake. RESULTS: The prevalence of CSTI was 33.3% ( n = 172), CSTIII was 39% ( n = 201), and CSTIV was 27.7% ( n = 143). Among the participants with CSTIII, higher L. crispatus RA was observed for those who reported milk/dairy intake (median = 0.02; interquartile range = 0.01-0.09) than those with no consumption (median = 0.01; interquartile range = 0-0.03) ( p = .03). Such difference was not observed for participants with CSTI and CSTIV. CONCLUSIONS: Women with vaginal microbiota dominated by L. iners who consume milk and/or dairy present increased abundances of L. crispatus . Therefore, they could benefit from L. crispatus protective properties conferring greater temporal microbiota stability and, consequently, increased protection against infections.

The influence of the low-frequency transcutaneous electrical nerve stimulation application moment in vocal quality of dysphonic women.

Objective: to compare the immediate effects of low-frequency TENS employment on vocal quality in women with behavioral dysphonia before and after vocal exercises.Methodology: 30 women (mean = 31.3 years old), diagnosed with behavioral dysphonia received low-frequency TENS before (TENS + VE Group) and after vocal exercises (VE + TENS Group) with a 1-week washout. They had their sustained vowel/a/and running speech recorded before and after each procedure for auditory-perceptual analysis and acoustic measures. The low-frequency TENS parameters applied were symmetrical biphasic quadratic pulse, 200 µs phase, 10 Hz frequency, intensity on the motor threshold, and the electrodes were positioned on the submandibular and superior fibers of the trapezius muscle region. The vocal exercises: tongue trill, humming, finger kazoo, and water resistance therapy were performed totalizing 20 min.Results: intragroup analysis of sustained vowel/a/showed reduction in both groups of strain parameter and increased the breathiness; only VE + TENS Group increased the instability parameter, decreased fundamental frequency, and increased in SPI values; the running speech analysis showed an increase in the overall degree, roughness, and breathiness parameters. However, in VE + TENS Group, there was a statistically significant decrease in the intensity of the strain and an increase in breathiness. The acoustic measures showed that VE + TENS Group had a higher variation than TENS + VE Group regarding NHR.Conclusion: vocal exercises followed by low-frequency TENS have more immediate positive effects on voice quality than the low-frequency TENS followed by vocal exercises. This is a preliminary immediate effects study, and these effects could be verified through long-term assessments.

Improving biological removal of pharmaceutical active compounds and estrogenic activity in a mesophilic anaerobic osmotic membrane bioreactor treating municipal sewage.

The contamination of water sources by pharmaceutically active compounds (PhACs) and their effect on aquatic communities and human health have become an environmental concern worldwide. Membrane bioreactors (MBRs) are an alternative to improve biological removal of recalcitrant organic compounds from municipal sewage. Their efficiency can be increased by using high retention membranes such as forward osmosis (FO) and membrane distillation (MD). Thus, this research aimed to evaluate the performance of an anaerobic osmotic MBR coupled with MD (OMBR-MD) in the treatment of municipal sewage containing PhACs and estrogenic activity. A submerged hybrid FO-MD module was integrated into the bioreactor. PhACs removal was higher than 96% due to biological degradation, biosorption and membrane retention. Biological removal of the PhACs was affected by the salinity build-up in the bioreactor, with reduction in biodegradation after 32 d. However, salinity increment had little or no effect on biosorption removal. The anaerobic OMBR-MD removed >99.9% of estrogenic activity, resulting in a distillate with 0.14 ng L-1 E2-eq, after 22 d, and 0.04 ng L-1 E2-eq, after 32 d. OMBR-MD treatment promoted reduction in environmental and human health risks from high to low, except for ketoprofen, which led to medium acute environmental and human health risks. Carcinogenic risks were reduced from unacceptable to negligible, regarding estrogenic activity. Thus, the hybrid anaerobic OMBR-MD demonstrated strong performance in reducing risks, even when human health is considered.

The Role of MicroRNAs in Proteostasis Decline and Protein Aggregation during Brain and Skeletal Muscle Aging.

Aging can be defined as the progressive deterioration of cellular, tissue, and organismal function over time. Alterations in protein homeostasis, also known as proteostasis, are a hallmark of aging that lead to proteome imbalances and protein aggregation, phenomena that also occur in age-related diseases. Among the various proteostasis regulators, microRNAs (miRNAs) have been reported to play important roles in the post-transcriptional control of genes involved in maintaining proteostasis during the lifespan in several organismal tissues. In this review, we consolidate recently published reports that demonstrate how miRNAs regulate fundamental proteostasis-related processes relevant to tissue aging, with emphasis on the two most studied tissues, brain tissue and skeletal muscle. We also explore an emerging perspective on the role of miRNA regulatory networks in age-related protein aggregation, a known hallmark of aging and age-related diseases, to elucidate potential miRNA candidates for anti-aging diagnostic and therapeutic targets.

Evaluation of the genetic risk for COVID-19 outcomes in COPD and differences among worldwide populations.

BACKGROUND: Populations seem to respond differently to the global pandemic of severe acute respiratory syndrome coronavirus 2. Recent studies show individual variability in both susceptibility and clinical response to COVID-19 infection. People with chronic obstructive pulmonary disease (COPD) constitute one of COVID-19 risk groups, being already associated with a poor prognosis upon infection. This study aims contributing to unveil the underlying reasons for such prognosis in people with COPD and the variability in the response observed across worldwide populations, by looking at the genetic background as a possible answer to COVID-19 infection response heterogeneity. METHODS: SNPs already associated with susceptibility to COVID-19 infection (rs286914 and rs12329760) and severe COVID-19 with respiratory failure (rs657152 and rs11385942) were assessed and their allelic frequencies used to calculate the probability of having multiple risk alleles. This was performed on a Portuguese case-control COPD cohort, previously clinically characterized and genotyped from saliva samples, and also on worldwide populations (European, Spanish, Italian, African, American and Asian), using publicly available frequencies data. A polygenic risk analysis was also conducted on the Portuguese COPD cohort for the two mentioned phenotypes, and also for hospitalization and survival to COVID-19 infection. FINDINGS: No differences in genetic risk for COVID-19 susceptibility, hospitalization, severity or survival were found between people with COPD and the control group (all p-values > 0.01), either considering risk alleles individually, allelic combinations or polygenic risk scores. All populations, even those with European ancestry (Portuguese, Spanish and Italian), showed significant differences from the European population in genetic risk for both COVID-19 susceptibility and severity (all p-values < 0.0001). CONCLUSION: Our results indicate a low genetic contribution for COVID-19 infection predisposition or worse outcomes observed in people with COPD. Also, our study unveiled a high genetic heterogeneity across major world populations for the same alleles, even within European sub-populations, demonstrating the need to build a higher resolution European genetic map, so that differences in the distribution of relevant alleles can be easily accessed and used to better manage diseases, ultimately, safeguarding populations with higher genetic predisposition to such diseases.

Sistema de informações sobre nascidos vivos: qualidade e perfil de nascimentos no extremo sul baiano / Information system on live births: quality and profile of births in Southern Bahia / Sistema de informaciones sobre nascidos vivos: cualidad y perfil de nacimientos en el extremo sur de Bahía

A alimentação adequada e a confiabilidade das informações do Sistema de Informações sobre Nascidos Vivos (Sinasc) têm importância decisiva para análise da saúde materno-infantil. Este estudo avaliou a cobertura e completude das informações do Sinasc e o perfil de nascimentos de grupos populacionais em uma região da Bahia, em 2002-2007-2012-2017. A cobertura foi calculada pela razão entre nascidos vivos informados e estimados; a completude dos dados e perfil foram analisados avaliando as características maternas, gestação, parto e recém-nascido. As coberturas variaram entre 28% e 100%, com menores valores para o grupo de municípios de menor porte. Na região, houve crescimento de 23% na cobertura do Sinasc entre 2002 e 2012 e de 17,4% entre 2002 e 2017. Todos os municípios alcançaram coberturas superiores a 60% nos dois últimos anos. Em 2002, variáveis importantes como raça/cor, escolaridade e teste Apgar 5o minuto registraram completude de preenchimento de ruim a regular. O perfil predominante é de mães jovens (20-29 anos), da raça/cor negra, baixa escolaridade, com acesso a sete ou mais consultas de pré-natal, gestações a termo e partos vaginais. Os grupos de Robson mais frequentes foram o G3/G1/G5, considerados baixo risco para cesáreas. As maiores proporções de baixo peso ao nascer foram para o grupo de maior porte e a presença de anomalias congênitas não ultrapassou 1%. O estudo destaca razoável incremento na qualidade das informações do Sinasc, elevação no nível de escolaridade materna, adolescentes contribuindo com 20%-37% dos nascimentos, ampliação no número de consultas de pré-natal e aumento da frequência de cesarianas e nascimentos prematuros.

Adequate input and reliability of information from the Information System on Live Births (Sinasc) is key for analysis of maternal and child health. This study evaluated the coverage and completeness of Sinasc information and the birth profile of populational groups in southern Bahia, in 2002, 2007, 2012 and 2017. Coverage was calculated by the ration between reported and estimated live births. Data completeness and profile were analyzed by assessing the maternal, pregnancy, birth, and newborn characteristics. Coverage ranged from 28% to 100%, with lower values for smaller municipalities. The region saw a 23% increase in Sinasc coverage between 2002 and 2012, and 17.4% between 2002 and 2017. All municipalities reached coverages greater than 60% in the last two years. In 2002, important variables such as race/color, schooling level and 5th minute Apgar score registered poor to regular completeness. The predominant profile is of young black mothers (20-29 years old) with low schooling level, access to seven or more pre-natal visits, full-term pregnancies, and vaginal births. The most frequent Robson groups were G3, G1 and G5, considered low risk for caesarian sections. Low birth weight was highest in the larger group, and the presence of congenital anomalies did not exceed 1%. The study highlights a reasonable increase in the quality of Sinasc information, an increase in maternal schooling, adolescents contributing to 20%-37% of births, an increase in pre-natal consultations, and an increase in caesarian sections and premature births.

La alimentación adecuada y la confiabilidad de informaciones del Sistema de Informaciones sobre Nacidos Vivos (Sinasc) son claves para el análisis de salud materno-infantil. Este estudio evaluó la cobertura y totalidad de las informaciones en el Sinasc y el perfil de nacimientos de grupos poblacionales de una región de Bahía (Brasil), en 2002-2007, y 2012 y 2017. La cobertura se calculó con la razón entre nacidos vivos informados y estimados; la totalidad de los datos y perfil se analizaron con base en las características maternas, gestación, parto y recién nacido. Las coberturas variaran del 28% al 100%, con menores números para el grupo de municipios menores. Hubo incremento del 23% en la cobertura del Sinasc entre 2002 y 2012, y del 17,4% entre 2002 y 2017. Todos los municipios alcanzaran coberturas superiores al 60% en los últimos dos años. En 2002, variables importantes, como raza/color, nivel de estudios y Apgar 5o minuto, registraran una totalidad de información de mala a regular. El perfil predominante es de madres jóvenes (20-29 años), raza/color negro, bajo nivel de estudios, con acceso a siete o más consultas prenatales, gestaciones a término y partos vaginales. Los grupos de Robson más frecuentes fueran G3, G1, G5, considerados de bajo riesgo para cesáreas. Las mayores proporciones de bajo peso al nacer fueron del grupo de municipios más grandes y la presencia de anomalías congénitas no ultrapasó el 1%. El estudio destaca un razonable aumento en la cualidad de informaciones en Sinasc, aumento del nivel de estudios de la madre, adolescentes contribuyendo con el 20%-37% de los nacimientos, ampliación de consultas prenatales y de la frecuencia de cesarianas y nacimientos prematuros.

Redox Imbalance and Methylation Disturbances in Early Childhood Obesity.

Obesity is increasing worldwide in prepubertal children, reducing the age of onset of associated comorbidities, including type 2 diabetes. Sulfur-containing amino acids, methionine, cysteine, and their derivatives play important roles in the transmethylation and transsulfuration pathways. Dysregulation of these pathways leads to alterations in the cellular methylation patterns and an imbalanced redox state. Therefore, we tested the hypothesis that one-carbon metabolism is already dysregulated in prepubertal children with obesity. Peripheral blood was collected from 64 children, and the plasma metabolites from transmethylation and transsulfuration pathways were quantified by HPLC. The cohort was stratified by BMI z-scores and HOMA-IR indices into healthy lean (HL), healthy obese (HO), and unhealthy obese (UHO). Fasting insulin levels were higher in the HO group compared to the HL, while the UHO had the highest. All groups presented normal fasting glycemia. Furthermore, high-density lipoprotein (HDL) was lower while triglycerides and lactate levels were higher in the UHO compared to HO subjects. S-adenosylhomocysteine (SAH) and total homocysteine levels were increased in the HO group compared to HL. Additionally, glutathione metabolism was also altered. Free cystine and oxidized glutathione (GSSG) were increased in the HO as compared to HL subjects. Importantly, the adipocyte secretory function was already compromised at this young age. Elevated circulating leptin and decreased adiponectin levels were observed in the UHO as compared to the HO subjects. Some of these alterations were concomitant with alterations in the DNA methylation patterns in the obese group, independent of the impaired insulin levels. In conclusion, our study informs on novel and important metabolic alterations in the transmethylation and the transsulfuration pathways in the early stages of obesity. Moreover, the altered secretory function of the adipocyte very early in life may be relevant in identifying early metabolic markers of disease that may inform on the increased risk for specific future comorbidities in this population.

Integration of segmented regression analysis with weighted gene correlation network analysis identifies genes whose expression is remodeled throughout physiological aging in mouse tissues.

Gene expression alterations occurring with aging have been described for a multitude of species, organs, and cell types. However, most of the underlying studies rely on static comparisons of mean gene expression levels between age groups and do not account for the dynamics of gene expression throughout the lifespan. These studies also tend to disregard the pairwise relationships between gene expression profiles, which may underlie commonly altered pathways and regulatory mechanisms with age. To overcome these limitations, we have combined segmented regression analysis with weighted gene correlation network analysis (WGCNA) to identify high-confidence signatures of aging in the brain, heart, liver, skeletal muscle, and pancreas of C57BL/6 mice in a publicly available RNA-Seq dataset (GSE132040). Functional enrichment analysis of the overlap of genes identified in both approaches showed that immune- and inflammation-related responses are prominently altered in the brain and the liver, while in the heart and the muscle, aging affects amino and fatty acid metabolism, and tissue regeneration, respectively, which reflects an age-related global loss of tissue function. We also explored sexual dimorphism in the aging mouse transcriptome and found the liver and the muscle to have the most pronounced gender differences in gene expression throughout the lifespan, particularly in proteostasis-related pathways. While the data showed little overlap among the age-dysregulated genes between tissues, aging triggered common biological processes in distinct tissues, which we highlight as important features of murine tissue physiological aging.

Protein Aggregation Patterns Inform about Breast Cancer Response to Antiestrogens and Reveal the RNA Ligase RTCB as Mediator of Acquired Tamoxifen Resistance.

The protein quality control network, including autophagy, the proteasome and the unfolded protein response (UPR), is triggered by stress and is overactive in acquired antiestrogen therapy resistance. We show for the first time that the aggresome load correlates with apoptosis and is increased in antiestrogen-sensitive cells compared to endocrine-resistant variants. LC-MS/MS analysis of the aggregated proteins obtained after 4OH-tamoxifen and Fulvestrant treatment identified proteins with essential function in protein quality control in antiestrogen-sensitive cells, but not in resistant variants. These include the UPR modulators RTCB and PDIA6, as well as many proteasome proteins such as PSMC2 and PSMD11. RTCB is a tRNA and XBP1 ligase and its aggregation induced by antiestrogens correlated with impaired XBP1s expression in sensitive cells. Knock down of RTCB was sufficient to restore sensitivity to tamoxifen in endocrine-resistant cells and increased the formation of aggresomes, leading to apoptotic cell death. Analysis of primary human breast cancer samples and their metastases appearing after endocrine treatment showed that RTCB is only localized to aggresomes in the primary tumors, while total aggresomes, including aggregated RTCB, were significantly reduced in the metastases. Therefore, different protein aggregation patterns may indicate loss of function of essential proteins resulting in enhanced protein aggregation that can be used to identify antiestrogen-resistant breast cancer cells and improve the response to antiestrogenic therapy.

Pens versus syringes to deliver insulin among elderly patients with type 2 diabetes: a randomized controlled clinical trial.

BACKGROUND: Diabetes mellitus (DM) is a prevalent disease among elderly population. As the disease progresses, insulin may become necessary. The use of pens application seems to be more practical. However, the influence of this method on glycemic control needs to be defined in elderly people. METHODS: Randomized clinical trial comparing pens and syringes for insulin application among patients with type 2 DM over 60 years old and Glycated Hemoglobin > 8.5% at baseline. The follow-up was 24 weeks, with monthly medical visits to adjust the treatment. All patients received insulin NPH and, if necessary, insulin Regular. We assessed glycemic control, adherence to treatment, hypoglycemia occurrence, need for adjustment in treatment and impact on quality of life, RESULTS: We included 121 patients with mean age of 65.75 years. Sixty-one were randomized for pen group (PG) and 60 patients for syringe group (SG). At baseline, mean HbA1c was 10.34 ± 1.66% and 9.90 ± 1.25% (p = 0.103) in PG and SG respectively. Mean HbA1c was 8.39 ± 1.28% in PG and 8.85 ± 1.74% in SG (p = 0.101) at 24 weeks. However, there was a more significant reduction in PG (- 1.94 ± 1.93% in PG and - 1.04 ± 1.46% in SG, p < 0.05) during follow-up. We found no difference in treatment adherence rates, hypoglycemia, greater need for insulin doses or oral medication, and progression to basal-bolus insulin scheme. We also found no difference in the impact of the disease on quality of life between groups. CONCLUSION: Although we did not find any difference in the impact on quality of life, frequency of hypoglycemia or adherence, the PG showed a reduction in HbA1c higher in 24 weeks of follow-up. CLINICAL TRIAL REGISTRATION: NCT02517242.

The role of non-standard translation in Candida albicans pathogenesis.

Candida albicans typically resides in the human gastrointestinal tract and mucosal membranes as a commensal organism. To adapt and cope with the host immune system, it has evolved a variety of mechanisms of adaptation such as stress-induced mutagenesis and epigenetic regulation. Niche-specific patterns of gene expression also allow the fungus to fine-tune its response to specific microenvironments in the host and switch from harmless commensal to invasive pathogen. Proteome plasticity produced by CUG ambiguity, on the other hand is emerging as a new layer of complexity in C. albicans adaptation, pathogenesis, and drug resistance. Such proteome plasticity is the result of a genetic code alteration where the leucine CUG codon is translated mainly as serine (97%), but maintains some level of leucine (3%) assignment. In this review, we dissect the link between C. albicans non-standard CUG translation, proteome plasticity, host adaptation and pathogenesis. We discuss published work showing how this pathogen uses the fidelity of protein synthesis to spawn novel virulence traits.

tRNAs as a Driving Force of Genome Evolution in Yeast.

Transfer RNAs (tRNAs) are widely known for their roles in the decoding of the linear mRNA information into amino acid sequences of proteins. They are also multifunctional platforms in the translation process and have other roles beyond translation, including sensing amino acid abundance, interacting with the general stress response machinery, and modulating cellular adaptation, survival, and death. In this mini-review, we focus on the emerging role of tRNA genes in the organization and modification of the genomic architecture of yeast and the role of tRNA misexpression and decoding infidelity in genome stability, evolution, and adaption. We discuss published work showing how quickly tRNA genes can mutate to meet novel translational demands, how tRNAs speed up genome evolution, and how tRNA genes can be sites of genomic instability. We highlight recent works showing that loss of tRNA decoding fidelity and small alterations in tRNA expression have unexpected and profound impacts on genome stability. By dissecting these recent evidence, we hope to lay the groundwork that prompts future investigations on the mechanistic interplay between tRNAs and genome modification that likely triggers genome evolution.

tRNA-modifying enzyme mutations induce codon-specific mistranslation and protein aggregation in yeast.

Protein synthesis rate and accuracy are tightly controlled by the cell and are essential for proteome homoeostasis (proteostasis); however, the full picture of how mRNA translational factors maintain protein synthesis accuracy and co-translational protein folding are far from being fully understood. To address this question, we evaluated the role of 70 yeast tRNA-modifying enzyme genes on protein aggregation and used mass spectrometry to identify the aggregated proteins. We show that modification of uridine at anticodon position 34 (U34) by the tRNA-modifying enzymes Elp1, Elp3, Sml3 and Trm9 is critical for proteostasis, the mitochondrial tRNA-modifying enzyme Slm3 plays a fundamental role in general proteostasis and that stress response proteins whose genes are enriched in codons decoded by tRNAs lacking mcm5U34, mcm5s2U34, ncm5U34, ncm5Um34, modifications are overrepresented in protein aggregates of the ELP1, SLM3 and TRM9 KO strains. Increased rates of amino acid misincorporation were also detected in these strains at protein sites that specifically mapped to the codons sites that are decoded by the hypomodified tRNAs, demonstrating that U34 tRNA modifications safeguard the proteome from translational errors, protein misfolding and proteotoxic stress.