Bernardo Lemos

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• Grodstein, F., Lemos, B., Yang, J., de Paiva Lopes, K., Vialle, R. A., Seyfried, N., Wang, Y., Shireby, G., Hannon, E., Thomas, A., Brookes, K., Mill, J., De Jager, P. L., & Bennett, D. A. (2024). Genetic architecture of epigenetic cortical clock age in brain tissue from older individuals: alterations in and other loci. Epigenetics, 19(1), 2392050.
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  The cortical epigenetic clock was developed in brain tissue as a biomarker of brain aging. As one way to identify mechanisms underlying aging, we conducted a GWAS of cortical age. We leveraged postmortem cortex tissue and genotyping array data from 694 participants of the Rush Memory and Aging Project and Religious Orders Study (ROSMAP; 11000,000 SNPs), and meta-analysed ROSMAP with 522 participants of Brains for Dementia Research (5,000,000 overlapping SNPs). We confirmed results using eQTL (cortical bulk and single nucleus gene expression), cortical protein levels (ROSMAP), and phenome-wide association studies (clinical/neuropathologic phenotypes, ROSMAP). In the meta-analysis, the strongest association was rs4244620 ( = 1.29 × 10), which also exhibited FDR-significant cis-eQTL effects for in bulk and single nucleus (microglia, astrocyte, oligodendrocyte, neuron) cortical gene expression. Additionally, rs4244620 was nominally associated with lower cognition, faster slopes of cognitive decline, and greater Parkinsonian signs (n ~ 1700 ROSMAP with SNP/phenotypic data; all  ≤ 0.04). In ROSMAP alone, the top SNP was rs4721030 ( = 8.64 × 10) annotated to and . Further, in ROSMAP ( = 849), TMEM106B and THSD7A protein levels in cortex were related to many phenotypes, including greater AD pathology and lower cognition (all  ≤ 0.0007). Overall, we identified converging evidence of and possibly for potential roles in cortical epigenetic clock age.
• Lumour-Mensah, T., & Lemos, B. (2024). Defining high confidence targets of differential CpG methylation in response to in utero arsenic exposure and implications for cancer risk. Toxicology and applied pharmacology, 482, 116768.
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  Arsenic is a relatively abundant metalloid that impacts DNA methylation and has been implicated in various adverse health outcomes including several cancers and diabetes. However, uncertainty remains about the identity of genomic CpGs that are sensitive to arsenic exposure, in utero or otherwise. Here we identified a high confidence set of CpG sites whose methylation is sensitive to in utero arsenic exposure. To do so, we analyzed methylation of infant CpGs as a function of maternal urinary arsenic in cord blood and placenta from geographically and ancestrally distinct human populations. Independent analyses of these distinct populations were followed by combination of results across sexes and populations/tissue types. Following these analyses, we concluded that both sex and tissue type are important drivers of heterogeneity in methylation response at several CpGs. We also identified 17 high confidence CpGs that were hypermethylated across sex, tissue type and population; 11 of these were located within protein coding genes. This pattern is consistent with hypotheses that arsenic increases cancer risk by inducing the hypermethylation of genic regions. This study represents an opportunity to understand consistent, reproducible patterns of epigenomic responses after in utero arsenic exposure and may aid towards novel biomarkers or signatures of arsenic exposure. Identifying arsenic-responsive sites can also contribute to our understanding of the biological mechanisms by which arsenic exposure can affect biological function and increase risk of cancer and other age-related diseases.
• Lumour-Mensah, T., & Lemos, B. (2024). Evidence of reduced gestational age in response to in utero arsenic exposure and implications for aging trajectories of the newborn. Environment international, 185, 108566.
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  Arsenic exposure is associated with a plethora of age-related health outcomes of disparate etiology. However, evidence of the impact of arsenic on aging remains limited. Here, we investigated the utility of epigenetic clocks in two different populations and the impact of maternal arsenic exposure during pregnancy on epigenetic gestational age at birth. To do this, we examined publicly available DNA methylation data and estimated gestational age across five gestational clocks in two unrelated human populations. These populations also differ in the extent of arsenic exposure and the targeted tissue of analysis (cord blood and placental tissue). Our results indicate that same-tissue clocks produce gestational age estimates that are more highly correlated with clinical gestational age. Interestingly, our results also indicate that arsenic exposure is associated with gestational age, with higher arsenic exposures associated with decreased gestational age. We also applied two pediatric clocks to evaluate infant biological age in the same samples. The data is suggestive of higher pediatric age in infants exposed to higher arsenic levels during gestation. Taken altogether, our findings are consistent with past work indicating that that in utero arsenic exposure is associated with decreased gestational maturity as characterized by infant outcomes such as low birthweight and lung underdevelopment and dysfunction in arsenic exposed infants. The findings are also consistent with arsenic exposure setting infants on a trajectory of accelerated epigenetic aging that starts at birth.
• Panis, C., & Lemos, B. (2024). Pesticide exposure and increased breast cancer risk in women population studies. The Science of the total environment, 933, 172988.
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  Pesticide exposure is emerging as a risk factor for various human diseases. Breast cancer (BC) is a multifactorial disease with known genetic and non-genetic risk factors. Most BC cases are attibutable to non-genetic risk factors, with a history of adverse environmental exposures playing a significant role. Pesticide exposure can occur at higher levels in female populations participating in rural activities such as spraying of pesticides in the field, unprotected handling of pesticides at home, and washing of contaminated clothes. Exposure can also be significant in the drinking water of certain populations. Here, we reviewed the literature on women's exposure to pesticides and the risk of BC. We summarize the main links between pesticide exposure and BC and discuss the role of dose and exposure context, as well as potential mechanisms of toxicity. Overall, reports reviewed here have documented stronger associations between higher levels of exposure and BC risk, including documenting direct and acute pesticide exposure in certain female populations. However, discrepancies among studies regarding dose and mode of exposure may result in misunderstandings about the risks posed by pesticide exposure. Plausible mechanisms linking pesticides to breast cancer risk include their impacts as endocrine disruptors, as well as their roles as genotoxic agents, and modulators of the epigenome. Besides establishing links between pesticide exposure and breast cancer, the literature also highlights the critical need to understand the routes and doses of women's exposure to pesticides and the specific associations and mechanisms that are determinants of disease etiology and prognosis.
• Panis, C., Candiotto, L. Z., Gaboardi, S. C., Teixeira, G. T., Alves, F. M., da Silva, J. C., Scandolara, T. B., Rech, D., Gurzenda, S., Ponmattam, J., Ohm, J., Castro, M. C., & Lemos, B. (2024). Exposure to Pesticides and Breast Cancer in an Agricultural Region in Brazil. Environmental science & technology, 58(24), 10470-10481.
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  Rural workers are disproportionally exposed to pesticides and might be at an increased risk of developing chronic diseases. Here, we investigated the impact of pesticide exposure on breast cancer (BC) risk and disease profile in rural female workers. This is a case-control study that prospectively included 758 individuals. The study was conducted in the Southwest region of Paraná state in Brazil, a region characterized by family-based agriculture and intensive use of pesticides. We found that this region has a 41% higher BC diagnosis rate and 14% higher BC mortality rate than the mean rates in Brazil, as well as a pesticide trade volume about 6 times higher than the national average. We showed substantial exposure in this population and found that even women who did not work in the fields but performed equipment decontamination and clothes washing of male partners who worked in the fields had urine samples positive for glyphosate, atrazine, and/or 2,4-D. The crude association showed a significantly higher risk of BC among women exposed to pesticides (OR: 1.58, 95% CI 1.18-2.13). Adjusted analyses showed a lower and nonstatistically significant association (OR: 1.30, 95% CI 41 0.87-1.95). Stratification on disease profile showed a significantly higher risk of lymph node metastasis (adjusted OR: 2.19, 95% CI 1.31-3.72) in women exposed to pesticides. Our findings suggest that female populations exposed to pesticides are at a higher risk of developing BC with a more aggressive profile and draw attention to the need to monitor rural populations potentially exposed to pesticides in the field or at home.
• Tindula, G., Mukherjee, S. K., Ekramullah, S. M., Arman, D. M., Islam, J., Biswas, S. K., Warf, B. C., Christiani, D. C., Lemos, B., Liang, L., Cardenas, A., & Mazumdar, M. (2024). Parental arsenic exposure and tissue-specific DNA methylation in Bangladeshi infants with spina bifida. Epigenetics, 19(1), 2416345.
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  An emerging hypothesis linking arsenic toxicity involves altered epigenetic mechanisms, such as DNA methylation. In this study, we examined the relationship between parents' arsenic exposure and DNA methylation in tissues obtained from 28 infants with spina bifida from Bangladesh. We analyzed arsenic in parents' toenails using inductively coupled plasma mass spectrometry (ICP-MS). DNA methylation was measured in infants' dural tissue, buccal swabs, and whole blood using the Illumina Infinium MethylationEPIC BeadChip. We performed epigenome-wide association analyses (EWAS) and tested differentially methylated regions (DMRs). In EWAS, DNA methylation at cg24039697 in dural tissue was positively associated (β = 0.59,  = 7.6 × 10) with father's toenail arsenic concentrations, adjusting for covariates. We did not identify any CpG sites related to father's arsenic exposure in the other tissues, or any CpG sites related to mother's arsenic exposure. Gene ontology analysis identified many biological pathways of interest, including the Wnt signaling pathways. We identified several DMRs across the tissues related to arsenic exposure that included probes mapping to genes that have previously been identified in studies of neural tube defects. This study emphasizes the potential impact of arsenic exposure in fathers, often understudied in epidemiological studies, on DNA methylation in a unique neurological tissue specific to spina bifida.
• Layh, S., Nagarajan-Radha, V., Lemos, B., & Dowling, D. K. (2023). Y chromosome-linked variation affects locomotor activity in male Drosophila melanogaster and is robust to differences in thermal environment. Heredity, 130(5), 312-319.
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  Although containing genes important for sex determination, genetic variation within the Y chromosome was traditionally predicted to contribute little to the expression of sexually dimorphic traits. This prediction was shaped by the assumption that the chromosome harbours few protein-coding genes, and that capacity for Y-linked variation to shape adaptation would be hindered by the chromosome's lack of recombination and holandric inheritance. Consequently, most studies exploring the genotypic contributions to sexually dimorphic traits have focused on the autosomes and X chromosome. Yet, several studies have now demonstrated that the Y chromosome harbours variation affecting male fitness, moderating the expression of hundreds of genes across the nuclear genome. Furthermore, emerging results have shown that expression of this Y-linked variation may be sensitive to environmental heterogeneity, leading to the prediction that Y-mediated gene-by-environment interactions will shape the expression of sexually dimorphic phenotypes. We tested this prediction, investigating whether genetic variation across six distinct Y chromosome haplotypes affects the expression of locomotor activity, at each of two temperatures (20 and 28 °C) in male fruit flies (Drosophila melanogaster). Locomotor activity is a sexually dimorphic trait in this species, previously demonstrated to be under intralocus sexual conflict. We demonstrate Y haplotype effects on male locomotor activity, but the rank order and magnitude of these effects were unaltered by differences in temperature. Our study contributes to a growing number of studies demonstrating Y-linked effects moderating expression of traits evolving under sexually antagonistic selection, suggesting a role for the Y chromosome in shaping outcomes of sexual conflict.
• Zhao, T., Sun, D., Long, K., Lemos, B., Zhang, Q., Man, J., Zhao, M., & Zhang, Z. (2023). N-methyladenosine upregulates ribosome biogenesis in environmental carcinogenesis. The Science of the total environment, 881, 163428.
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  Many trace metal pollutants in surface water, the atmosphere, and soil are carcinogenic, and ribosome biogenesis plays an important role in the carcinogenicity of heavy metals. However, the contradiction between upregulated ribosome biogenesis and decreased ribosomal DNA copy number in environmental carcinogenesis is not fully understood. Here, from a perspective of the most predominant and abundant RNA epigenetic modification, N-methyladenosine (mA), we explored the reason behind this contradiction at the post-transcriptional level using arsenite-induced skin carcinogenesis models both in vitro and in vivo. Based on the mA microarray assay and a series of experiments, we found for the first time that the elevated mA in arsenite-induced transformation is mainly enriched in the genes regulating ribosome biogenesis. mA upregulates ribosome biogenesis post-transcriptionally by stabilizing ribosomal proteins and modulating non-coding RNAs targeting ribosomal RNAs and proteins, leading to arsenite-induced skin carcinogenesis. Using multi-omics analysis of human subjects and experimental validation, we identified an unconventional role of a well-known key proliferative signaling node AKT1 as a vital mediator between mA and ribosome biogenesis in arsenic carcinogenesis. mA activates AKT1 and transmits proliferative signals to ribosome biogenesis, exacerbating the upregulation of ribosome biogenesis in arsenite-transformed keratinocytes. Similarly, mA promotes cell proliferation by upregulating ribosome biogenesis in cell transformation induced by carcinogenic heavy metals (chromium and nickel). Importantly, inhibiting mA reduces ribosome biogenesis. Targeted inhibition of mA-upregulated ribosome biogenesis effectively prevents cell transformation induced by trace metals (arsenic, chromium, and nickel). Our results reveal the mechanism of ribosome biogenesis upregulated by mA in the carcinogenesis of trace metal pollutants. From the perspective of RNA epigenetics, our study improves our understanding of the contradiction between upregulated ribosome biogenesis and decreased ribosomal DNA copy number in the carcinogenesis of environmental carcinogens.
• Lemos, B. L., Bortolin, V. A., Amaral, R. L., Mazzetto, M., Cestari, I. A., & Meneghini, J. R. (2022). Effect of the bileaflet inlet valve angle on the flow of a pediatric ventricular assist device: Experimental analysis. Artificial organs, 46(9), 1833-1846.
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  Mechanical heart valves (MHV) and its fluid dynamics inside a pulsatile pediatric ventricular assist device (PVAD) can be associated with blood degradation. In this article, flow structures are analyzed and compared by an experimental investigation on the effect of bileaflet MHV positioned at varying angles in the inlet port orifice of a PVAD.
• Mallik, S., Grodstein, F., Bennett, D. A., Vavvas, D. G., & Lemos, B. (2022). Novel Epigenetic Clock Biomarkers of Age-Related Macular Degeneration. Frontiers in medicine, 9, 856853.
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  Age-Related Macular Degeneration (AMD) is a bilateral ocular condition resulting in irreversible vision impairment caused by the progressive loss of photoreceptors in the macula, a region at the center of the retina. The progressive loss of photoreceptor is a key feature of dry AMD but not always wet AMD, though both forms of AMD can lead to loss of vision. Regression-based biological age clocks are one of the most promising biomarkers of aging but have not yet been used in AMD. Here we conducted analyses to identify regression-based biological age clocks for the retina and explored their use in AMD using transcriptomic data consisting of a total of 453 retina samples including 105 Minnesota Grading System (MGS) level 1 samples, 175 MGS level 2, 112 MGS level 3 and 61 MGS level 4 samples, as well as 167 fibroblast samples. The clocks yielded good separation among AMD samples with increasing severity score viz., MGS1-4, regardless of whether clocks were trained in retina tissue, dermal fibroblasts, or in combined datasets. Clock application to cultured fibroblasts, embryonic stem cells, and induced Pluripotent Stem Cells (iPSCs) were consistent with age reprograming in iPSCs. Moreover, clock application to neuronal differentiation suggests broader applications. Interesting, many of the age clock genes identified include known targets mechanistically linked to AMD and aging, such as GDF11, C16ORF72, and FBN2. This study provides new observations for retina age clocks and suggests new applications for monitoring neuronal differentiation. These clocks could provide useful markers for AMD monitoring and possible intervention, as well as potential targets for screens.
• Panis, C., Candiotto, L. Z., Gaboardi, S. C., Gurzenda, S., Cruz, J., Castro, M., & Lemos, B. (2022). Widespread pesticide contamination of drinking water and impact on cancer risk in Brazil. Environment international, 165, 107321.
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  Pesticides, which are associated with endocrine dysfunction, immunological dysregulation, and cancer, are widespread sources of drinking water contamination. The state of Paraná has a population of 11 million, is the second largest grain producer in Brazil and is a leading consumer of pesticides. In this study, we analyzed the extent of drinking water contamination from 11 proven, probable, or potentially carcinogenic pesticides (alachlor, aldrin-dieldrin, atrazine, chlordane, DDT-DDD-DDE, diuron, glyphosate-AMPA, lindane-γ-HCH, mancozeb-ETU, molinate, and trifluralin) in 127 grain-producing municipalities in the state of Paraná. Extensive contamination of drinking water was found, including legacy pesticides such as aldrin-dieldrin (mean 0.047 ppb), DDT-DDD-DDE (mean: 0.07), chlordane (mean: 0.181), and lindane-HCH (mean: 2.17). Most of the municipalities were significantly above the maximum limits for each one of the currently allowed pesticides (67% for alachlor, 9.44% for atrazine, 96.85% for diuron, 100% for glyphosate-AMPA, 80.31% for mancozeb-ETU, 91.33% for molinate, and 12.6% for trifluralin). Ninety-seven percent of municipalities presented a sum of all pesticides at levels significantly above (189.84 ppb) the European Union preconized limits (
• Santana, D. A., Bedrat, A., Puga, R. D., Turecki, G., Mechawar, N., Faria, T. C., Gigek, C. O., Payão, S. L., Smith, M. A., Lemos, B., & Chen, E. S. (2022). The role of H3K9 acetylation and gene expression in different brain regions of Alzheimer's disease patients. Epigenomics, 14(11), 651-670.
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  To evaluate H3K9 acetylation and gene expression profiles in three brain regions of Alzheimer's disease (AD) patients and elderly controls, and to identify AD region-specific abnormalities. Brain samples of auditory cortex, hippocampus and cerebellum from AD patients and controls underwent chromatin immunoprecipitation sequencing, RNA sequencing and network analyses. We found a hyperacetylation of AD cerebellum and a slight hypoacetylation of AD hippocampus. The transcriptome revealed differentially expressed genes in the hippocampus and auditory cortex. Network analysis revealed Rho GTPase-mediated mechanisms. These findings suggest that some crucial mechanisms, such as Rho GTPase activity and cytoskeletal organization, are differentially dysregulated in brain regions of AD patients at the epigenetic and transcriptomic levels, and might contribute toward future research on AD pathogenesis.
• Stern, R. A., Charness, M. E., Gupta, K., Koutrakis, P., Linsenmeyer, K., Madjarov, R., Martins, M. A., Lemos, B., Dowd, S. E., & Garshick, E. (2022). Concordance of SARS-CoV-2 RNA in Aerosols From a Nurses Station and in Nurses and Patients During a Hospital Ward Outbreak. JAMA network open, 5(6), e2216176.
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  Aerosol-borne SARS-CoV-2 has not been linked specifically to nosocomial outbreaks.
• Almeida, R., Manarte-Monteiro, P., Domingues, J., Falcão, C., Herrero-Climent, M., Ríos-Carrasco, B., & Lemos, B. F. (2021). High-Power LED Units Currently Available for Dental Resin-Based Materials-A Review. Polymers, 13(13).
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  The pursuit of less time-consuming procedures led to the development of high-power light-curing-units (LCU) to light-cure dental-resin-based-materials. This review aims to describe high-power light-emitting-diode (LED)-LCUs, by a bibliometric systematization of in vitro and in vivo studies. The research-question, by PICO model, aimed to assess the current knowledge on dentistry-based high-power LED-LCUs by analyzing to what extent their use can promote adverse events on materials and patients' oral condition when compared to low-power LED-LCUs, on daily dental practice. PubMed and B-on database search focused on high-power (≥2000 mW/cm) LED-LCUs outputs. Studies assessing performance of high-power LED-LCUs for light-curing dental-resin-based-materials were included. From 1822 screened articles, 21 fulfilled the inclusion criteria. Thirty-two marketed units with high levels of radiant emittance (≥2000 mW/cm up to 6000 mW/cm) were identified. Most output values vary on 2000-3000 mW/cm. The highest output found was 6000 mW/cm, in FlashMaxP3. Reports suggest that light-curing protocols with lower emittance irradiance and longer exposure outperforms all other combination, however in some clinical procedures high-power LED-LCUs are advocated when compared to low-power LED-LCUs. Moreover, long time exposures and over-curing can be dangerous to the biological vital pulp, and other oral tissues. Evidence showing that high-power LCUs are the best clinical option is still very scarce.
• Cruz, J., & Lemos, B. (2021). Post-transcriptional diversity in riboproteins and RNAs in aging and cancer. Seminars in cancer biology, 76, 292-300.
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  Post-transcriptional (PtscM) and post-translational (PtrnM) modifications of nucleotides and amino acids are covalent modifications able to change physio-chemical properties of RNAs and proteins. In the ribosome, the adequate assembly of rRNAs and ribosomal protein subunits in the nucleolus ensures suitable translational activity, with protein synthesis tuned according to intracellular demands of energy production, replication, proliferation, and growth. Disruption in the regulatory control of PtscM and PtrnM can impair ribosome biogenesis and ribosome function. Ribosomal impairment may, in turn, impact the synthesis of proteins engaged in functions as varied as telomere maintenance, apoptosis, and DNA repair, as well as intersect with mitochondria and telomerase activity. These cellular processes often malfunction in carcinogenesis and senescence. Here we discuss regulatory mechanisms of PtscMs and PtrnMs on ribosomal function. We also address chemical modification in rRNAs and their impacts on cellular metabolism, replication control, and senescence. Further, we highlight similarities and differences of PtscMs and PtrnMs in ribosomal intermediates during aging and carcinogenesis. Understanding these regulatory mechanisms may uncover critical steps for the development of more efficient oncologic and anti-aging therapies.
• Grodstein, F., Lemos, B., Yu, L., Klein, H. U., Iatrou, A., Buchman, A. S., Shireby, G. L., Mill, J., Schneider, J. A., De Jager, P. L., & Bennett, D. A. (2021). The association of epigenetic clocks in brain tissue with brain pathologies and common aging phenotypes. Neurobiology of disease, 157, 105428.
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  Epigenetic clocks are calculated by combining DNA methylation states across select CpG sites to estimate biologic age, and have been noted as the most successful markers of biologic aging to date. Yet, limited research has considered epigenetic clocks calculated in brain tissue. We used DNA methylation states in dorsolateral prefrontal cortex specimens from 721 older participants of the Religious Orders Study and Rush Memory and Aging Project, to calculate DNA methylation age using four established epigenetic clocks: Hannum, Horvath, PhenoAge, GrimAge, and a new Cortical clock. The four established clocks were trained in blood samples (Hannum, PhenoAge, GrimAge) or using 51 human tissue and cell types (Horvath); the recent Cortical clock is the first trained in postmortem cortical tissue. Participants were recruited beginning in 1994 (Religious Orders Study) and 1997 (Memory and Aging Project), and followed annually with questionnaires and clinical evaluations; brain specimens were obtained for 80-90% of participants. Mean age at death was 88.0 (SD 6.7) years. We used linear regression, logistic regression, and linear mixed models, to examine relations of epigenetic clock ages to neuropathologic and clinical aging phenotypes, controlling for chronologic age, sex, education, and depressive symptomatology. Hannum, Horvath, PhenoAge and Cortical clock ages were related to pathologic diagnosis of Alzheimer's disease (AD), as well as to Aβ load (a hallmark pathology of Alzheimer's disease). However, associations were substantially stronger for the Cortical than other clocks; for example, each standard deviation (SD) increase in Hannum, Horvath, and PhenoAge clock age was related to approximately 30% greater likelihood of pathologic AD (all p 
• Lou, J., Yu, S., Feng, L., Guo, X., Wang, M., Branco, A. T., Li, T., & Lemos, B. (2021). Environmentally induced ribosomal DNA (rDNA) instability in human cells and populations exposed to hexavalent chromium [Cr (VI)]. Environment international, 153, 106525.
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  Hexavalent Chromium [Cr (VI)] is an established toxicant, carcinogen, and a significant source of public health concern. The multicopy ribosomal DNA (rDNA) array is mechanistically linked to aging and cancer, is the most evolutionarily conserved segment of the human genome, and gives origin to nucleolus, a nuclear organelle where ribosomes are assembled. Here we show that exposure to Cr (VI) induces instability in the rDNA, triggering cycles of rapid, specific, and transient amplification and contraction of the array in human cells. The dynamic of environmentally responsive rDNA copy number (CN) amplification and contraction occurs at doses to which millions of individuals are regularly exposed. Finally, analyses of human populations occupationally exposed to Cr (VI) indicate that environmental exposure history and drinking habits but not age shape extensive naturally occurring rDNA copy number variation. Our observations identify a novel pathway of response to hexavalent chromium exposure and raise the prospect that a suite of environmental determinants of rDNA copy number remain to be discovered.
• Marques, S., Ribeiro, P., Falcão, C., Lemos, B. F., Ríos-Carrasco, B., Ríos-Santos, J. V., & Herrero-Climent, M. (2021). Digital Impressions in Implant Dentistry: A Literature Review. International journal of environmental research and public health, 18(3).
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  Digital impressions in implant dentistry rely on many variables, and their accuracy, particularly in complete edentulous patients, is not well understood. The purpose of this literature review was to determine which factors may influence the accuracy of digital impressions in implant dentistry. Emphasized attention was given to the design of the intra-oral scan body (ISB) and scanning techniques.
• Stern, R. A., Koutrakis, P., Martins, M. A., Lemos, B., Dowd, S. E., Sunderland, E. M., & Garshick, E. (2021). Characterization of hospital airborne SARS-CoV-2. Respiratory research, 22(1), 73.
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  The mechanism for spread of SARS-CoV-2 has been attributed to large particles produced by coughing and sneezing. There is controversy whether smaller airborne particles may transport SARS-CoV-2. Smaller particles, particularly fine particulate matter (≤ 2.5 µm in diameter), can remain airborne for longer periods than larger particles and after inhalation will penetrate deeply into the lungs. Little is known about the size distribution and location of airborne SARS-CoV-2 RNA.
• Grodstein, F., Lemos, B., Yu, L., Iatrou, A., De Jager, P. L., & Bennett, D. A. (2020). Characteristics of Epigenetic Clocks Across Blood and Brain Tissue in Older Women and Men. Frontiers in neuroscience, 14, 555307.
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  Epigenetic clocks are among the most promising biomarkers of aging. It is particularly important to establish biomarkers of brain aging to better understand neurodegenerative diseases. To advance application of epigenetic clocks-which were largely created with DNA methylation levels in blood samples-for use in brain, we need clearer evaluation of epigenetic clock behavior in brain, including direct comparisons of brain specimens with blood, a more accessible tissue for research. We leveraged data from the Religious Orders Study and Rush Memory and Aging Project to examine three established epigenetic clocks (Horvath, Hannum, PhenoAge clocks) and a newer clock, trained in cortical tissue. We calculated each clock in three different specimens: (1) antemortem CD4+ cells derived from blood ( = 41); (2) postmortem dorsolateral prefrontal cortex (DLPFC, = 730); and (3) postmortem posterior cingulate cortex (PCC, = 186), among older women and men, age 66-108 years at death. Across all clocks, epigenetic age calculated from blood and brain specimens was generally lower than chronologic age, although differences were smallest for the Cortical clock when calculated in the brain specimens. Nonetheless, we found that Pearson correlations of epigenetic to chronologic ages in brain specimens were generally reasonable for all clocks; correlations for the Horvath, Hannum, and PhenoAge clocks largely ranged from 0.5 to 0.7 (all < 0.0001). The Cortical clock outperformed the other clocks, reaching a correlation of 0.83 in the DLFPC ( < 0.0001) for epigenetic vs. chronologic age. Nonetheless, epigenetic age was quite modestly correlated across blood and DLPFC in 41 participants with paired samples [Pearson r from 0.21 ( = 0.2) to 0.32 ( = 0.05)], indicating that broader research in neurodegeneration may benefit from clocks using CpG sites better conserved across blood and brain. Finally, in analyses stratified by sex, by pathologic diagnosis of Alzheimer disease, and by clinical diagnosis of Alzheimer dementia, correlations of epigenetic to chronologic age remained consistently high across all groups. Future research in brain aging will benefit from epigenetic clocks constructed in brain specimens, including exploration of any advantages of focusing on CpG sites conserved across brain and other tissue types.
• Lemos, B. F., Lopez-Jarana, P., Falcao, C., Ríos-Carrasco, B., Gil, J., Ríos-Santos, J. V., & Herrero-Climent, M. (2020). Effects of Different Undersizing Site Preparations on Implant Stability. International journal of environmental research and public health, 17(23).
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  As immediate loading protocols are becoming more frequent, the primary stability of implants has become an essential criterion for the osseointegration of dental implants. Based on this, the objective of this study was to understand the influence of different undersized surgical preparation sites on the insertion torque (IT) and implant stability quotient (ISQ). Four different site-preparation protocols were performed on fresh humid type III bovine bone: one control, the standard protocol recommended by the manufacturer (P1), and three variations of undersized techniques (P2, P3 and P4). The implant used was VEGA by Klockner Implant System. The sample size was n = 40 for each of the four groups. A torquemeter was used to measure the IT, and the ISQ was measured with a Penguin RFA. Both variables showed a tendency to increase as the preparation technique was reduced, although not all the values were statistically significant ( < 0.05) when comparing with the standard preparation. The preparations without a cortical drill, P2 and P4, showed better results than those with a cortical drill. Given the limitations of this study, it can be concluded that reducing the implant preparation can increase both the IT and ISQ. Removing the cortical drill is an effective method for increasing implant stability, although it should be used carefully.
• Rosa-Fernandes, L., Barbosa, R. H., Dos Santos, M. L., Angeli, C. B., Silva, T. P., Melo, R. C., de Oliveira, G. S., Lemos, B., Van Eyk, J. E., Larsen, M. R., Cardoso, C. A., & Palmisano, G. (2020). Cellular Imprinting Proteomics Assay: A Novel Method for Detection of Neural and Ocular Disorders Applied to Congenital Zika Virus Syndrome. Journal of proteome research, 19(11), 4496-4515.
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  Congenital Zika syndrome was first described due to increased incidence of congenital abnormalities associated with Zika virus (ZIKV) infection. Since the eye develops as part of the embryo central nervous system (CNS) structure, it becomes a specialized compartment able to display symptoms of neurodegenerative diseases and has been proposed as a noninvasive approach to the early diagnosis of neurological diseases. Ocular lesions result from defects that occurred during embryogenesis and can become apparent in newborns exposed to ZIKV. Furthermore, the absence of microcephaly cannot exclude the occurrence of ocular lesions and other CNS manifestations. Considering the need for surveillance of newborns and infants with possible congenital exposure, we developed a method termed cellular imprinting proteomic assay (CImPA) to evaluate the ocular surface proteome specific to infants exposed to ZIKV during gestation compared to nonexposure. CImPA combines surface cells and fluid capture using membrane disks and a large-scale quantitative proteomics approach, which allowed the first-time report of molecular alterations such as neutrophil degranulation, cell death signaling, ocular and neurological pathways, which are associated with ZIKV infection with and without the development of congenital Zika syndrome, CZS. Particularly, infants exposed to ZIKV during gestation and without early clinical symptoms could be detected using the CImPA method. Lastly, this methodology has broad applicability as it could be translated in the study of several neurological diseases to identify novel diagnostic biomarkers. Data are available via ProteomeXchange with identifier PXD014038.
• Tao, T., Shi, H., Wang, M., Perez-Atayde, A. R., London, W. B., Gutierrez, A., Lemos, B., Durbin, A. D., & Look, A. T. (2020). Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors. The Journal of experimental medicine, 217(10).
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  Peripheral sympathetic nervous system tumors are the most common extracranial solid tumors of childhood and include neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Surgery is the only effective therapy for ganglioneuroma, which may be challenging due to the location of the tumor and involvement of surrounding structures. Thus, there is a need for well-tolerated presurgical therapies that could reduce the size and extent of ganglioneuroma and therefore limit surgical morbidity. Here, we found that an AKT-mTOR-S6 pathway was active in human ganglioneuroma but not neuroblastoma samples. Zebrafish transgenic for constitutively activated myr-Akt2 in the sympathetic nervous system were found to develop ganglioneuroma without progression to neuroblastoma. Inhibition of the downstream AKT target, mTOR, in zebrafish with ganglioneuroma effectively reduced the tumor burden. Our results implicate activated AKT as a tumorigenic driver in ganglioneuroma. We propose a clinical trial of mTOR inhibitors as a means to shrink large ganglioneuromas before resection in order to reduce surgical morbidity.
• Zhang, Y., Wolosker, M. B., Zhao, Y., Ren, H., & Lemos, B. (2020). Exposure to microplastics cause gut damage, locomotor dysfunction, epigenetic silencing, and aggravate cadmium (Cd) toxicity in Drosophila. The Science of the total environment, 744, 140979.
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  The interactions of microplastics (MPs) with other chemicals and the range of outcomes are of great importance to enhance understanding of their environmental impacts and health risks. Cadmium (Cd) and cadmium compounds are widely used as pigments and stabilizers in plastics, but they readily leach out. Here we addressed the impacts of MPs, Cd, and their joint exposure in a tractable Drosophila melanogaster model. We show that exposure to MPs lead to extensive particle size depended gut damage early in life and an enhancement of Cd-induced inhibition of locomotor-behavioral function in adult flies. In addition, we show that Cd exposure induces epigenetic gene silencing via position-effect variegation (PEV) in somatic tissues that was dramatically enhanced by co-exposure with MPs. The results indicate that MPs can aggravate the toxicity of other environmental contaminants and induce adverse effects across a range of diverse outcomes in a tractable and widely used model organism. These observations raise the prospects of using Drosophila as a tool for the rapid assessment of MP-mediated toxicity.

Reviews

• Reis, A. H., Figalo, L. B., Orsini, M., & Lemos, B. (2023. The implications of DNA methylation for amyotrophic lateral sclerosis(pp e20230277).
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  Amyotrophic lateral sclerosis (ALS) is a complex and serious neurodegenerative disorder that develops in consequence of the progressive loss of the upper and lower motor neurons. Cases of ALS are classified as sporadic (sALS), or familial (fALS). Over 90% of cases are sALS, while roughly 10% are related to inherited genetic mutations (fALS). Approximately 70% of the genetic mutations that contribute to fALS have been identified. On the other hand, the majority of the sALS cases have an undetermined genetic contributor and few mutations have been described, despite the advanced genetic analysis methods. Also, several factors contribute to the onset and progression of ALS. Numerous lines of evidence indicate that epigenetic changes are linked to aging, as well as neurodegenerative disorders, such as ALS. In most cases, they act as the heritable regulation of transcription by DNA methylation, histone modification and expression of noncoding RNAs. Mechanisms involving aberrant DNA methylation could be relevant to human ALS pathobiology and therapeutic targeting. Despite advances in research to find factors associated with ALS and more effective treatments, this disease remains complex and has low patient survival. Here, we provide a narrative review of the role of DNA methylation for this complex neurodegenerative disorder.