👤 Katlyn Djéssi Silva Andrade

Neurodevelopmental disorders have been increasingly associated with maternal immune activation (MIA) during pregnancy, particularly in response to viral infections. However, the impact of human respiratory syncytial virus (hRSV) infection during gestation on offspring neurodevelopment remains poorly understood. This study aimed to characterize hRSV-induced MIA and evaluate its effects on fetal brain development and offspring behavior using a murine model. Pregnant mice were infected with hRSV at gestational day 14, and tissues were analyzed at day 19. Infection induced pulmonary inflammation, evidenced by increased neutrophil infiltration, and viral replication was detected in maternal lungs and placental tissue, but not in fetal organs. Placental infection was associated with increased decidual immune cells and a shift toward a pro-inflammatory cytokine profile, including elevated IL-6, TNF-α, IFN-γ, and IL-1β, along with decreased IL-10 and IFN-λ. Increased levels of IL-6, TNF-α, and IL-4 were also detected in maternal serum and fetal brains, suggesting vertical transfer of cytokines. Additionally, reduced brain-derived neurotrophic factor levels and altered expression of tight junction-related genes were observed in fetal brains. Behavioral analyses revealed that offspring of infected dams exhibited impaired short-term memory and altered anxiety-like and repetitive behaviors, which persisted or intensified with age. These findings demonstrate that maternal hRSV infection induces MIA, disrupts the fetal neuroimmune environment, and leads to long-term behavioral alterations in offspring, highlighting hRSV as a potential risk factor for neurodevelopmental disorders. Show less

Cerebrospinal fluid amyloid beta 42, total tau, and phosphorylated tau 181 are well accepted markers of Alzheimer's disease. These biomarkers better reflect disease pathogenesis compared to clinical diagnosis. Here, we perform a genome wide association study meta-analysis including 18,948 individuals of European ancestry and identify 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicate the association of biomarkers with APOE, CR1, GMNC/CCDC50 and C16orf95/MAP1LC3B. Novel loci include BIN1 for amyloid beta and GNA12, MS4A6A, SLCO1A2 with both total tau and phosphorylated tau 181, as well as additional loci on chr. 8, near ANGPT1 and chr. 9 near SMARCA2. We also demonstrate that these variants have significant association with Alzheimer's disease risk, disease progression and/or brain amyloidosis. The associated genes are implicated in lipid metabolism independent of APOE, coupled with autophagy and brain volume regulation driven by total tau and phosphorylated tau 181 dysregulation. Show less

Individuals with atrial fibrillation (AF) are at increased risk of stroke, cognitive impairment and dementia. Observational studies suggest that anticoagulation may reduce the risk of cognitive decline in patients with AF and elevated thromboembolic risk, implicating subclinical cerebral emboli as a potential mechanistic link. Whether anticoagulation prevents cognitive deterioration in patients with AF at low risk of stroke remains uncertain. Here we conducted a multicenter, double-blind, placebo-controlled trial in which participants with AF and low thromboembolic risk (CHA Show less

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive loss of cognitive functions, and it is the most prevalent type of dementia worldwide, accounting for 60 to 70% of cases. The pathogenesis of AD seems to involve three main factors: deficiency in cholinergic transmission, formation of extracellular deposits of β-amyloid peptide, and accumulation of deposits of a phosphorylated form of the TAU protein. The currently available drugs are prescribed for symptomatic treatment and present adverse effects such as hepatotoxicity, hypertension, and weight loss. There is urgency in finding new drugs capable of preventing the progress of the disease, controlling the symptoms, and increasing the survival of patients with AD. This study aims to present new multipurpose compounds capable of simultaneously inhibiting acetylcholinesterase (AChE), butyrylcholinesterase (BChE)-responsible for recycling acetylcholine in the synaptic cleft-and beta-secretase 1 (BACE-1)-responsible for the generation of amyloid-β plaques. AChE, BChE, and BACE-1 are currently considered the best targets for the treatment of patients with AD. Virtual hierarchical screening based on a pharmacophoric model for BACE-1 inhibitors and a dual pharmacophoric model for AChE and BChE inhibitors were used to filter 214,446 molecules by QFIT Show less

We have previously shown that histone deacetylase (HDAC) inhibition and cranial radiotherapy (RT) independently improve molecular and behavioral Alzheimer's disease (AD)-like phenotypes. In the present study, we investigate the synergistic potential of using both RT and HDACi as a low-dose combination therapy (LDCT) to maximize disease modification (reduce neuroinflammation and amyloidogenic APP processing, increase neurotrophic gene expression) while minimizing the potential for treatment-associated side effects.LDCT consisted of daily administration of the HDAC3 inhibitor RGFP966 and/or bi-weekly cranial x-irradiation. Amyloid-beta precursor protein (APP) processing and innate immune response to LDCT were assessed in vitro and in vivo using human and murine cell models and 3xTg-AD mice. After 2 months of LDCT in mice, behavioral analyses as well as expression and modification of key AD-related targets (Aβ, tau, Csf1r, Bdnf, etc.) were assessed in the hippocampus (HIP) and prefrontal cortex (PFC).LDCT induced a tolerant, anti-inflammatory innate immune response in microglia and increased non-amyloidogenic APP processing in vitro. Both RT and LDCT improved the rate of learning and spatial memory in the Barnes maze test. LDCT induced a unique anti-AD HIP gene expression profile that included upregulation of neurotrophic genes and downregulation of inflammation-related genes. RT lowered HIP Aβ Show less

Urea cycle disorders (UCD) are inborn errors of metabolism caused by deficiency of enzymes required to convert nitrogen from ammonia into urea. Current paradigms of treatment focus on dietary manipulations, ammonia scavenger drugs, and liver transplantation. The aim of this study was to describe the characteristics and indication of liver transplantation in UCD in a tertiary hospital. We performed a retrospective study of children with UCD seen in the period 2000-2021. Data was collected on clinical onset, hyperammonemia severity, evolution and liver transplantation. There were 33 patients in the study period, whose diagnosis were: ornithine transcarbamylase (OTC, Show less

The objective of this research was to evaluate the effectiveness of using LPL (Low power laser) to reduce pain, edema, and trismus after impacted lower third molar extraction. A split-mouth randomized triple-blind clinical trial was conducted at the Federal University of Ceará. For inclusion criteria, it was necessary that the patient presented a clear indication for removal of both lower third molars, in addition to both molars being in similar positions. The third molars (38 and 48) were randomly allocated to the test group that received the LPL application protocol, and to the placebo group that received a simulation of the protocol, making a total sample of 44 surgeries. Patients in the test group used an average of 50% of the amount of analgesics that was used by the placebo group, however, there was a statistically significant difference only on days four and five. Regarding trismus, the test group presented wide mouth openings, both at 48 hours and at 7 days after surgery compared to the placebo group, but without a statistically significant difference. For edema, we noted an equilibrium between the test group and the placebo group, but no measurement obtained a statistically significant difference. The use of LPL presented better pain and trismus indicators after complex extractions. The use of LPL is thus indicated as a complementary therapy to reduce postoperative discomfort caused by complex tooth extractions. Show less

The main aim was to evaluate changes in urea cycle enzymes in NAFLD patients and in two preclinical animal models mimicking this entity. Seventeen liver specimens from NAFLD patients were included for immunohistochemistry and gene expression analyses. Three-hundred-and-eighty-two biopsy-proven NAFLD patients were genotyped for rs1047891, a functional variant located in carbamoyl phosphate synthetase-1 (CPS1) gene. Two preclinical models were employed to analyse CPS1 by immunohistochemistry, a choline deficient high-fat diet model (CDA-HFD) and a high fat diet LDLr knockout model (LDLr -/-). A significant downregulation in mRNA was observed in CPS1 and ornithine transcarbamylase (OTC1) in simple steatosis and NASH-fibrosis patients versus controls. Further, age, obesity (BMI > 30 kg/m Show less

After initiating antiretroviral therapy (ART), approximately 25% of people with HIV (PWH) may develop Immune Reconstitution Inflammatory Syndrome (IRIS), which is associated with increased morbidity and mortality. Several reports have demonstrated that low haemoglobin (Hb) levels are a risk factor for IRIS. To what extent the severity of anaemia contributes to the risk of IRIS and/or death is still insufficiently explored. We investigated both the presence and severity of anaemia in PWH in a multinational cohort of ART-na..ve patients. A large panel of plasma biomarkers was measured pre-ART and patients were followed up for 6 months. IRIS or deaths during this period were considered as outcomes. We performed multidimensional analyses, logistic regression, and survival curves to delineate associations. Patients with severe anaemia (SA) presented a distinct systemic inflammatory profile, characterized by higher TNF, IL-6, and IL-27 levels. SA was independently associated with IRIS, with a higher risk of both early IRIS onset and death. Among IRIS patients, those with SA had a higher risk of mycobacterial IRIS. PWH with SA display a more pronounced inflammatory profile, with an elevated risk of developing IRIS earlier and a statistically significant higher risk of death. Intramural Research Program of National Institute of Allergy and Infectious Diseases/National Institutes of Health (NIAID/NIH). Coordena...·o de Aperfei..oamento de Pessoal de N.ível Superior (Finance code: 001) and the Conselho Nacional de Desenvolvimento Cient.ífico e Tecnol..gico (CNPq), Brazil. Show less

Immune reconstitution inflammatory syndrome (IRIS) is a common cause of morbidity among people with human immunodeficiency virus (PWH) who initiate antiretroviral therapy (ART) with severe lymphopenia. Easily accessible tools that reliably predict emergence and elucidate pathogenesis of IRIS are needed to facilitate improved clinical management. Plasma levels of biomarkers were measured before ART initiation in a large multinational cohort of ART-naive PWH with severe immunosuppression (CD4+ count <100 cells/mm3) in United States, Kenya, and Thailand. We performed a series of multiparametric analyses of inflammatory and clinical biomarkers and developed a composite score merging relevant biomarkers for use in a prediction model. We identified a distinct baseline inflammatory profile and changes in inflammatory networks among biomarkers in participants who subsequently developed mycobacterial or viral IRIS. We also developed a composite score incorporating biomarkers associated with IRIS (interleukin-6 [IL-6], IL-10, IL-27, sCD14, interferon-γ, tumor necrosis factor-α, hyaluronic acid, D-dimer, body mass index, and hemoglobin) that accurately predicted mycobacterial IRIS and death in this cohort. Systemic inflammatory profiles in PWH with severe immunosuppression are predictive of IRIS. Composite scores for the prediction of mycobacterial IRIS and death could be useful for risk stratification in PWH and lymphopenia initiating ART. NCT00286767. Show less

To determine the diagnostic yield of a commercial epilepsy gene panel in adults with chronic epilepsy and accompanying intellectual disability, given that genetic evaluation is often overlooked in this group of patients. This is a cross-sectional study analyzing the results of epilepsy gene panels including up to 185 genes in adult epilepsy patients with intellectual disability, according to Diagnostic and Statistical Manual of Mental Disorders, fifth edition. Patients with acquired structural brain abnormalities or known chromosomal abnormalities were excluded. From approximately 600 patients seen from January 2017 to June 2018 at a single academic epilepsy center, 64 probands and two affected relatives (32 males, mean age = 31 years ± 10) were selected and clinically tested. Fourteen probands (14/64 = 22%; four males, mean age = 32 years ± 10) were found to have pathogenic or likely pathogenic variants in the following genes: SCN1A, GABRB3, UBE3A, KANSL1, SLC2A1, KCNQ2, SLC6A1, HNRNPU, STX1B, SCN2A, PURA, and CHD2. Six variants arose de novo, and the inheritance was not determined in eight. Nine probands (64%) had severe or profound intellectual disability, and five (35%) had autistic features. Eight patients (57%) had a diagnostic change from presumptive clinical diagnosis prior to genetic testing. We were able to demonstrate that a commercial epilepsy gene panel can be an important resource in clinical practice, identifying the etiology in 22% of adults with epilepsy and intellectual disability. The diagnostic yield is similar to previously reported pediatric cohorts. Larger samples would be required to evaluate the more prevalent genotypes among adult epilepsy patients. Show less

Recent genome-wide association studies in the Mexican population have identified several genetic loci associated with blood lipid levels in adults. However, studies focusing on the fatty acid desaturase (FADS) gene cluster have been understudied in this population, even though it seems associated with lipid profiles in other ethnicities. The aim of this study was to test associations between single nucleotide polymorphisms (SNPs) in the FADS cluster (rs174546, rs1535, rs174548, rs174550, rs174450, and rs174618) and serum lipid profiles in young Mexicans. Anthropometrics, serum lipid profiles, and FADS SNPs were measured in 998 subjects in the UP-AMIGOS cohort study. Genotype-phenotype (total cholesterol [TC], triglyceride [TG], high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], and very-low-density lipoprotein [VLDL]) associations were assessed using PLINK adjusted for sex, age, and body mass index (BMI). Among 6 FADS SNPs, we found that carriers of the C-allele of the FADS1-rs174546 showed a significant association with lower TG concentrations (β = -12.6 mg/dL, p = 0.009) and lower VLDL concentrations (β = -2.52 mg/dL, p = 0.005). We found that rs174546, rs1535, and rs174550 were in high linkage disequilibrium (r2 > 0.80). There were no significant associations between rs174550, rs174548, and rs174618 and lipid profiles. A genetic variant in the FADS1 (rs174546) gene is a major contributor of plasma TG and VLDL concentrations in healthy young Mexicans. Show less

ARPP-16 (cAMP-regulated phospho-protein of molecular weight 16 kDa) is one of several small acid-soluble proteins highly expressed in medium spiny neurons of striatum that are phosphorylated in response to dopamine acting via D1 receptor/protein kinase A (PKA) signaling. We show here that ARPP-16 is also phosphorylated Show less

Spinal cord injury (SCI) results in loss of movement, sensibility, and autonomic control at the level of the lesion and at lower parts of the body. Several experimental strategies have been used in attempts to increase endogenous mechanisms of neuroprotection, neuroplasticity, and repair, but with limited success. It is known that glucose-dependent insulinotropic peptide (GIP) and its receptor (GIPR) can enhance synaptic plasticity, neurogenesis, and axonal outgrowth. However, their role in the injury has never been studied. The aim of this study was to evaluate the changes in expression levels of both GIP and GIPR in acute and chronic phases of SCI in rats. Following SCI (2 to 24 h after damage), the rat spinal cord showed a lesion in which the epicenter had a cavity with hemorrhage and necrosis. Furthermore, the lesion cavity also showed ballooned cells 14 and 28 days after injury. We found that SCI induced increases in GIPR expression in areas neighboring the site of injury at 6 h and 28 days after the injury. Moreover, higher GIP expression was observed in these regions on day 28. Neuronal projections from the injury epicenter showed an increase in GIP immunoreactivity 24 h and 14 and 28 days after SCI. Interestingly, GIP was also found in progenitor cells at the spinal cord canal 24 h after injury, whereas both GIP and GIPR were present in progenitor cells at the injury epicenter 14 days after in SCI animals. These results suggest that GIP and its receptor might be implicated with neurogenesis and the repair process after SCI. Show less

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD. Show less

Hypertriglyceridemia is an important independent risk factor for coronary artery diseases and is determined by a wide range of factors, both genetic and exogenous. The A5 apolipoprotein, which is associated with the synthesis and removal of triglycerides (TG), is encoded by the APOA5 gene. One of the polymorphisms of this gene that has been the focus of a large number of studies, and which appears to be associated with increased TG, is S19W (rs 3135506). In this study, we examined the influence of this single nucleotide polymorphism (SNP) on TG levels of a sample of southern Brazilians. Samples obtained from 567 people of European descent were genotyped; interactions between this variant and anthropometric variables were analyzed, and the effects of lifestyle, sex, menopause, and variations of the APOE gene were evaluated. We found that the 19W allele is associated with increased TG (p = 0.025) and that this influence was modulated by sex (p = 0.003), menopause (p = 0.022) and the presence of the E*4 allele (p = 0.027). Our data showed, for the first time, the importance and magnitude of the influence of the S19W variant in a southern Brazilian population. Show less

Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney. Show less

Genetic factors play important roles in lung cancer susceptibility. In this study, we replicated the association of 5p15.33 and 6p21.33 with familial lung cancer. Taking into account the previously identified genetic susceptibility variants on 6q23-25/RGS17 and 15q24-25.1, we further determined the cumulative association of these four genetic regions and the population attributable risk percent of familial lung cancer they account for. One hundred ninety-four case patients and 219 cancer-free control subjects from the Genetic Epidemiology of Lung Cancer Consortium were used for the association analysis. Each familial case was chosen from one high-risk lung cancer family that has three or more affected members. Single nucleotide polymorphisms (SNP) on chromosomal regions 5p15.33, 6p21.33, 6q23-25/RGS17, and 15q24-25.1 were assessed for their associations with familial lung cancer. The cumulative association of the four chromosomal regions with familial lung cancer was evaluated with the use of a linear logistic model. Population attributable risk percent was calculated for each SNP using risk ratio. SNP rs31489 showed the strongest evidence of familial lung cancer association on 5p15.33 (P = 2 x 10(-4); odds ratio, 0.57; 95% confidence interval, 0.42-0.77), whereas rs3117582 showed a weak association on 6p21.33 (P = 0.09; odds ratio, 1.47; 95% confidence interval, 0.94-2.31). Analysis of a combination of SNPs from the four regions provided a stronger cumulative association with familial lung cancer (P = 6.70 x 10(-6)) than any individual SNPs. The risk of lung cancer was increased to 3- to 11-fold among those subjects who had at least one copy of risk allele at each region compared with subjects without any of the risk factors. These four genetic regions contribute to a total of 34.6% of familial lung cancer in smokers. The SNPs in four chromosomal regions have a cumulative and significant association with familial lung cancer and account for about one-third of the population attributable risk for familial lung cancer. Show less

We have previously mapped a major susceptibility locus influencing familial lung cancer risk to chromosome 6q23-25. However, the causal gene at this locus remains undetermined. In this study, we further refined this locus to identify a single candidate gene, by fine mapping using microsatellite markers and association studies using high-density single nucleotide polymorphisms (SNP). Six multigenerational families with five or more affected members were chosen for fine-mapping the 6q linkage region using microsatellite markers. For association mapping, we genotyped 24 6q-linked cases and 72 unrelated noncancer controls from the Genetic Epidemiology of Lung Cancer Consortium resources using the Affymetrix 500K chipset. Significant associations were validated in two independent familial lung cancer populations: 226 familial lung cases and 313 controls from the Genetic Epidemiology of Lung Cancer Consortium, and 154 familial cases and 325 controls from Mayo Clinic. Each familial case was chosen from one high-risk lung cancer family that has three or more affected members. A region-wide scan across 6q23-25 found significant association between lung cancer susceptibility and three single nucleotide polymorphisms in the first intron of the RGS17 gene. This association was further confirmed in two independent familial lung cancer populations. By quantitative real-time PCR analysis of matched tumor and normal human tissues, we found that RGS17 transcript accumulation is highly and consistently increased in sporadic lung cancers. Human lung tumor cell proliferation and tumorigenesis in nude mice are inhibited upon knockdown of RGS17 levels. RGS17 is a major candidate for the familial lung cancer susceptibility locus on chromosome 6q23-25. Show less

APOC3 polymorphisms were associated with lipid parameters and coronary artery disease in several populations but not all. Considering the multifactorial inheritance and environmental factors that underlie the determination of triglyceride (TG) and HDL-C levels, the aims of the present study were to perform association analyses of APOC3 polymorphisms and these lipids in a southern Brazilian population of European descent to investigate possible interactions with other genetic and/or environmental factors. Six hundred and seventy-three subjects participated in the study. -482C>T, -455T>C and 3238C>G polymorphisms genotyping were carried out by PCR followed by restriction enzyme digestion. In female subjects the APOC3-APOE genotype combinations had a significant effect on triglyceride levels (ANOVA, P=0.009). Post hoc analysis showed that the observed differences were between APOC3 S(*)2 carriers and S(*)1S(*)1 homozygotes in individuals with an APOE(*)3/3 genotype (Tukey HSD post hoc test, P=0.027). In APOE(*)3/(*)3 subjects, the raising effect of APOC3 S(*)2 allele on TG concentrations was more pronounced in female smokers (+59.4%) than in nonsmokers (+18.8%, P of S(*)2-smoking interaction=0.009). Among APOE(*)3/(*)3 subjects, male carriers of the less common alleles -482T and -455C had significant lower levels of HDL-C compared to homozygotes -482C/C and -455T/T (P=0.02 and P=0.006, respectively). APOC3 polymorphisms were associated with lipid variables, but the magnitude of these associations was modulated by additional genetic, biologic and/or environmental factors. Show less

Many intracellular pathogens, including Toxoplasma gondii, survive within macrophages by residing in vacuoles that avoid fusion with lysosomes. It is important to determine whether cell-mediated immunity can trigger macrophage antimicrobial activity by rerouting these vacuoles to lysosomes. We report that CD40 stimulation of human and mouse macrophages infected with T. gondii resulted in fusion of parasitophorous vacuoles and late endosomes/lysosomes. Vacuole/lysosome fusion took place even when CD40 was ligated after the formation of parasitophorous vacuoles. Genetic and pharmacological approaches that impaired phosphoinositide-3-class 3 (PIK3C3), Rab7, vacuolar ATPase, and lysosomal enzymes revealed that vacuole/lysosome fusion mediated antimicrobial activity induced by CD40. Ligation of CD40 caused colocalization of parasitophorous vacuoles and LC3, a marker of autophagy, which is a process that controls lysosomal degradation. Vacuole/lysosome fusion and antimicrobial activity were shown to be dependent on autophagy. Thus, cell-mediated immunity through CD40 stimulation can reroute an intracellular pathogen to the lysosomal compartment, resulting in macrophage antimicrobial activity. Show less