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1.
Curr Biol ; 30(11): 2068-2077.e4, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32359429

RESUMO

African naked mole-rats were likely the first mammals to evolve eusociality, and thus required adaptations to conserve energy and tolerate the low oxygen (O2) and high carbon dioxide (CO2) of a densely populated fossorial nest. As hypercapnia is known to suppress neuronal activity, we studied whether naked mole-rats might demonstrate energy savings in GABAergic inhibition. Using whole-colony behavioral monitoring of captive naked mole-rats, we found a durable nest, characterized by high CO2 levels, where all colony members spent the majority of their time. Analysis of the naked mole-rat genome revealed, uniquely among mammals, a histidine point variation in the neuronal potassium-chloride cotransporter 2 (KCC2). A histidine missense substitution mutation at this locus in the human ortholog of KCC2, found previously in patients with febrile seizures and epilepsy, has been demonstrated to diminish neuronal Cl- extrusion capacity, and thus impairs GABAergic inhibition. Seizures were observed, without pharmacological intervention, in adult naked mole-rats exposed to a simulated hyperthermic surface environment, causing systemic hypocapnic alkalosis. Consistent with the diminished function of KCC2, adult naked mole-rats demonstrate a reduced efficacy of inhibition that manifests as triggering of seizures at room temperature by the GABAA receptor (GABAAR) positive allosteric modulator diazepam. These seizures are blocked in the presence of nest-like levels of CO2 and likely to be mediated through GABAAR activity, based on in vitro recordings. Thus, altered GABAergic inhibition adds to a growing list of adaptations in the naked mole-rat and provides a plausible proximate mechanism for nesting behavior, where a return to the colony nest restores GABA-mediated inhibition.


Assuntos
Dióxido de Carbono/metabolismo , Suscetibilidade a Doenças/veterinária , Ratos-Toupeira , Receptores de GABA-A/metabolismo , Doenças dos Roedores/fisiopatologia , Convulsões/veterinária , Animais , Suscetibilidade a Doenças/etiologia , Suscetibilidade a Doenças/metabolismo , Feminino , Masculino , Doenças dos Roedores/genética , Convulsões/genética , Convulsões/fisiopatologia
2.
Oncogene ; 38(29): 5751-5765, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31222103

RESUMO

We previously reported that the dismutase SOD1 is overexpressed in breast cancer. However, whether SOD1 plays an active role in tumor formation in vivo has never been demonstrated. Further, as luminal cells of normal breast epithelial cells are enriched in SOD1, whether SOD1 is essential for normal mammary gland development has never been determined. We initiated this study to investigate the role of SOD1 in mammary gland tumorigenesis as well as in normal mammary gland development. We crossed the inducible erbB2 (MMTV-iErbB2) and Wnt (MMTV-Wnt) transgenic mice to the SOD1 heterozygote or knockout mice. Our results show that SOD1 is essential for oncogene-driven proliferation, but not normal proliferation of the mammary gland associated with pregnancy or other normal proliferative tissues such as skin and intestines. We show that activation of the oncogene ErbB2 is associated with increased ROS and that high ROS sub-population of ErbB2 cancer cells show elevated SOD1. In the same cells, decrease in SOD1 is associated with an elevation in both apoptosis as well as oncogene-induced senescence. Based on these results, we suggest that SOD1 carries a housekeeping function that maintains ROS levels below a threshold that supports oncogene-dependent proliferation, while allowing escape from oncogene-induced senescence, independently of the oncogene driving tumor formation. These results identify SOD1 as an ideal target for cancer therapy as SOD1 inhibitors hold the potential to prevent the growth of cancers cells of diverse genotypes, activate multiple modes of cell death therefore making acquired resistance more difficult, while sparing normal tissues.


Assuntos
Carcinogênese/genética , Proliferação de Células , Neoplasias Mamárias Animais/genética , Oncogenes , Superóxido Dismutase-1/genética , Animais , Apoptose/genética , Feminino , Genes Essenciais , Humanos , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/patologia , Camundongos , Camundongos Transgênicos , Estresse Oxidativo , Gravidez , Receptor ErbB-2/genética , Superóxidos/metabolismo
3.
Autism Res ; 11(5): 707-712, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29394471

RESUMO

Folate deficiency can affect fetal and neonatal brain development Considering the reported association of Folate receptor alpha (FRα) autoantibodies (Abs) with autism and developmental disorders, we sought to confirm this in families of 82 children with ASD, 53 unaffected siblings, 65 fathers, and 70 mothers, along with 52 unrelated normal controls. Overall, 76% of the affected children, 75% of the unaffected siblings, 69% of fathers and 59% of mothers were positive for either blocking or binding Ab, whereas the prevalence of this Ab in the normal controls was 29%. The Ab was highly prevalent in affected families including unaffected siblings. The appearance of these antibodies may have a familial origin but the risk of developing ASD is likely influenced by other mitigating factors since some siblings who had the antibodies were not affected. The antibody response appears heritable with the blocking autoantibody in the parents and affected child increasing the risk of ASD. Autism Res 2018, 11: 707-712. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Folate is an essential nutrient during fetal and infant development. Autoantibodies against the folate receptor alpha can block folate transport from the mother to the fetus and to the brain in infants. Children diagnosed with autism and their immediate family members were evaluated for the prevalence of folate receptor autoantibodies. The autoantibody was highly prevalent in affected families with similar distribution in parents, normal siblings and affected children. The presence of these antibodies appears to have a familial origin and may contribute to developmental deficits when combined with other factors.


Assuntos
Transtorno do Espectro Autista/imunologia , Autoanticorpos/imunologia , Receptor 1 de Folato/imunologia , Pais , Irmãos , Adulto , Transtorno do Espectro Autista/diagnóstico , Criança , Pré-Escolar , Feminino , Humanos , Masculino
4.
Am J Med Genet B Neuropsychiatr Genet ; 174(8): 772-778, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28856789

RESUMO

Telomere shortening was shown to parallel Alzheimer's disease (AD) associated dementia. By using a dual PNA Probe system we have developed a practical method for comparing telomere length in T-lymphocyte interphases from individuals with Down syndrome (DS) with and without "mild cognitive impairment" (MCI-DS) and demonstrated that telomere length can serve as a valid biomarker for the onset of MCI-DS in this high-risk population. To verify progressive cognitive decline we have now examined sequential changes in telomere length in 10 adults with DS (N = 4 Female, N = 6 Male) developing MCI-DS. Cases were selected blind to telomere length from a sample of adults with DS previously enrolled in a prospective longitudinal study at 18-month intervals with clinical and telomere assessments: (1) MCI-DS group data were collected approximately three years prior to development of MCI-DS; (2) 18 months later; (3) when MCI-DS was first observed. These telomere measures were compared to those from another 10 adults with DS matched by sex and approximate age but without indications of MCI-DS (Controls). PNA (peptide nucleic acid) probes for telomeres together with a chromosome two centromere probe were used. Findings indicated telomere shortening over time for both Cases and Controls. Group differences emerged by 18-months prior to recognition of MCI-DS onset and completely non-overlapping distributions of telomere measures were observed by the time of MCI-DS onset. This study adds to accumulating evidence of the value of telomere length, as an early biomarker of AD progression in adults with Down syndrome.


Assuntos
Doença de Alzheimer/patologia , Biomarcadores/análise , Disfunção Cognitiva/patologia , Síndrome de Down/patologia , Encurtamento do Telômero , Adulto , Idoso , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Disfunção Cognitiva/complicações , Disfunção Cognitiva/genética , Progressão da Doença , Síndrome de Down/complicações , Síndrome de Down/genética , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
5.
Adv Exp Med Biol ; 975 Pt 1: 3-16, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28849439

RESUMO

Taurine is a sulfur-containing amino acid which is not incorporated into protein. However, taurine has various critical physiological functions including development of the eye and brain, reproduction, osmoregulation, and immune functions including anti-inflammatory as well as anti-oxidant activity. The causes of autistic spectrum disorder (ASD) are not clear but a high heritability implicates an important role for genetic factors. Reports also implicate oxidative stress and inflammation in the etiology of ASD. Thus, taurine, a well-known antioxidant and regulator of inflammation, was investigated here using the sera from both girls and boys with ASD as well as their siblings and parents. Previous reports regarding taurine serum concentrations in ASD from various laboratories have been controversial. To address the potential role of taurine in ASD, we collected sera from 66 children with ASD (males: 45; females: 21, age 1.5-11.5 years, average age 5.2 ± 1.6) as well as their unaffected siblings (brothers: 24; sisters: 32, age 1.5-17 years, average age 7.0 ± 2.0) as controls of the children with ASD along with parents (fathers: 49; mothers: 54, age 28-45 years). The sera from normal adult controls (males: 47; females: 51, age 28-48 years) were used as controls for the parents. Taurine concentrations in all sera samples were measured using high performance liquid chromatography (HPLC) using a phenylisothiocyanate labeling technique. Taurine concentrations from female and male children with ASD were 123.8 ± 15.2 and 145.8 ± 8.1 µM, respectively, and those from their unaffected brothers and sisters were 142.6 ± 10.4 and 150.8 ± 8.4 µM, respectively. There was no significant difference in taurine concentration between autistic children and their unaffected siblings. Taurine concentrations in children with ASD were also not significantly different from their parents (mothers: 139.6 ± 7.7 µM, fathers: 147.4 ± 7.5 µM). No significant difference was observed between adult controls and parents of ASD children (control females: 164.8 ± 4.8 µM, control males: 163.0 ± 7.0 µM). However, 21 out of 66 children with ASD had low taurine concentrations (<106 µM). Since taurine has anti-oxidant activity, children with ASD with low taurine concentrations will be examined for abnormal mitochondrial function. Our data imply that taurine may be a valid biomarker in a subgroup of ASD.


Assuntos
Transtorno do Espectro Autista/sangue , Biomarcadores/sangue , Taurina/sangue , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino
6.
Am J Med Genet B Neuropsychiatr Genet ; 171B(2): 169-74, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26593971

RESUMO

Previous studies have suggested that Alzheimer's disease (AD) causes an accelerated shortening of telomeres, the ends of chromosomes consisting of highly conserved TTAGGG repeats that, because of unidirectional 5'-3' DNA synthesis, lose end point material with each cell division. Our own previous work suggested that telomere length of T-lymphocytes might be a remarkably accurate biomarker for "mild cognitive impairment" in adults with Down syndrome (MCI-DS), a population at dramatically high risk for AD. To verify that the progression of cognitive and functional losses due to AD produced this observed telomere shortening, we have now examined sequential changes in telomere length in five individuals with Down syndrome (3F, 2M) as they transitioned from preclinical AD to MCI-DS (N = 4) or dementia (N = 1). As in our previous studies, we used PNA (peptide nucleic acid) probes for telomeres and the chromosome 2 centromere (as an "internal standard" expected to be unaffected by aging or dementia status), with samples from the same individuals now collected prior to and following development of MCI-DS or dementia. Consistent shortening of telomere length was observed over time. Further comparisons with our previous cross-sectional findings indicated that telomere lengths prior to clinical decline were similar to those of other adults with Down syndrome (DS) who have not experienced clinical decline while telomere lengths following transition to MCI-DS or dementia in the current study were comparable to those of other adults with DS who have developed MCI-DS or dementia. Taken together, findings indicate that telomere length has significant promise as a biomarker of clinical progression of AD for adults with DS, and further longitudinal studies of a larger sample of individuals with DS are clearly warranted to validate these findings and determine if and how factors affecting AD risk also influence these measures of telomere length.


Assuntos
Demência/complicações , Demência/genética , Síndrome de Down/complicações , Síndrome de Down/genética , Encurtamento do Telômero/genética , Adulto , Biomarcadores/metabolismo , Feminino , Humanos , Masculino , Metáfase/genética , Pessoa de Meia-Idade , Linfócitos T/metabolismo
7.
Taiwan J Obstet Gynecol ; 54(5): 527-31, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26522104

RESUMO

OBJECTIVE: To investigate the clinical efficiency of noninvasive prenatal test (NIPT) identifying fetal chromosomal aneuploidies. MATERIALS AND METHODS: In the present study, 917 women with high-risk pregnancies were invited to participate in an NIPT trial based on an Illumina HiSeq massively parallel sequencing platform. Abnormal cases in NIPT were validated by karyotyping and fluorescence in situ hybridization (FISH) analysis. All of the participants' infants were examined clinically and followed up for at least 6 months. RESULTS: A total of 35 (3.82%) high-risk pregnancies were detected with abnormal results in NIPT, which included 25 cases (2.73%) of trisomy 21 (Tri21), four cases (0.44%) of trisomy 18 (Tri18), four cases (0.44%) of Turner syndrome (45, X), one cases (0.11%) of Klinefelter's syndrome (47, XXY), and one cases (0.11%) with lower X chromosome concentration. Further validation indicated that one case of Tri18 and the case with lower X chromosome concentration were false positive results (0.22%) in NIPT. Furthermore, it was found that the false positive case with lower X chromosome concentration in NIPT was caused by maternal sex chromosomal mosaicism (45, X and 46, XX). CONCLUSION: Our findings indicated that maternal mosaicism of sex chromosome could cause discordant sex chromosomal aneuploidies associated with NIPT. We highly recommended that maternal karyotype should be confirmed for the cases with abnormal results in NIPT.


Assuntos
Cromossomos Humanos Par 18/genética , Cromossomos Humanos X , Síndrome de Down/diagnóstico , Mosaicismo , Diagnóstico Pré-Natal/métodos , Aberrações dos Cromossomos Sexuais , Cromossomos Sexuais/genética , Adolescente , Adulto , Síndrome de Down/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Pessoa de Meia-Idade , Gravidez , Análise de Sequência de DNA , Adulto Jovem
8.
Cancer Res ; 75(22): 4830-8, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26527289

RESUMO

Estrogen stimulation promotes epithelial cell proliferation in estrogen receptor (ERα)-positive breast cancer. Many ERα target genes have been enumerated, but the identities of the key effectors mediating the estrogen signal remain obscure. During mouse mammary gland development, the estrogen growth factor receptor (EGFR) ligand amphiregulin acts as an important stage-specific effector of estrogen signaling. In this study, we investigated the role of amphiregulin in breast cancer cell proliferation using human tissue samples and tumor xenografts in mice. Amphiregulin was enriched in ERα-positive human breast tumor cells and required for estrogen-dependent growth of MCF7 tumor xenografts. Furthermore, amphiregulin levels were suppressed in patients treated with endocrine therapy. Suppression of EGF receptor signaling appeared necessary for the therapeutic response in this setting. Our findings implicate amphiregulin as a critical mediator of the estrogen response in ERα-positive breast cancer, emphasizing the importance of EGF receptor signaling in breast tumor pathogenesis and therapeutic response.


Assuntos
Neoplasias da Mama/metabolismo , Família de Proteínas EGF/metabolismo , Receptor alfa de Estrogênio/metabolismo , Estrogênios/metabolismo , Transdução de Sinais/fisiologia , Anfirregulina , Animais , Linhagem Celular Tumoral , Ensaio de Imunoadsorção Enzimática , Feminino , Xenoenxertos , Humanos , Imuno-Histoquímica , Camundongos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise Serial de Tecidos
9.
Neurobiol Aging ; 36(10): 2907.e1-10, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26166206

RESUMO

We examined the contribution of candidates genes for Alzheimer's disease (AD) to individual differences in levels of beta amyloid peptides in adults with Down syndrom, a population at high risk for AD. Participants were 254 non-demented adults with Down syndrome, 30-78 years of age. Genomic deoxyribonucleic acid was genotyped using an Illumina GoldenGate custom array. We used linear regression to examine differences in levels of Aß peptides associated with the number of risk alleles, adjusting for age, sex, level of intellectual disability, race and/or ethnicity, and the presence of the APOE ε4 allele. For Aß42 levels, the strongest gene-wise association was found for a single nucleotide polymorphism (SNP) on CAHLM1; for Aß40 levels, the strongest gene-wise associations were found for SNPs in IDE and SOD1, while the strongest gene-wise associations with levels of the Aß42/Aß40 ratio were found for SNPs in SORCS1. Broadly classified, variants in these genes may influence amyloid precursor protein processing (CALHM1, IDE), vesicular trafficking (SORCS1), and response to oxidative stress (SOD1).


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/sangue , DNA/genética , Síndrome de Down/sangue , Síndrome de Down/genética , Estudos de Associação Genética , Adulto , Idoso , Alelos , Apolipoproteínas E/genética , Canais de Cálcio/genética , Feminino , Técnicas de Genotipagem , Humanos , Modelos Lineares , Masculino , Glicoproteínas de Membrana/genética , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Fragmentos de Peptídeos/sangue , Polimorfismo de Nucleotídeo Único , Receptores de Superfície Celular/genética , Risco , Superóxido Dismutase/genética , Superóxido Dismutase-1
10.
Am J Reprod Immunol ; 74(3): 237-57, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26073538

RESUMO

PROBLEM: We have previously determined that long non-coding RNAs (lncRNAs) are differentially expressed in preterm premature rupture of membranes (PPROM) and hypothesized that the collagenolysis ubiquitin-proteasome system may be activated by infection and inflammation. However, direct evidence of the involvement of lncRNAs in transcriptional and posttranscriptional regulation of the infection-triggered alteration of collagen is lacking. METHOD OF STUDY: A previously developed mouse model with MHV68 viral infection was assessed to determine whether viral infection may induce differential expression of lncRNAs in mouse placentas and amniotic sacs. RESULTS: Differential expression of lncRNAs that are associated with collagen was found in HMV68 viral-infected, compared to non-infected, mouse placentas and amniotic sacs. Differential expression of messenger RNAs (mRNAs) of collagen was also documented. CONCLUSIONS: Our data demonstrate, for the first time, that viral infection may induce the differential expression of lncRNAs that are associated with collagen. Based on this finding, we propose that lncRNA may have involved in regulating of infection-induced collagen transcription.


Assuntos
Âmnio/metabolismo , Colágeno/metabolismo , Regulação Viral da Expressão Gênica , Placenta/metabolismo , RNA Longo não Codificante/metabolismo , Proteínas do Envelope Viral , Âmnio/virologia , Animais , Feminino , Ruptura Prematura de Membranas Fetais/metabolismo , Ruptura Prematura de Membranas Fetais/virologia , Perfilação da Expressão Gênica , Camundongos , Dados de Sequência Molecular , Placenta/virologia , Gravidez , RNA Longo não Codificante/genética
11.
BMC Pregnancy Childbirth ; 15: 35, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-25884766

RESUMO

BACKGROUND: Preterm premature rupture of membranes (PPROM) is responsible for one third of all preterm births (PTBs). We have recently demonstrated that long noncoding RNAs (lncRNAs) are differentially expressed in human placentas derived from PPROM, PTB, premature rupture of the membranes (PROM), and full-term birth (FTB), and determined the major biological pathways involved in PPROM. METHODS: Here, we further investigated the relationship of lncRNAs, which are differentially expressed in spontaneous PTB (sPTB) and PPROM placentas and are found to overlap a coding locus, with the differential expression of transcribed mRNAs at the same locus. Ten lncRNAs (five up-regulated and five down-regulated) and the lncRNA-associated 10 mRNAs (six up- and four down-regulated), which were identified by microarray in comparing PPROM vs. sPTB, were then validated by real-time quantitative PCR. RESULTS: A total of 62 (38 up- and 24 down-regulated) and 1,923 (790 up- and 1,133 down-regulated) lncRNAs were identified from placentas of premature labor (sPTB + PPROM), as compared to those from full-term labor (FTB + PROM) and from premature rupture of membranes (PPROM + PROM), as compared to those from non-rupture of membranes (sPTB + FTB), respectively. We found that a correlation existed between differentially expressed lncRNAs and their associated mRNAs, which could be grouped into four categories based on the gene strand (sense or antisense) of lncRNA and its paired transcript. These findings suggest that lncRNA regulates mRNA transcription through differential mechanisms. Differential expression of the transcripts PPP2R5C, STAM, TACC2, EML4, PAM, PDE4B, STAM, PPP2R5C, PDE4B, and EGFR indicated a co-expression among these mRNAs, which are involved in the ubiquitine-proteasome system (UPS), in addition to signaling transduction and beta adrenergic signaling, suggesting that imbalanced regulation of UPS may present an additional mechanism underlying the premature rupture of membrane in PPROM. CONCLUSION: Differentially expressed lncRNAs that were identified from the human placentas of sPTB and PPROM may regulate their associated mRNAs through differential mechanisms and connect the ubiquitin-proteasome system with infection-inflammation pathways. Although the detailed mechanisms by which lncRNAs regulate their associated mRNAs in sPTB and PPROM are yet to be clarified, our findings open a new approach to explore the pathogenesis of sPTB and PPROM.


Assuntos
Ruptura Prematura de Membranas Fetais , Complexo de Endopeptidases do Proteassoma , RNA Longo não Codificante , Ubiquitina , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas de Transporte/genética , Regulação para Baixo , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Epigênese Genética , Feminino , Ruptura Prematura de Membranas Fetais/genética , Ruptura Prematura de Membranas Fetais/patologia , Humanos , Recém-Nascido , Masculino , Fosfoproteínas/genética , Placenta/patologia , Gravidez , Nascimento Prematuro/genética , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteína Fosfatase 2/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Transdução de Sinais/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina/genética , Ubiquitina/metabolismo , Regulação para Cima
12.
Am J Reprod Immunol ; 72(4): 359-75, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24916667

RESUMO

PROBLEM: Spontaneous abortion (SA) occurs before 20 gestational weeks. Approximately, half of recurrent SA has no identifiable cause. No report has yet been investigated the possible involvement of lncRNA in pregnancy loss. METHOD OF STUDY: Sixteen pairs of pregnancies with spontaneous abortions (SA) and induced abortions (IA) were studied. Embryonic sacs and decidua were collected for each pregnancy. A Human LncRNA Array was employed to profile genomewide lncRNAs, which were then validated by RT-PCR. RESULTS: Differentially expressed lncRNAs were identified. Biological pathways were categorized into six major groups: infection and inflammation, metabolism, signaling and transcriptional regulation, smooth muscle contraction, cell process, and coagulation. CONCLUSIONS: Infection and inflammation pathways regulated by lncRNAs were determined as the predominant pathogenetic factors underlying the SA. Finding that antisense lncRNAs have been either up- or down-regulated suggests that they may have both cis- and trans-regulations.


Assuntos
Aborto Espontâneo/genética , Decídua/citologia , Regulação da Expressão Gênica no Desenvolvimento , Inflamação/genética , RNA Longo não Codificante/genética , Aborto Induzido , Sequência de Bases , Epigenômica , Feminino , Perfilação da Expressão Gênica , Humanos , Inflamação/imunologia , Análise de Sequência com Séries de Oligonucleotídeos , Gravidez , Complicações na Gravidez/genética , Análise de Sequência de RNA , Transdução de Sinais/genética
13.
Dev Dyn ; 243(2): 229-42, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24038847

RESUMO

BACKGROUND: The mammary gland is an ideal model to study the link between form and function in normal tissue. Perhaps as interesting as the cues necessary to generate this structure are the signals required to maintain its branched architecture over the lifetime of the organism, since likely these pathways are de-regulated in malignancies. Previously, we have shown that the Na(+) /H(+) exchanger 1 (NHE1), a critical regulator of intracellular pH, was necessary for mammary branching morphogenesis. Here we provide strong evidence that NHE1 function is also necessary for maintaining mammary branched architecture. RESULTS: Inhibition of NHE1 with 5-N-Methy-N-isobutyl amiloride (MIA) on branched structures resulted in a rapid (within 24 hr) and reversible loss of branched architecture that was not accompanied by any overt changes in cell proliferation or cell death. NHE1 inhibition led to a significant acidification of intracellular pH in the branched end buds that preceded a number of events, including altered tissue polarity of myoepithelial cells, loss of NHE1 basal polarity, F-actin rearrangements, and decreased E-cadherin expression. CONCLUSIONS: Our results implicate NHE1 function and intracellular pH homeostasis as key factors that maintain mammary tissue architecture, thus, indirectly allowing for mammary function as a milk-providing (form) and -producing (function) gland.


Assuntos
Proteínas de Transporte de Cátions/metabolismo , Polaridade Celular/fisiologia , Glândulas Mamárias Animais/anatomia & histologia , Glândulas Mamárias Animais/fisiologia , Trocadores de Sódio-Hidrogênio/metabolismo , Actinas/metabolismo , Amilorida/análogos & derivados , Amilorida/farmacologia , Animais , Caderinas/metabolismo , Proteínas de Transporte de Cátions/antagonistas & inibidores , Morte Celular/fisiologia , Células Cultivadas , Feminino , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Immunoblotting , Queratinas/metabolismo , Glândulas Mamárias Animais/efeitos dos fármacos , Camundongos , Faloidina , Trocador 1 de Sódio-Hidrogênio , Trocadores de Sódio-Hidrogênio/antagonistas & inibidores , Proteína da Zônula de Oclusão-1/metabolismo
14.
Brain Dev ; 36(4): 322-9, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23838310

RESUMO

The pathological role of autoantibodies in development of CNS disorders is a new idea with growing interest among neuroscientists. The involvement of autoimmune response in the pathogenesis of autism spectrum disorders (ASD) has been suggested by the presence of multiple brain-specific autoantibodies in children with ASD and in their mothers. The possibility of the effect of autoimmunity on neurogenesis and postnatal brain plasticity has not been determined. The presence of autoantibodies against human neuronal progenitor cells (NPCs) stimulated for neuronal differentiation in culture was tested in sera from children with autism (n=20) and age-matched controls (n=18) by immunoblotting and immunocytochemistry. Immunoreactivity against multiple NPCs proteins of molecular sizes of approximately 55 kDa, 105 kDa, 150 kDa, and 210 kDa in sera from individuals with autism had a higher incidence and was stronger than in control sera which immunoreacted mainly with a 150 kDa protein. The sera from children with autism immunoreacted the strongest with NPCs expressing neuronal markers Tuj1 and doublecortin, but not astrocyte marker GFAP. The epitopes recognized by antibodies from sera were not human-specific because they detected also NPCs in situ in murine hippocampus. The autoimmune reactions against NPCs suggest an impaired tolerance to neural antigens in autism. These autoantibodies may be symptomatic for autism and furthermore, their presence suggests that autoimmunity may affect postnatal neuronal plasticity particularly after impairment of blood-brain barrier. Future studies will determine the diagnostic value of the presence of autoantibodies in autism and the therapeutic value of prevention of autoimmunity in autism.


Assuntos
Transtorno Autístico/sangue , Autoanticorpos/sangue , Proteínas do Tecido Nervoso/imunologia , Células-Tronco Neurais/imunologia , Neurogênese/imunologia , Animais , Células Cultivadas , Pré-Escolar , Proteínas do Domínio Duplacortina , Feminino , Imunofluorescência , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/imunologia , Humanos , Immunoblotting , Imuno-Histoquímica , Lactente , Masculino , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Neuropeptídeos/metabolismo , Tubulina (Proteína)/metabolismo
15.
PLoS One ; 8(11): e79897, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24312190

RESUMO

Preterm birth (PTB) is a live birth delivered before 37 weeks of gestation (GW). About one-third of PTBs result from the preterm premature rupture of membranes (PPROM). Up to the present, the pathogenic mechanisms underlying PPROM are not clearly understood. Here, we investigated the differential expression of long chain non-coding RNAs (lncRNAs) in placentas of PTBs with PPROM, and their possible involvement in the pathogenic pathways leading to PPROM. A total number of 1954, 776, and 1050 lncRNAs were identified with a microarray from placentas of PPROM (group A), which were compared to full-term birth (FTB) (group B), PTB (group C), and premature rupture of membrane (PROM) (group D) at full-term, respectively. Instead of investigating the individual pathogenic role of each lncRNA involved in the molecular mechanism underlying PPROM, we have focused on investigating the metabolic pathways and their functions to explore what is the likely association and how they are possibly involved in the development of PPROM. Six groups, including up-regulation and down-regulation in the comparisons of A vs. B, A vs. C, and A vs. D, of pathways were analyzed. Our results showed that 22 pathways were characterized as up-regulated 7 down-regulated in A vs. C, 18 up-regulated and 15 down-regulated in A vs. D, and 33 up-regulated and 7 down-regulated in A vs. B. Functional analysis showed pathways of infection and inflammatory response, ECM-receptor interactions, apoptosis, actin cytoskeleton, and smooth muscle contraction are the major pathogenic mechanisms involved in the development of PPROM. Characterization of these pathways through identification of lncRNAs opened new avenues for further investigating the epigenomic mechanisms of lncRNAs in PPROM as well as PTB.


Assuntos
Epigênese Genética , Epigenômica , Ruptura Prematura de Membranas Fetais/genética , RNA Longo não Codificante/genética , Adulto , Epigenômica/métodos , Feminino , Ruptura Prematura de Membranas Fetais/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Redes e Vias Metabólicas , Anotação de Sequência Molecular , Gravidez , Nascimento Prematuro/genética , Nascimento Prematuro/metabolismo , RNA Longo não Codificante/metabolismo , Reprodutibilidade dos Testes
16.
Am J Med Genet B Neuropsychiatr Genet ; 159B(5): 598-604, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22592955

RESUMO

Previously, we established that short-term T lymphocyte cultures from people with Down syndrome (DS) and dementia (Alzheimer's disease) had shorter telomeres than did those from age- and sex-matched people with DS only, quantified as significantly reduced numbers of signals of peptide nucleic acid (PNA) telomere probes in whole metaphases [Jenkins et al. (2008); Neurosci Lett 440:340-343] as well as reduced telomere probe light intensity values in interphases [Jenkins et al. (2010); Neurobiol Aging 31:765-771]. We now describe shorter telomere length in adults with DS and mild cognitive impairment (MCI) compared to age- and sex-matched individuals with DS without MCI. Telomere length is quantified by reduced telomere signal numbers and shorter chromosome 1 telomeres measured in micrometers (microns). These findings were in agreement with quantitative light intensity measurements of chromosome 1 and chromosome 21 PNA telomere probes with and without the use of a "normalizing ratio" involving the fluorescence exhibited by a PNA probe for centromere 2, and with the use of light intensity measurements of interphase preparations. Most importantly, the distributions of chromosome 1 telomere lengths (in microns) were completely non-overlapping for adults with and without MCI, indicating that this measure has great promise as a biomarker for MCI as well as dementia in this population.


Assuntos
Disfunção Cognitiva/complicações , Disfunção Cognitiva/genética , Síndrome de Down/complicações , Síndrome de Down/genética , Encurtamento do Telômero/genética , Telômero/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Centrômero/metabolismo , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 21/genética , Feminino , Humanos , Interfase , Luz , Masculino , Metáfase , Pessoa de Meia-Idade , Ácidos Nucleicos Peptídicos/metabolismo
17.
Curr Gerontol Geriatr Res ; 2012: 974253, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22570648

RESUMO

A myriad of ophthalmic disorders is associated with the phenotype of Down syndrome including strabismus, cataracts, and refractive errors potentially resulting in significant visual impairment. Ophthalmic sequelae have been extensively studied in children and adolescents with Down syndrome but less often in older adults. In-depth review of medical records of older adults with Down syndrome indicated that ophthalmic disorders were common. Cataracts were the most frequent ophthalmic disorder reported, followed by refractive errors, strabismus, and presbyopia. Severity of intellectual disability was unrelated to the presence of ophthalmic disorders. Also, ophthalmic disorders were associated with lower vision-dependent functional and cognitive abilities, although not to the extent that was expected. The high prevalence of ophthalmic disorders highlights the need for periodic evaluations and individualized treatment plans for adults with Down syndrome, in general, but especially when concerns are identified.

18.
Am J Med Genet A ; 158A(5): 1060-5, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22489017

RESUMO

We reported previously that 10 older men (66.4 ± 4.6 years) with premutation alleles (55-200 CGG repeats) of the FMR1 gene, with or without FXTAS, had decreased telomere length when compared to sex- and age-matched controls. Extending our use of light intensity measurements from a telomere probe hybridized to interphase preparations, we have now found shortened telomeres in 9 younger male premutation carriers (31.7 ± 17.6 years). We have also shown decreased telomere length in T lymphocytes from 6 male individuals (12.0 ± 1.8 years) with full mutation FMR1 alleles (>200 CGG repeats). These findings support our hypothesis that reduced telomere length is a component of the sub-cellular pathology of FMR1-associated disorders. The experimental approach involved pair-wise comparisons of light intensity values of 20 cells from an individual with either premutation or full mutation CGG-repeat expansions relative to an equivalent number of cells from a sex- and age-matched control. In addition, we demonstrated reduced telomere size in T-lymphocyte cultures from eight individuals with the FMR1 premutation using six different measures. Four relied on detection of light intensity differences, and two involved measuring the whole chromosome, including the telomere, in microns. This new approach confirmed our findings with light intensity measurements and demonstrated the feasibility of direct linear measurements for detecting reductions in telomere size. We have thus confirmed our hypothesis that reduced telomere length is associated with both premutation and full mutation-FMR1 alleles and have demonstrated that direct measurements of telomere length can reliably detect such reductions.


Assuntos
Proteína do X Frágil da Deficiência Intelectual/genética , Mutação , Telômero/patologia , Adolescente , Adulto , Estudos de Casos e Controles , Pré-Escolar , Humanos , Luz , Masculino , Pessoa de Meia-Idade , Técnicas de Sonda Molecular , Sequências Repetitivas de Ácido Nucleico , Linfócitos T/ultraestrutura , Adulto Jovem
19.
Cryobiology ; 65(1): 72-3, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22465657

RESUMO

We have observed evidence of increased telomere shortening in short-term T-lymphocyte cultures following freezing and thawing of the original inoculum obtained by ficoll-paque gradient centrifugation, compared to T-lymphocytes that were cultured immediately without freezing and thawing from the same blood sample from 3 female and 3 male adults. Because freezing may have similar effects on other cell types, and because telomere shortening may only manifest its effects after many years or decades, we suggest there is a pressing need for evaluation of the effects of freezing on any cells envisioned for clinical applications, including embryo implantation.


Assuntos
Encurtamento do Telômero , Telômero/fisiologia , Adulto , Idoso , Feminino , Congelamento , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Linfócitos T/metabolismo , Telômero/genética , Telômero/metabolismo
20.
Int J Cell Biol ; 2012: 379685, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22536248

RESUMO

A large amount of data supports the view that PTEN is a bona fide tumor suppressor gene. However, recent evidence suggests that derailment of cellular localization and expression levels of functional nonmutated PTEN is a determining force in inducing abnormal cellular and tissue outcomes. As the cellular mechanisms that regulate normal PTEN enzymatic activity resolve, it is evident that deregulation of these mechanisms can alter cellular processes and tissue architecture and ultimately lead to oncogenic transformation. Here we discuss PTEN ubiquitination, PTEN complex formation with components of the adherens junction, PTEN nuclear localization, and microRNA regulation of PTEN as essential regulatory mechanisms that determine PTEN function independent of gene mutations and epigenetic events.

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