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1.
Mar Drugs ; 22(5)2024 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-38786608

RESUMO

We identified a new human voltage-gated potassium channel blocker, NnK-1, in the jellyfish Nemopilema nomurai based on its genomic information. The gene sequence encoding NnK-1 contains 5408 base pairs, with five introns and six exons. The coding sequence of the NnK-1 precursor is 894 nucleotides long and encodes 297 amino acids containing five presumptive ShK-like peptides. An electrophysiological assay demonstrated that the fifth peptide, NnK-1, which was chemically synthesized, is an effective blocker of hKv1.3, hKv1.4, and hKv1.5. Multiple-sequence alignment with cnidarian Shk-like peptides, which have Kv1.3-blocking activity, revealed that three residues (3Asp, 25Lys, and 34Thr) of NnK-1, together with six cysteine residues, were conserved. Therefore, we hypothesized that these three residues are crucial for the binding of the toxin to voltage-gated potassium channels. This notion was confirmed by an electrophysiological assay with a synthetic peptide (NnK-1 mu) where these three peptides were substituted with 3Glu, 25Arg, and 34Met. In conclusion, we successfully identified and characterized a new voltage-gated potassium channel blocker in jellyfish that interacts with three different voltage-gated potassium channels. A peptide that interacts with multiple voltage-gated potassium channels has many therapeutic applications in various physiological and pathophysiological contexts.


Assuntos
Peptídeos , Bloqueadores dos Canais de Potássio , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Cifozoários , Animais , Humanos , Bloqueadores dos Canais de Potássio/farmacologia , Bloqueadores dos Canais de Potássio/química , Canais de Potássio de Abertura Dependente da Tensão da Membrana/antagonistas & inibidores , Peptídeos/farmacologia , Peptídeos/química , Sequência de Aminoácidos , Venenos de Cnidários/farmacologia , Venenos de Cnidários/química , Alinhamento de Sequência
2.
J Fish Dis ; 47(1): e13865, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37731267

RESUMO

Enteromyxum leei and Enteromyxum fugu, which are myxosporean parasites, were first found in cultured tiger puffer Takifugu rubripes in Korea. We collected four tiger puffers that showed severe emaciation signs for our experiments. DNA sequencing was confirmed that the tiger puffers were coinfected with E. leei and E. fugu. Furthermore, similar amounts of E. leei and E. fugu were confirmed using real-time PCR in the intestine. To the best of our knowledge, there have been no reports of E. fugu infection in the olive flounder Paralichthys olivaceus. However, the diagnosis of inflowing water, discharged water and olive flounder samples using highly sensitive diagnostic methods confirmed the presence of E. fugu in water and fish samples from olive flounder farms near the tiger puffer farm. Therefore, the present study aimed to develop highly sensitive diagnostic methods such as real-time and two-step PCR for early diagnosis and follow-up of the emaciation disease and multiplex PCR for rapid diagnosis. The multiplex PCR method exhibited the same sensitivity as the one-step PCR method developed in this study, demonstrating its efficacy for rapid diagnosis. Therefore, the suggested methods can be utilized for the early diagnosis and rapid diagnosis of emaciation diseases and reduction of economic losses through rapid disease control.


Assuntos
Doenças dos Peixes , Linguado , Myxozoa , Animais , Takifugu , Emaciação , Doenças dos Peixes/diagnóstico , Doenças dos Peixes/parasitologia , Linguado/parasitologia , Myxozoa/genética , República da Coreia , Água
3.
J Med Virol ; 95(9): e29108, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37715715

RESUMO

Live varicella vaccines are known to provide robust immunity against varicella zoster virus (VZV) infections. However, problems with viral attenuation have led to pathogenic VZV vaccine strains causing varicella-like rash and herpes zoster in immunocompetent children after immunization. We report the first fatal case of VZV infection caused by OKA/SK strain contained in the vaccine administrated as a booster shot in an immunocompetent child, which has been independently developed from any currently available varicella vaccines that are OKA strain or MAV/06 strain based. The patient died due to sudden pulmonary alveolar hemorrhage as a secondary complication of VZV pneumonitis. Sequencing of the four SNPs unique to the OKA/SK strain (SNP loci 14 035T; 32 626C; 58 777G; 70 319G) enabled discrimination of the strain responsible for the disseminated infection. OKA/SK strain does not have any SNPs in ORF62 postulated to be responsible for the attenuation of varicella vaccines which have been safely and effectively used world-wide or locally, and exclusively enriches a virulent factor in ORF31 identified in parental OKA strain, thus possibly resulting in disseminated VZV infection leading to mortality. Therefore, actions need to be taken to prevent vaccine related morbidity and mortality in children.


Assuntos
Varicela , Vacina contra Herpes Zoster , Herpes Zoster , Vacinas Virais , Criança , Humanos , Varicela/complicações , Vacina contra Varicela/efeitos adversos , Vacinas Atenuadas , Antígenos Virais
4.
Dev Psychopathol ; 35(3): 1159-1170, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-34689856

RESUMO

Early life adversity (ELA) has been linked with increased arousal responses to threat, including increased amygdala reactivity. Effects of ELA on brain function are well recognized, and emerging evidence suggests that caregivers may influence how environmental stressors impact children's brain function. We investigated the hypothesis that positive interaction between mother and child can buffer against ELA effects on children's neural responses to threat, and related symptoms. N = 53 mother-child pairs (children ages 8-14 years) were recruited from an urban population at high risk for violence exposure. Maternal caregiving was measured using the Parenting Questionnaire and in a cooperation challenge task. Children viewed fearful and neutral face stimuli during functional magnetic resonance imaging. Children who experienced greater violence at home showed amygdala sensitization, whereas children experiencing more school and community violence showed amygdala habituation. Sensitization was in turn linked with externalizing symptoms. However, maternal warmth was associated with a normalization of amygdala sensitization in children, and fewer externalizing behaviors prospectively up to 1 year later. Findings suggested that the effects of violence exposure on threat-related neural circuitry depend on trauma context (inside or outside the home) and that primary caregivers can increase resilience.


Assuntos
Exposição à Violência , Violência , Feminino , Humanos , Mães , Tonsila do Cerebelo/diagnóstico por imagem , Medo
5.
Biochem Biophys Res Commun ; 607: 1-8, 2022 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-35358871

RESUMO

Drug-induced liver injury (DILI) is a condition caused by drugs that leads to abnormal hepatic function. Hepatotoxicity caused by DILI has been shown to be due to cellular stress, mitochondrial dysfunction, cell necrosis and apoptosis and many types of hepatotoxicity, such as phospholipidosis, steatosis and hepatitis, commonly share intracellular molecular mechanisms. Metabolomics can be useful for mechanism-based toxicity evaluations and has been recently utilized as a scientific technique that can effectively predict the risk factors for chemical substances. To evaluate the key events in hepatotoxicity associated with lysosomal phospholipase A2 (LPLA2) inhibition by cationic amphiphilic drugs (CADs), LPLA2 inhibition assays and phospholipid accumulation assays were performed in HepG2 cells. Additionally, to suggest the integrative molecular mechanisms of hepatotoxicity by CADs, we profiled intracellular metabolites. Cell-based metabolomics was performed using an UPLC-Orbitrap-MS instrument equipped with heated electrospray ionization in positive and negative ion modes. As a result, CADs such as amiodarone, fluoxetine, chlorpromazine and tamoxifen significantly inhibited LPLA2 and accumulated phospholipids. In metabolomics, a total of 17 significant metabolites were identified, and the changed metabolite types were as follows: nucleotide sugars, conjugated bile acids, branched-chain amino acids, polyamine biosynthesis, and long-chain fatty acid and glycerophospholipid metabolism. From these data, it was suggested that the integrative mechanism of DILI could be verified and that a toxicological approach is possible using metabolomics.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Cátions , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Humanos , Lisossomos/metabolismo , Metabolômica , Fosfolipases A2/metabolismo , Fosfolipídeos/metabolismo
6.
Psychosom Med ; 84(9): 1013-1020, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35980788

RESUMO

OBJECTIVE: Experiences of child maltreatment are associated with cardiovascular risk and disease in adulthood; however, the mechanisms underlying these associations are poorly understood. METHODS: We examined associations between retrospectively self-reported exposure to child maltreatment (Early Trauma Inventory Self-Report Short Form) and inflammatory responses to mental stress among adults (mean age = 50 years) who recently had a myocardial infarction ( n = 227). Inflammation was assessed as blood interleukin-6 (IL-6), matrix metalloproteinase-9 (MMP-9), and monocyte chemoattractant protein-1 concentrations, measured before and after a standardized public speaking stress task. We used mixed linear regression models adjusting for cardiovascular disease severity, medication usage, and psychosocial, demographic, and life-style factors. RESULTS: In women, increases in IL-6 levels and MMP-9 levels with stress were smaller in those exposed to sexual abuse, relative to those unexposed (IL-6 geometric mean increases = 1.6 [95% confidence interval {CI} = 1.4-1.9] pg/ml versus 2.1 [95% CI = 1.8-2.4] pg/ml; MMP-9 geometric mean increases = 1.0 [95% CI = 0.9-1.2] ng/ml versus 1.2 [95% CI = 1.1-1.4] ng/ml). No differences were noted for emotional or physical abuse. By contrast in men, individuals exposed to sexual abuse had larger IL-6 responses than those not exposed to abuse. CONCLUSIONS: These findings suggest sex differences in stress response among survivors of a myocardial infarction exposed to abuse early in life. They also underscore the importance of examining sex as an effect modifier of relationships between exposure to early life adversity and inflammatory responses to mental stressors in midlife.


Assuntos
Maus-Tratos Infantis , Infarto do Miocárdio , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metaloproteinase 9 da Matriz , Interleucina-6 , Estudos Retrospectivos , Maus-Tratos Infantis/psicologia , Infarto do Miocárdio/epidemiologia
7.
Optom Vis Sci ; 99(4): 372-382, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35383736

RESUMO

SIGNIFICANCE: Both the Melbourne Rapid Fields (MRF) tablet and home versions are easy-to-use, portable, and low-cost and accurate methods of evaluating visual fields. PURPOSE: This study aimed to investigate the clinical capabilities of the MRF perimetry test by comparing it with the Humphrey Field Analyzer (HFA), determine MRF consistency, assess the influence of refractive error, ascertain ambient illumination effects, and evaluate the consistency between the tablet and Internet Web site versions of the MRF. METHODS: Forty healthy young participants with normal visual function (33 female, 7 male; average age, 24 years) underwent two MRF office-based tablet, two HFA tests, and two MRF Web site-based tests, one in our laboratory and one at home on their own computer using the 24-2 test pattern each time. An additional six healthy participants with normal visual function performed the 24-2 test with varying amounts of blur. RESULTS: The average individual sensitivity values of MRF and HFA were within 4.02 dB (right eye) and 4.15 dB (left eye). The dynamic range of the MRF was smaller (30 dB) than that of the HFA. When sensitivity values greater than 30 dB were excluded, the sensitivity differences were within 2.2 dB (right eye) and 2.46 dB (left eye) of each other. Only a small number of cases produced reliability values (false positives, false negatives, fixation losses) that were outside of normal limits. There was a high correlation between test results obtained with the tablet version of the MRF test when compared with the Internet-based Web site version. CONCLUSIONS: Quantitative visual field testing and perimetric screening procedures can be performed effectively and can provide results that are comparable with bowl perimeter test results.


Assuntos
Erros de Refração , Testes de Campo Visual , Adulto , Olho , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , Campos Visuais , Adulto Jovem
8.
J Trauma Stress ; 35(2): 521-532, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35032417

RESUMO

Early life stress (ELS) has been associated with an increased risk of cardiovascular disease. We examined whether ELS was associated with autonomic function and stress reactivity among individuals with coronary heart disease (CHD). We included patients with stable CHD from two parallel studies, the Mental Stress Ischemia Prognosis Study (MIPS) and the Myocardial Infarction and Mental Stress Study 2 (MIMS2), and assessed ELS using the Early Trauma Inventory-Self-Report-Short Form. Participants underwent a laboratory-based mental stress task while undergoing ambulatory electrocardiographic monitoring. We used multivariate linear regression models to estimate the associations between ELS and heart rate variability (HRV; low frequency [LF], high frequency [HF], and LF and HF [LH] ratio). The analytic sample included 405 MIPS and 284 MIMS2 participants. Most participants endorsed at least one experience of ELS (92.2%). Although we did not observe associations between ELS and HRV outcomes in the overall sample, ELS was associated with lower LH ratio HRV during recovery in the posttraumatic stress disorder (PTSD) subgroup, ELS x PTSD interaction, p = .041. In the MIMS2 subgroup, ELS was associated with lower resting period LF HRV, B ̂ $ \widehat{B} $  = -0.16 ln ms2 ; 95% CI [-0.31, -0.02]. Exposure to physical trauma was associated with decreased HF HRV overall reactivity only among participants with high to moderate depressive symptoms, B ̂ $ \widehat{B} $  = -0.52 ln ms2 vs. B ̂ $ \widehat{B} $  = 0.01 ln ms2 , p = .013. Overall, heterogeneous associations between ELS and HRV emerged, suggesting the need for additional research regarding longer-term ambulatory HRV.


Assuntos
Experiências Adversas da Infância , Doença das Coronárias , Transtornos de Estresse Pós-Traumáticos , Sistema Nervoso Autônomo , Frequência Cardíaca/fisiologia , Humanos
9.
Mar Drugs ; 20(5)2022 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-35621979

RESUMO

Discovering new drug candidates with high efficacy and few side effects is a major challenge in new drug development. The two evolutionarily related peptides oxytocin (OXT) and arginine vasopressin (AVP) are known to be associated with a variety of physiological and psychological processes via the association of OXT with three types of AVP receptors. Over decades, many synthetic analogs of these peptides have been designed and tested for therapeutic applications; however, only a few studies of their natural analogs have been performed. In this study, we investigated the bioactivity and usefulness of two natural OXT/AVP analogs that originate from the marine invertebrate Octopus vulgaris, named octopressin (OTP) and cephalotocin (CPT). By measuring the intracellular Ca2+ or cyclic AMP increase in each OXT/AVP receptor subtype-overexpressing cell, we found that CPT, but not OTP, acts as a selective agonist of human AVP type 1b and 2 receptors. This behavior is reminiscent of desmopressin, the most widely prescribed antidiuretic drug in the world. Similar to the case for desmopressin, a single intravenous tail injection of CPT into Sprague-Dawley rats reduced urine output and increased urinary osmolality. In conclusion, we suggest that CPT has a significant antidiuretic effect and that CPT might be beneficial for treating urological conditions such as nocturia, enuresis, and diabetes insipidus.


Assuntos
Antidiuréticos , Octopodiformes , Ocitocina , Animais , Antidiuréticos/farmacologia , Arginina Vasopressina/análogos & derivados , Desamino Arginina Vasopressina/farmacologia , Felipressina/farmacologia , Octopodiformes/metabolismo , Ocitocina/análogos & derivados , Ocitocina/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Vasopressinas/agonistas , Receptores de Vasopressinas/metabolismo
10.
Toxicol Appl Pharmacol ; 428: 115696, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34419494

RESUMO

Bisphenol A (BPA) is a well-known endocrine-disrupting chemical that is widely used in a variety of products, including plastics, medical equipment and receipts. Hence, most people are exposed to BPA through the skin, via inhalation and via the digestive system, and such exposure has been linked to cardiovascular diseases including coronary artery disease, hypertension, atherosclerosis, and myocardial infarction. However, the underlying mechanisms of cardiac dysfunction caused by BPA remain poorly understood. In this study, we found that BPA exposure altered cardiac function in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Acute BPA exposure in hiPSC-CMs resulted in reduced field potential, as measured by multielectrode array (MEA). Furthermore, we observed that BPA dose-dependently inhibited ICa, INa or IKr channels. In addition, BPA exposure dose-dependently inhibited calcium transients and contraction in hiPSC-CMs. Our findings suggest that BPA exposure leads to cardiac dysfunction and cardiac risk factors such as arrhythmia.


Assuntos
Poluentes Ocupacionais do Ar/toxicidade , Compostos Benzidrílicos/toxicidade , Cardiotoxinas/toxicidade , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Fenóis/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia
11.
Nanotechnology ; 32(27)2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33780921

RESUMO

Photodynamic therapy (PDT) has been extensively explored as a promising alternative therapeutic approach for many malignant tumors. However, the PDT system generally involves unsatisfactory tumor specificity and nonspecific accumulation of photosensitizers around the target cancer cells, leading to phototoxic damage to adjacent healthy normal cells. In this study, we developed pheophorbide a (Pheo a)/human epidermal growth factor receptor 2 (HER2) targeting peptide (epitope form, HLTV, PEG2-LTVSPWY)-co-conjugated methoxy poly(ethylene glycol)-block-poly(L-lysine hydrochloride) (PEG-PLL)/hyaluronic acid (HA) (P3H2) polymeric micelles via a self-assembly method for HER2-targeted PDT treatment for breast cancer, thereby enhancing the PDT efficacy. The synthesized P3H2 polymeric micelles were spherical, with an average diameter of 125.7 ± 21.2 nm in an aqueous solution. The results ofin vitrocytotoxicity assays demonstrated that the P3H2 polymeric micelles significantly improved PDT efficacy on the SK-BR-3 cells due to the enhanced targeting ability. In addition, PDT treatment using the P3H2 polymeric micelles effectively killed breast cancer cells by inducing higher intracellular reactive oxygen species generation and apoptotic cell death. In particular, the three-dimensional cell culture model proved the synergistic PDT efficacy using P3H2 polymeric micelles on the SK-BR-3 cells. Based on these results, the PDT treatment using P3H2 polymeric micelles can serve as a highly effective therapeutic modality for breast cancer.


Assuntos
Apoptose/efeitos dos fármacos , Micelas , Fármacos Fotossensibilizantes/farmacologia , Receptor ErbB-2/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Clorofila/análogos & derivados , Clorofila/química , Clorofila/farmacologia , Clorofila/uso terapêutico , Feminino , Humanos , Ácido Hialurônico/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêutico , Polietilenoglicóis/química , Polilisina/química
12.
Int J Mol Sci ; 22(19)2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34638948

RESUMO

We reveal the significance of plasmonic nanoparticle's (NP) shape and its surface morphology en route to an efficient self-assembled plasmonic nanoparticle cluster. A simplified model is simulated in the form of free-space dimer and trimer nanostructures (NPs in the shape of a sphere, cube, and disk). A ~200% to ~125% rise in near-field strength (gap mode enhancement) is observed for spherical NPs in comparison with cubical NPs (from 2 nm to 8 nm gap sizes). Full-width three-quarter maximum reveals better broad-spectral optical performance in a range of ~100 nm (dimer) and ~170 nm (trimer) from spherical NPs as compared to a cube (~60 nm for dimer and trimer). These excellent properties for sphere-based nanostructures are merited from its dipole mode characteristics.


Assuntos
Dimerização , Nanopartículas Metálicas/química , Nanotecnologia/métodos , Ressonância de Plasmônio de Superfície/métodos , Simulação por Computador , Campos Eletromagnéticos , Luz , Modelos Químicos , Tamanho da Partícula , Propriedades de Superfície
13.
J Virol ; 92(15)2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29743376

RESUMO

Interferon-stimulated gene 15 (ISG15) encodes a ubiquitin-like protein that can be conjugated to proteins via an enzymatic cascade involving the E1, E2, and E3 enzymes. ISG15 expression and protein ISGylation modulate viral infection; however, the viral mechanisms regulating the function of ISG15 and ISGylation are not well understood. We recently showed that ISGylation suppresses the growth of human cytomegalovirus (HCMV) at multiple steps of the virus life cycle and that the virus-encoded pUL26 protein inhibits protein ISGylation. In this study, we demonstrate that the HCMV UL50-encoded transmembrane protein, a component of the nuclear egress complex, also inhibits ISGylation. pUL50 interacted with UBE1L, an E1-activating enzyme for ISGylation, and (to a lesser extent) with ISG15, as did pUL26. However, unlike pUL26, pUL50 caused proteasomal degradation of UBE1L. The UBE1L level induced in human fibroblast cells by interferon beta treatment or virus infection was reduced by pUL50 expression. This activity of pUL50 involved the transmembrane (TM) domain within its C-terminal region, although pUL50 could interact with UBE1L in a manner independent of the TM domain. Consistently, colocalization of pUL50 with UBE1L was observed in cells treated with a proteasome inhibitor. Furthermore, we found that RNF170, an endoplasmic reticulum (ER)-associated ubiquitin E3 ligase, interacted with pUL50 and promoted pUL50-mediated UBE1L degradation via ubiquitination. Our results demonstrate a novel role for the pUL50 transmembrane protein of HCMV in the regulation of protein ISGylation.IMPORTANCE Proteins can be conjugated covalently by ubiquitin or ubiquitin-like proteins, such as SUMO and ISG15. ISG15 is highly induced in viral infection, and ISG15 conjugation, termed ISGylation, plays important regulatory roles in viral growth. Although ISGylation has been shown to negatively affect many viruses, including human cytomegalovirus (HCMV), viral countermeasures that might modulate ISGylation are not well understood. In the present study, we show that the transmembrane protein encoded by HCMV UL50 inhibits ISGylation by causing proteasomal degradation of UBE1L, an E1-activating enzyme for ISGylation. This pUL50 activity requires membrane targeting. In support of this finding, RNF170, an ER-associated ubiquitin E3 ligase, interacts with pUL50 and promotes UL50-mediated UBE1L ubiquitination and degradation. Our results provide the first evidence, to our knowledge, that viruses can regulate ISGylation by directly targeting the ISGylation E1 enzyme.


Assuntos
Citomegalovirus/metabolismo , Regulação para Baixo , Fibroblastos/metabolismo , Proteólise , Enzimas Ativadoras de Ubiquitina/metabolismo , Ubiquitinação , Proteínas Virais/metabolismo , Citomegalovirus/genética , Fibroblastos/virologia , Glicosilação , Células HEK293 , Humanos , Domínios Proteicos , Enzimas Ativadoras de Ubiquitina/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Virais/genética
15.
Depress Anxiety ; 36(7): 647-658, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31260599

RESUMO

BACKGROUND: Amygdala hyperreactivity to threat has been proposed to be a causal contributor to posttraumatic stress disorder (PTSD). However, emerging literature in healthy samples shows higher test-retest reliability for amygdala habituation (the change over time in response to repeated stimuli) than for its reactivity to threat. Amygdala habituation has received relatively little attention in relationship to PTSD, despite the key role of this region in the etiology of the disorder. Thus, we investigated habituation to repeated fearful face stimuli and PTSD, in a large sample of trauma exposed African American women. METHODS: African American women (N = 100) were recruited from a nonprofit hospital serving a largely low-income population with a high risk of trauma exposure. Participants underwent functional magnetic resonance imaging, passively viewing fearful and neutral face stimuli, and reported their history of trauma exposure and current PTSD symptoms. We examined associations between PTSD symptom severity and amygdala reactivity (fearful > neutral) and habituation (early > late) to fearful faces. Secondary analyses tested whether amygdala habituation to fearful faces mediated the association between childhood trauma and PTSD. RESULTS: PTSD symptom severity and PTSD status (based on self-report measure) were both positively associated with amygdala habituation to repeated fearful face stimuli. Whole-brain analysis showed that this association extended to the bilateral hippocampus and left fusiform gyrus. The association held when controlling for trauma history and depressive symptoms. Amygdala habituation to fearful faces partially mediated the association between childhood trauma severity and PTSD symptom severity. CONCLUSION: Individuals with greater PTSD symptom severity showed greater amygdala habituation to social threat cues (fearful faces), and greater habituation may partly explain the association between childhood trauma exposure and current PTSD symptoms. Further examination of the dynamics of the amygdala response to threat cues may lead to new insights in the understanding and treatment of stress-related disorders.


Assuntos
Tonsila do Cerebelo/fisiopatologia , Medo/fisiologia , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Adulto , Mapeamento Encefálico , Criança , Sinais (Psicologia) , Expressão Facial , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Adulto Jovem
16.
PLoS Pathog ; 12(8): e1005850, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27564865

RESUMO

Interferon-stimulated gene 15 (ISG15) encodes an ubiquitin-like protein that covalently conjugates protein. Protein modification by ISG15 (ISGylation) is known to inhibit the replication of many viruses. However, studies on the viral targets and viral strategies to regulate ISGylation-mediated antiviral responses are limited. In this study, we show that human cytomegalovirus (HCMV) replication is inhibited by ISGylation, but the virus has evolved multiple countermeasures. HCMV-induced ISG15 expression was mitigated by IE1, a viral inhibitor of interferon signaling, however, ISGylation was still strongly upregulated during virus infection. RNA interference of UBE1L (E1), UbcH8 (E2), Herc5 (E3), and UBP43 (ISG15 protease) revealed that ISGylation inhibits HCMV growth by downregulating viral gene expression and virion release in a manner that is more prominent at low multiplicity of infection. A viral regulator pUL26 was found to interact with ISG15, UBE1L, and Herc5, and be ISGylated. ISGylation of pUL26 regulated its stability and inhibited its activities to suppress NF-κB signaling and complement the growth of UL26-null mutant virus. Moreover, pUL26 reciprocally suppressed virus-induced ISGylation independent of its own ISGylation. Consistently, ISGylation was more pronounced in infections with the UL26-deleted mutant virus, whose growth was more sensitive to IFNß treatment than that of the wild-type virus. Therefore, pUL26 is a viral ISG15 target that also counteracts ISGylation. Our results demonstrate that ISGylation inhibits HCMV growth at multiple steps and that HCMV has evolved countermeasures to suppress ISG15 transcription and protein ISGylation, highlighting the importance of the interplay between virus and ISGylation in productive viral infection.


Assuntos
Citocinas/metabolismo , Infecções por Citomegalovirus/imunologia , Regulação Viral da Expressão Gênica/fisiologia , Interações Hospedeiro-Parasita/fisiologia , Ubiquitinas/metabolismo , Proteínas Virais/metabolismo , Linhagem Celular , Citocinas/imunologia , Citomegalovirus/imunologia , Citomegalovirus/metabolismo , Infecções por Citomegalovirus/metabolismo , Imunofluorescência , Humanos , Immunoblotting , Imunoprecipitação , Reação em Cadeia da Polimerase , Transfecção , Técnicas do Sistema de Duplo-Híbrido , Ubiquitinas/imunologia , Proteínas Virais/imunologia
17.
J Org Chem ; 83(22): 13847-13853, 2018 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-30351945

RESUMO

Birch reduction of aromatic systems by solvated electrons in alkali metal-ammonia solutions is widely recognized as a key reaction that functionalizes highly stable π-conjugated organic systems. In spite of recent advances in Birch reduction with regard to reducing agent and reaction conditions, there remains an ongoing challenge to develop a simple and efficient Birch reaction under mild conditions. Here, we demonstrate that the inorganic electride [Ca2N]+•e- promotes the Birch reduction of polycyclic aromatic hydrocarbons (PAHs) and naphthalene under alcoholic solvent in the vicinity of room temperature as a solid-type analogy to solvated electrons in alkali metal ammonia solutions. The anionic electrons from electride [Ca2N]+•e- are transferred to PAHs and naphthalene via alcoholysis in a polar cosolvent medium. It is noteworthy that a high conversion yield to the hydrogenated products is ascribed to the extremely high electron transfer efficiency of 98%. This simple protocol utilizing an inorganic electride offers a direct and practical strategy for the reduction of aromatic compounds and provides an outstanding reducing agent for synthetic chemistry.

18.
Retina ; 38(11): 2168-2176, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28930802

RESUMO

PURPOSE: To investigate morphologic features associated with fibrotic scarring after anti-vascular endothelial growth factor therapy in polypoidal choroidal vasculopathy (PCV). METHODS: This retrospective study included 293 patients who had been diagnosed with PCV and treated with anti-vascular endothelial growth factor monotherapy during a 12-month follow-up period. Associations of morphologic features, including type of PCV, location of the polypoidal lesion, greatest linear dimension, largest polyp diameter, choroidal vascular hyperpermeability, pigment epithelial detachment, intraretinal fluid, and subretinal hyperreflective material (SHRM) with fibrotic scar at 12 months were analyzed. RESULTS: Fibrotic scars were noted in 15 eyes (5.1%). The incidence of fibrotic scars was higher in Type 1 PCV (8 of 76 eyes) than in Type 2 PCV (7 of 217 eyes, P = 0.028). The incidence was also higher in eyes with SHRM (14 of 124 eyes) than in eyes without SHRM (1 of 169 eyes, P < 0.001). In multivariate analysis, SHRM was associated with fibrotic scar (P = 0.005). Among the SHRM cases, the incidence of the scar was 12.9% in eyes with submacular hemorrhage and 8.5% in eyes without hemorrhage. CONCLUSION: Although fibrotic scar is an infrequent finding in PCV, the possibility of scarring should be considered in eyes with SHRM, particularly in submacular hemorrhage cases.


Assuntos
Doenças da Coroide/diagnóstico , Corioide/irrigação sanguínea , Pólipos/diagnóstico , Ranibizumab/efeitos adversos , Acuidade Visual , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Corioide/diagnóstico por imagem , Doenças da Coroide/tratamento farmacológico , Cicatriz/etiologia , Cicatriz/patologia , Fibrose/patologia , Angiofluoresceinografia , Seguimentos , Fundo de Olho , Humanos , Injeções Intravítreas , Pólipos/tratamento farmacológico , Ranibizumab/administração & dosagem , Estudos Retrospectivos , Fatores de Tempo , Tomografia de Coerência Óptica , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
19.
Langmuir ; 33(4): 954-958, 2017 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-28068474

RESUMO

Halogenated organic compounds are important anthropogenic chemicals widely used in chemical industry, biology, and pharmacology; however, the persistence and inertness of organic halides cause human health problems and considerable environmental pollution. Thus, the elimination or replacement of halogen atoms with organic halides has been considered a central task in synthetic chemistry. In dehalogenation reactions, the consecutive single-electron transfer from reducing agents generates the radical and corresponding carbanion and thus removes the halogen atom as the leaving group. Herein, we report a new strategy for an efficient chemoselective hydrodehalogenation through the formation of stable carbanion intermediates, which are simply achieved by using highly mobile two-dimensional electrons of inorganic electride [Ca2N]+·e- with effective electron transfer ability. The consecutive single-electron transfer from inorganic electride [Ca2N]+·e- stabilized free carbanions, which is a key step in achieving the selective reaction. Furthermore, a determinant more important than leaving group ability is the stability control of free carbanions according to the s character determined by the backbone structure. We anticipate that this approach may provide new insight into selective chemical formation, including hydrodehalogenation.

20.
J Am Chem Soc ; 138(8): 2496-9, 2016 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-26840946

RESUMO

Angle-resolved photoemission spectroscopy (ARPES) study of a layered electride Ca2N was carried out to reveal its quasi-two-dimensional electronic structure. The band dispersions and the Fermi-surface map are consistent with the density functional theory results except for a chemical potential shift that may originate from the high reactivity of surface excess electrons. Thus, the existence of anionic excess electrons in the interlayer region of Ca2N is strongly supported by ARPES.

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