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1.
Anesthesiology ; 2022 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-36538354

RESUMO

BACKGROUND: Delirium poses significant risks to patients, but countermeasures can be taken to mitigate negative outcomes. Accurately forecasting delirium in ICU patients could guide proactive intervention. Our primary objective was to predict ICU delirium by applying machine learning to clinical and physiological data routinely collected in electronic health records. METHODS: Two prediction models were trained and tested using a multi-center database (years of data collection 2014-15), and externally validated on two single-center databases (2001-2012 and 2008-2019). The primary outcome variable was delirium defined as a positive Confusion Assessment Method for the ICU screen, or an Intensive Care Delirium Screening Checklist ≥4. The first model, named "24-hour model", used data from the 24 hours following ICU admission to predict delirium any time afterwards. The second model designated "dynamic model", predicted the onset of delirium up to 12 hours in advance. Model performance was compared to results using features from a widely-cited reference model. RESULTS: For the 24-hour model, delirium was identified in 2,536/18,305 (13.9%), 768/5,299 (14.5%), and 5,955/36,194 (11.9%) of patient stays respectively in the development sample and two validation samples. For the 12-hour lead time dynamic model, delirium was identified in 3,791/22,234 (17.0%), 994/6,166 (16.1%), and 5,955/28,440 (20.9%) patient stays, respectively. Mean AUC (95% CI) for the first 24-hour model was 0.785 (0.769, 0.801), significantly higher than the modified reference model with AUC of 0.730 (0.704, 0.757). The dynamic model had a mean AUC of 0.845 (0.831, 0.859) when predicting delirium 12 hours in advance. Calibration was similar in both models (mean Brier Score [95% CI] 0.102 [0.097, 0.108] and 0.111 [0.106, 0.116]). Model discrimination and calibration were maintained when tested on the validation datasets. CONCLUSIONS: Machine learning models trained with clinical and physiological data predict ICU delirium and support dynamic time-sensitive forecasting.

2.
Sci Data ; 9(1): 442, 2022 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-35871169

RESUMO

Widespread sex-dimorphism is observed in the mammalian immune system. Consistently, studies have reported sex differences in the transcriptome of immune cells at the bulk level, including neutrophils. Neutrophils are the most abundant cell type in human blood, and they are key components of the innate immune system as they form a first line of defense against pathogens. Neutrophils are produced in the bone marrow, and differentiation and maturation produce distinct neutrophil subpopulations. Thus, single-cell resolution studies are crucial to decipher the biological significance of neutrophil heterogeneity. However, since neutrophils are very RNA-poor, single-cell profiling of these cells has been technically challenging. Here, we generated a single-cell RNA-seq dataset of primary neutrophils from adult female and male mouse bone marrow. After stringent quality control, we found that previously characterized neutrophil subpopulations can be detected in both sexes. Additionally, we confirmed that canonical sex-linked markers are differentially expressed between female and male cells across neutrophil subpopulations. This dataset provides a groundwork for comparative studies on the lifelong transcriptional sexual dimorphism of neutrophils.


Assuntos
Medula Óssea , Neutrófilos , RNA-Seq , Animais , Medula Óssea/metabolismo , Diferenciação Celular , Feminino , Masculino , Camundongos , Neutrófilos/metabolismo , Análise de Célula Única , Transcriptoma
3.
Diagn Cytopathol ; 50(5): 235-252, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35092649

RESUMO

BACKGROUND: Ancillary studies are commonly performed on cell blocks prepared from fine-needle aspiration (FNA) specimens. There are limited studies in application of ancillary studies on cell blocks from salivary gland (SG) FNAs. This multi-institutional study evaluates the role of ancillary studies performed on cell blocks in the diagnosis of SG lesions, and their impact on clinical management. METHOD: The electronic pathology archives of three large academic institutions were searched for SG FNAs with ancillary studies performed on cell blocks. The patient demographics, FNA site, cytologic diagnosis, ancillary studies, and surgical follow-up were recorded. If needed, the cytologic diagnoses were reclassified as per the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC). RESULTS: 117 SG FNA cases were identified including 3, 10, 11, 6, 23, 4, and 60 cases in MSRSGC categories I, II, III, IVa, IVb, V, VI, respectively with surgical follow-up available ranging from 27% to 100% within each category. Ancillary studies including histochemistry, immunocytochemistry (IHC), and in situ hybridization (ISH) were beneficial in 60%-100% of cases in each category. Risk of malignancy was 100% in both the suspicious for malignancy (V) and malignant (VI) categories. Ancillary studies improved diagnosis in 60% of non-neoplastic cases (II, 6/10), 100% of benign neoplasm cases (IVa, 6/6), and 98.3% of malignant cases (VI, 59/60). CONCLUSION: Judicious and case-based ancillary studies performed on SG FNA cell blocks with sufficient material can improve the diagnostic yield by further characterization of the atypical/neoplastic cells, particularly in MSRSGC categories IVa-VI.


Assuntos
Neoplasias das Glândulas Salivares , Biópsia por Agulha Fina , Histocitoquímica , Humanos , Estudos Retrospectivos , Neoplasias das Glândulas Salivares/diagnóstico , Neoplasias das Glândulas Salivares/patologia , Glândulas Salivares/patologia
4.
Brief Funct Genomics ; 21(1): 43-55, 2022 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-33690792

RESUMO

The aging population is at a higher risk for age-related diseases and infections. This observation could be due to immunosenescence: the decline in immune efficacy of both the innate and the adaptive immune systems. Age-related immune decline also links to the concept of 'inflamm-aging,' whereby aging is accompanied by sterile chronic inflammation. Along with a decline in immune function, aging is accompanied by a widespread of 'omics' remodeling. Transcriptional landscape changes linked to key pathways of immune function have been identified across studies, such as macrophages having decreased expression of genes associated to phagocytosis, a major function of macrophages. Therefore, a key mechanism underlying innate immune cell dysfunction during aging may stem from dysregulation of youthful genomic networks. In this review, we discuss both molecular and cellular phenotypes of innate immune cells that contribute to age-related inflammation.


Assuntos
Imunossenescência , Idoso , Envelhecimento/genética , Genômica , Humanos , Sistema Imunitário , Imunossenescência/fisiologia , Inflamação/genética
5.
STAR Protoc ; 2(4): 100948, 2021 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-34820637

RESUMO

Studies involving neutrophils are steadily increasing, thus creating a need for more optimized and thorough protocols for studying neutrophil function. Here, we present our protocol for extracting mouse bone marrow neutrophils, estimating the purity of isolated neutrophils, and assessing their ability to induce NETosis upon an external cue. We test two isolation protocols that can be used to attain neutrophils to assess NETosis induction. This approach allows for the parallel assessment of NETosis induction in cohorts larger than 10 samples. For complete details on the use and execution of this protocol, please refer to Lu et al., 2021.


Assuntos
Armadilhas Extracelulares/metabolismo , Citometria de Fluxo/métodos , Neutrófilos/citologia , Animais , Células Cultivadas , Feminino , Masculino , Camundongos
6.
Elife ; 102021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34448454

RESUMO

Longevity is often associated with stress resistance, but whether they are causally linked is incompletely understood. Here we investigate chemosensory-defective Caenorhabditis elegans mutants that are long-lived and stress resistant. We find that mutants in the intraflagellar transport protein gene osm-3 were significantly protected from tunicamycin-induced ER stress. While osm-3 lifespan extension is dependent on the key longevity factor DAF-16/FOXO, tunicamycin resistance was not. osm-3 mutants are protected from bacterial pathogens, which is pmk-1 p38 MAP kinase dependent, while TM resistance was pmk-1 independent. Expression of P-glycoprotein (PGP) xenobiotic detoxification genes was elevated in osm-3 mutants and their knockdown or inhibition with verapamil suppressed tunicamycin resistance. The nuclear hormone receptor nhr-8 was necessary to regulate a subset of PGPs. We thus identify a cell-nonautonomous regulation of xenobiotic detoxification and show that separate pathways are engaged to mediate longevity, pathogen resistance, and xenobiotic detoxification in osm-3 mutants.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efeitos dos fármacos , Resistência a Medicamentos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Longevidade , Receptores Citoplasmáticos e Nucleares/metabolismo , Tunicamicina/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Cinesinas/genética , Cinesinas/metabolismo , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Mutação , Receptores Citoplasmáticos e Nucleares/genética , Fatores de Tempo , Tunicamicina/metabolismo
7.
Front Cell Neurosci ; 15: 666706, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335184

RESUMO

Sensorineural hearing loss is irreversible and is associated with the loss of spiral ganglion neurons (SGNs) and sensory hair cells within the inner ear. Improving spiral ganglion neuron (SGN) survival, neurite outgrowth, and synaptogenesis could lead to significant gains for hearing-impaired patients. There has therefore been intense interest in the use of neurotrophic factors in the inner ear to promote both survival of SGNs and re-wiring of sensory hair cells by surviving SGNs. Neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF) represent the primary neurotrophins in the inner ear during development and throughout adulthood, and have demonstrated potential for SGN survival and neurite outgrowth. We have pioneered a hybrid molecule approach to maximize SGN stimulation in vivo, in which small molecule analogues of neurotrophins are linked to bisphosphonates, which in turn bind to cochlear bone. We have previously shown that a small molecule BDNF analogue coupled to risedronate binds to bone matrix and promotes SGN neurite outgrowth and synaptogenesis in vitro. Because NT-3 has been shown in a variety of contexts to have a greater regenerative capacity in the cochlea than BDNF, we sought to develop a similar approach for NT-3. 1Aa is a small molecule analogue of NT-3 that has been shown to activate cells through TrkC, the NT-3 receptor, although its activity on SGNs has not previously been described. Herein we describe the design and synthesis of 1Aa and a covalent conjugate of 1Aa with risedronate, Ris-1Aa. We demonstrate that both 1Aa and Ris-1Aa stimulate neurite outgrowth in SGN cultures at a significantly higher level compared to controls. Ris-1Aa maintained its neurotrophic activity when bound to hydroxyapatite, the primary mineral component of bone. Both 1Aa and Ris-1Aa promote significant synaptic regeneration in cochlear explant cultures, and both 1Aa and Ris-1Aa appear to act at least partly through TrkC. Our results provide the first evidence that a small molecule analogue of NT-3 can stimulate SGNs and promote regeneration of synapses between SGNs and inner hair cells. Our findings support the promise of hydroxyapatite-targeting bisphosphonate conjugation as a novel strategy to deliver neurotrophic agents to SGNs encased within cochlear bone.

8.
Nat Commun ; 12(1): 470, 2021 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-33473109

RESUMO

Healthy aging can be promoted by enhanced metabolic fitness and physical capacity. Mitochondria are chief metabolic organelles with strong implications in aging that also coordinate broad physiological functions, in part, using peptides that are encoded within their independent genome. However, mitochondrial-encoded factors that actively regulate aging are unknown. Here, we report that mitochondrial-encoded MOTS-c can significantly enhance physical performance in young (2 mo.), middle-age (12 mo.), and old (22 mo.) mice. MOTS-c can regulate (i) nuclear genes, including those related to metabolism and proteostasis, (ii) skeletal muscle metabolism, and (iii) myoblast adaptation to metabolic stress. We provide evidence that late-life (23.5 mo.) initiated intermittent MOTS-c treatment (3x/week) can increase physical capacity and healthspan in mice. In humans, exercise induces endogenous MOTS-c expression in skeletal muscle and in circulation. Our data indicate that aging is regulated by genes encoded in both of our co-evolved mitochondrial and nuclear genomes.


Assuntos
Envelhecimento/genética , Homeostase/fisiologia , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Músculo Esquelético/metabolismo , Adulto , Animais , Linhagem Celular , Núcleo Celular , Regulação da Expressão Gênica , Humanos , Masculino , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Musculares/metabolismo , Mioblastos/metabolismo , Estresse Fisiológico , Adulto Jovem
9.
Nature ; 597(7878): 715-719, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34526722

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer deaths worldwide1. Studies in human tissues and in mouse models have suggested that for many cancers, stem cells sustain early mutations driving tumour development2,3. For the pancreas, however, mechanisms underlying cellular renewal and initiation of PDAC remain unresolved. Here, using lineage tracing from the endogenous telomerase reverse transcriptase (Tert) locus, we identify a rare TERT-positive subpopulation of pancreatic acinar cells dispersed throughout the exocrine compartment. During homeostasis, these TERThigh acinar cells renew the pancreas by forming expanding clones of acinar cells, whereas randomly marked acinar cells do not form these clones. Specific expression of mutant Kras in TERThigh acinar cells accelerates acinar clone formation and causes transdifferentiation to ductal pre-invasive pancreatic intraepithelial neoplasms by upregulating Ras-MAPK signalling and activating the downstream kinase ERK (phospho-ERK). In resected human pancreatic neoplasms, we find that foci of phospho-ERK-positive acinar cells are common and frequently contain activating KRAS mutations, suggesting that these acinar regions represent an early cancer precursor lesion. These data support a model in which rare TERThigh acinar cells may sustain KRAS mutations, driving acinar cell expansion and creating a field of aberrant cells initiating pancreatic tumorigenesis.


Assuntos
Células Acinares/citologia , Carcinogênese , Pâncreas/citologia , Animais , Carcinoma Ductal Pancreático/patologia , Transdiferenciação Celular , Transformação Celular Neoplásica/genética , Homeostase , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos , Mutação , Pâncreas/patologia , Pâncreas/fisiologia , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Telomerase/genética
10.
Nat Aging ; 1(8): 715-733, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34514433

RESUMO

Neutrophils are the most abundant human white blood cell and constitute a first line of defense in the innate immune response. Neutrophils are short-lived cells, and thus the impact of organismal aging on neutrophil biology, especially as a function of biological sex, remains poorly understood. Here, we describe a multi-omic resource of mouse primary bone marrow neutrophils from young and old female and male mice, at the transcriptomic, metabolomic and lipidomic levels. We identify widespread regulation of neutrophil 'omics' landscapes with organismal aging and biological sex. In addition, we leverage our resource to predict functional differences, including changes in neutrophil responses to activation signals. To date, this dataset represents the largest multi-omics resource for neutrophils across sex and ages. This resource identifies neutrophil characteristics which could be targeted to improve immune responses as a function of sex and/or age.

11.
Int J Radiat Biol ; 96(12): 1534-1540, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33074046

RESUMO

PURPOSE: Agents that increase tumor radiosensitivity are of interest in improving outcomes in radiotherapy (XRT). DNA-PK inhibitors radiosensitize and alter cell adhesion proteins. We investigated combination radiation and a DNA-PK inhibitor in monolayers vs spheroids. MATERIALS AND METHODS: Using HER2 positive mammary carcinoma cells, we investigated the impact of NU7441, a DNA-PK inhibitor, on irradiated monolayer and spheroid cultures. Colony formation assays were performed with monolayer culture cells and spheroids after irradiation with/without NU7441 (5 µM). RESULTS: In monolayer culture cells, α/ß increased from 3.0 ± 0.2 Gy (XRT alone) to 6.9 ± 0.2 Gy (XRT+NU7441). Corresponding α/ß values for cells obtained by disaggregating treated spheroids were 3.6 ± 0.7 Gy (XRT alone) and 3.5 ± 0.2 Gy (XRT+NU7441). However, spheroid survival was highly sensitive to NU7441 incubation. After 4 Gy XRT alone 75% of the irradiated spheroids remained intact; when NU7441 treatment was involved, 13% remained intact. No spheroids survived to 3 weeks at 6 Gy or more. The discrepancy between the minimal change in α/ß from cells derived from spheroids and the spheroid growth response was not related to poor penetration of NU7441. CONCLUSIONS: DNA-PK inhibitor NU7441 radiosensitized monolayer cells but not cells obtained from spheroids. NU7441 and radiation increased spheroid fragmentation.


Assuntos
Neoplasias da Mama/patologia , Proteína Quinase Ativada por DNA/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/efeitos da radiação , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/radioterapia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Humanos , Inibidores de Proteínas Quinases/uso terapêutico , Esferoides Celulares/patologia
12.
J Am Soc Cytopathol ; 9(3): 185-190, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32197966

RESUMO

INTRODUCTION: Insulinoma-associated protein 1 (INSM-1) is expressed in both normal tissues and neoplasms with neuroendocrine differentiation such as small cell lung carcinoma and pancreatic neuroendocrine tumors. The aim of this study was to evaluate the INSM-1 expression in medullary thyroid carcinoma (MTC) in the aspirated material and its preoperative diagnostic value. MATERIALS AND METHODS: MTC cases with available cytological material from 5 institutions were retrospectively identified. INSM-1 expression was analyzed in 48 cell blocks prepared from fine-needle aspiration samples from histologically confirmed cases of MTC. Twenty-nine samples were aspirates from primary thyroid lesions and 19 from secondary lesions lymph node or liver lesions. INSM-1 immunostain was done using the Ventana Automatic System (Ventana Medical Systems, Tucson, AZ). The control group consisted of 20 samples from histologically confirmed cases of papillary, follicular, and anaplastic thyroid carcinomas and secondary thyroid malignancies (squamous cell carcinoma, malignant melanoma). RESULTS: The male to female (M:F) ratio in MTC group was 1:1.5 and the average age was 55.6 years (range: 24-84 years). INSM-1 nuclear staining in at least 5% of cells was considered positive. Forty-five (93.75%) MTC samples were positive including all primary tumor aspirates. All control samples were negative. CONCLUSIONS: INSM-1 nuclear positivity is a reliable marker of MTC neuroendocrine differentiation on cytology material from both primary tumor and metastases. INSM-1 can also discriminate MTC from other primary and secondary thyroid carcinomas when there are cytomorphologic overlaps.


Assuntos
Carcinoma Neuroendócrino , Proteínas Repressoras/metabolismo , Neoplasias da Glândula Tireoide , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/metabolismo , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Coloração e Rotulagem/métodos , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/metabolismo , Adulto Jovem
13.
Hum Genet ; 139(3): 333-356, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31677133

RESUMO

Although aging is a conserved phenomenon across evolutionary distant species, aspects of the aging process have been found to differ between males and females of the same species. Indeed, observations across mammalian studies have revealed the existence of longevity and health disparities between sexes, including in humans (i.e. with a female or male advantage). However, the underlying mechanisms for these sex differences in health and lifespan remain poorly understood, and it is unclear which aspects of this dimorphism stem from hormonal differences (i.e. predominance of estrogens vs. androgens) or from karyotypic differences (i.e. XX vs. XY sex chromosome complement). In this review, we discuss the state of the knowledge in terms of sex dimorphism in various aspects of aging and in human age-related diseases. Where the interplay between sex differences and age-related differences has not been explored fully, we present the state of the field to highlight important future research directions. We also discuss various dietary, drug or genetic interventions that were shown to improve longevity in a sex-dimorphic fashion. Finally, emerging tools and models that can be leveraged to decipher the mechanisms underlying sex differences in aging are also briefly discussed.


Assuntos
Envelhecimento/fisiologia , Animais , Humanos , Longevidade/fisiologia , Caracteres Sexuais
14.
Cancer Cytopathol ; 127(5): 306-315, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31050186

RESUMO

BACKGROUND: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) is a 6-tier diagnostic category system with associated risks of malignancy (ROMs) and management recommendations. Submandibular gland fine-needle aspiration (FNA) is uncommon with a higher frequency of inflammatory lesions and a higher relative proportion of malignancy, and this may affect the ROM and subsequent management. This study evaluated the application of the MSRSGC and the ROM for each diagnostic category for 734 submandibular gland FNAs. METHODS: Submandibular gland FNA cytology specimens from 15 international institutions (2013-2017) were retrospectively assigned to an MSRSGC diagnostic category as follows: nondiagnostic, nonneoplastic, atypia of undetermined significance (AUS), benign neoplasm, salivary gland neoplasm of uncertain malignant potential (SUMP), suspicious for malignancy (SM), or malignant. A correlation with the available histopathologic follow-up was performed, and the ROM was calculated for each MSRSGC diagnostic category. RESULTS: The case cohort of 734 aspirates was reclassified according to the MSRSGC as follows: nondiagnostic, 21.4% (0%-50%); nonneoplastic, 24.2% (9.1%-53.6%); AUS, 6.7% (0%-14.3%); benign neoplasm, 18.3% (0%-52.5%); SUMP, 12% (0%-37.7%); SM, 3.5% (0%-12.5%); and malignant, 13.9% (2%-31.3%). The histopathologic follow-up was available for 333 cases (45.4%). The ROMs were as follows: nondiagnostic, 10.6%; nonneoplastic, 7.5%; AUS, 27.6%; benign neoplasm, 3.2%; SUMP, 41.9%; SM, 82.3%; and malignant, 93.6%. CONCLUSIONS: This multi-institutional study shows that the ROM of each MSRSGC category for submandibular gland FNA is similar to that reported for parotid gland FNA, although the reported rates for the different MSRSGC categories were variable across institutions. Thus, the MSRSGC can be reliably applied to submandibular gland FNA.


Assuntos
Citodiagnóstico/métodos , Citodiagnóstico/normas , Lesões Pré-Cancerosas/diagnóstico , Medição de Risco/métodos , Neoplasias das Glândulas Salivares/classificação , Neoplasias das Glândulas Salivares/diagnóstico , Glândula Submandibular/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Biópsia por Agulha Fina , Criança , Pré-Escolar , Feminino , Seguimentos , Instalações de Saúde , Humanos , Lactente , Agências Internacionais , Masculino , Registros Médicos/estatística & dados numéricos , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
15.
BMB Rep ; 52(1): 86-108, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30526773

RESUMO

In multi-cellular organisms, the control of gene expression is key not only for development, but also for adult cellular homeostasis, and gene expression has been observed to be deregulated with aging. In this review, we discuss the current knowledge on the transcriptional alterations that have been described to occur with age in metazoans. First, we discuss age-related transcriptional changes in protein-coding genes, the expected functional impact of such changes, and how known pro-longevity interventions impact these changes. Second, we discuss the changes and impact of emerging aspects of transcription in aging, including age-related changes in splicing, lncRNAs and circRNAs. Third, we discuss the changes and potential impact of transcription of transposable elements with aging. Fourth, we highlight small ncRNAs and their potential impact on the regulation of aging phenotypes. Understanding the aging transcriptome will be key to identify important regulatory targets, and ultimately slow-down or reverse aging and extend healthy lifespan in humans. [BMB Reports 2019; 52(1): 86-108].


Assuntos
Envelhecimento/genética , Longevidade/genética , Transcriptoma/genética , Animais , Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Homeostase , Humanos , Fenótipo , RNA não Traduzido/genética , RNA não Traduzido/fisiologia
16.
J Vis Exp ; (139)2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30295663

RESUMO

Boron carbide (B4C) is one of the hardest materials in existence. However, this attractive property also limits its machineability into complex shapes for high wear, high hardness, and lightweight material applications such as armors. To overcome this challenge, negative additive manufacturing (AM) is employed to produce complex geometries of boron carbides at various length scales. Negative AM first involves gelcasting a suspension into a 3D-printed plastic mold. The mold is then dissolved away, leaving behind a green body as a negative copy. Resorcinol-formaldehyde (RF) is used as a novel gelling agent because unlike traditional hydrogels, there is little to no shrinkage, which allows for extremely complex molds to be used. Furthermore, this gelling agent can be pyrolyzed to leave behind ~50 wt% carbon, which is a highly effective sintering aid for B4C. Due to this highly homogenous distribution of in situ carbon within the B4C matrix, less than 2% porosity can be achieved after sintering. This protocol highlights in detail the methodology for creating near fully dense boron carbide parts with highly complex geometries.


Assuntos
Compostos de Boro/química
17.
ACS Appl Mater Interfaces ; 7(36): 20034-45, 2015 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-26302772

RESUMO

As more research findings have shown the correlation between ordering in organic semiconductor thin films and device performance, it is becoming more essential to exercise control of the ordering through structural tuning. Many recent studies have focused on the influence of side chain engineering on polymer packing orientation in thin films. However, the impact of the size and conformation of aromatic surfaces on thin film ordering has not been investigated in great detail. Here we introduce a disk-shaped polycyclic aromatic hydrocarbon building block with a large π surface, namely, thienoazacoronenes (TACs), as a donor monomer for conjugated polymers. A series of medium bandgap conjugated polymers have been synthesized by copolymerizing TAC with electron donating monomers of varying size. The incorporation of the TAC unit in such semiconducting polymers allows a systematic investigation, both experimentally and theoretically, of the relationships between polymer conformation, electronic structure, thin film morphology, and charge transport properties. Field effect transistors based on these polymers have shown good hole mobilities and photoresponses, proving that TAC is a promising building block for high performance optoelectronic materials.

18.
Curr Eye Res ; 34(3): 184-95, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19274525

RESUMO

PURPOSE: The prostamide bimatoprost and prostanoid FP receptor agonists are highly efficacious drugs for glaucoma treatment. The presence of both prostamide and prostanoid FP receptors in bimatoprost-sensitive preparations has made prostamide receptor classification difficult. This study investigated a novel bimatoprost-sensitive preparation. METHODS: Human peripheral blood T lymphoblasts (Molt-3) and human osteoblasts (hFOB) were cultured for intracellular calcium signaling studies and quantitative real-time PCR analysis of RNA. RESULTS: Bimatoprost stimulated concentration-related increases in [Ca(2 +)](i) in a human T-cell line that does not express human FP receptor/variants, according to PCR analysis. The calcium signal induced by bimatoprost was not antagonized by prostanoid FP receptor antagonist/partial agonist AL-8810 or selective TP receptor antagonist SQ 29548. Conversely, bimatoprost did not elevate [Ca(2 +)](i) in human osteoblasts, which were confirmed to contain RNA of human FP receptor/variants. CONCLUSIONS: Molt-3 cells have been identified as a bimatoprost-sensitive preparation in which the activity of bimatoprost is independent of prostanoid FP receptors.


Assuntos
Amidas/farmacologia , Anti-Hipertensivos/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Cálcio/metabolismo , Cloprostenol/análogos & derivados , Receptores de Prostaglandina/metabolismo , Receptores de Tromboxanos/metabolismo , Linfócitos T/metabolismo , Bimatoprost , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Células Cultivadas , Cloprostenol/farmacologia , Relação Dose-Resposta a Droga , Humanos , Osteoblastos/metabolismo , Receptores de Prostaglandina/agonistas , Receptores de Prostaglandina/antagonistas & inibidores , Receptores de Tromboxanos/agonistas , Receptores de Tromboxanos/antagonistas & inibidores , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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