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1.
Front Aging Neurosci ; 16: 1350239, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38915346

RESUMO

The glucagon-like peptide-1 receptor (GLP-1R) agonists reduce glycated hemoglobin in patients with type 2 diabetes. Mounting evidence indicates that the potential of GLP-1R agonists, mimicking a 30 amino acid ligand, GLP-1, extends to the treatment of neurodegenerative conditions, with a particular focus on Alzheimer's disease (AD). However, the mechanism that underlies regulation of GLP-1R availability in the brain with AD remains poorly understood. Here, using whole transcriptome RNA-Seq of the human postmortem caudate nucleus with AD and chronic hydrocephalus (CH) in the elderly, we found that GLP-1R and select mRNAs expressed in glucose dysmetabolism and dyslipidemia were significantly altered. Furthermore, we detected human RNA indicating a deficiency in doublecortin (DCX) levels and the presence of ferroptosis in the caudate nucleus impacted by AD. Using the genome data viewer, we assessed mutability of GLP-1R and 39 other genes by two factors associated with high mutation rates in chromosomes of four species. Surprisingly, we identified that nucleotide sizes of GLP-1R transcript exceptionally differed in all four species of humans, chimpanzees, rats, and mice by up to 6-fold. Taken together, the protein network database analysis suggests that reduced GLP-1R in the aged human brain is associated with glucose dysmetabolism, ferroptosis, and reduced DCX+ neurons, that may contribute to AD.

2.
NPJ Microgravity ; 10(1): 18, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38365862

RESUMO

While the effects of microgravity on inducing skeletal muscle atrophy have been extensively studied, the impacts of microgravity on myogenesis and its mechanisms remain unclear. In this study, we developed a microphysiological system of engineered muscle tissue (EMT) fabricated using a collagen / Matrigel composite hydrogel and murine skeletal myoblasts. This 3D EMT model allows non-invasive quantitative assessment of contractile function. After applying a 7-day differentiation protocol to induce myotube formation, the EMTs clearly exhibited sarcomerogenesis, myofilament formation, and synchronous twitch and tetanic contractions with electrical stimuli. Using this 3D EMT system, we investigated the effects of simulated microgravity at 10-3 G on myogenesis and contractile function utilizing a random positioning machine. EMTs cultured for 5 days in simulated microgravity exhibited significantly reduced contractile forces, myofiber size, and differential expression of muscle contractile, myogenesis regulatory, and mitochondrial biogenesis-related proteins. These results indicate simulated microgravity attenuates myogenesis, resulting in impaired muscle function.

3.
iScience ; 26(9): 107522, 2023 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-37646016

RESUMO

Quantifying the risk of progression to Alzheimer's disease (AD) could help identify persons who could benefit from early interventions. We used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 544, discovery cohort) and the National Alzheimer's Coordinating Center (NACC, n = 508, validation cohort), subdividing individuals with mild cognitive impairment (MCI) into risk groups based on cerebrospinal fluid amyloid-ß levels and identifying differential gray matter patterns. We then created models that fused neural networks with survival analysis, trained using non-parcellated T1-weighted brain MRIs from ADNI data, to predict the trajectories of MCI to AD conversion within the NACC cohort (integrated Brier score: 0.192 [discovery], and 0.108 [validation]). Using modern interpretability techniques, we verified that regions important for model prediction are classically associated with AD. We confirmed AD diagnosis labels using postmortem data. We conclude that our framework provides a strategy for risk-based stratification of individuals with MCI and for identifying regions key for disease prognosis.

4.
Adv Healthc Mater ; 12(23): e2300157, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37483106

RESUMO

The growing interest in bioengineering in-vivo-like 3D functional tissues has led to novel approaches to the biomanufacturing process as well as expanded applications for these unique tissue constructs. Microgravity, as seen in spaceflight, is a unique environment that may be beneficial to the tissue-engineering process but cannot be completely replicated on Earth. Additionally, the expense and practical challenges of conducting human and animal research in space make bioengineered microphysiological systems an attractive research model. In this review, published research that exploits real and simulated microgravity to improve the biomanufacturing of a wide range of tissue types as well as those studies that use microphysiological systems, such as organ/tissue chips and multicellular organoids, for modeling human diseases in space are summarized. This review discusses real and simulated microgravity platforms and applications in tissue-engineered microphysiological systems across three topics: 1) application of microgravity to improve the biomanufacturing of tissue constructs, 2) use of tissue constructs fabricated in microgravity as models for human diseases on Earth, and 3) investigating the effects of microgravity on human tissues using biofabricated in vitro models. These current achievements represent important progress in understanding the physiological effects of microgravity and exploiting their advantages for tissue biomanufacturing.


Assuntos
Ausência de Peso , Animais , Humanos , Engenharia Tecidual , Organoides , Sistemas Microfisiológicos
5.
Elife ; 122023 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-37326306

RESUMO

Communication between distant cells can be mediated by extracellular vesicles (EVs) that deliver proteins and RNAs to recipient cells. Little is known about how EVs are targeted to specific cell types. Here, we identify the Drosophila cell-surface protein Stranded at second (Sas) as a targeting ligand for EVs. Full-length Sas is present in EV preparations from transfected Drosophila Schneider 2 (S2) cells. Sas is a binding partner for the Ptp10D receptor tyrosine phosphatase, and Sas-bearing EVs preferentially target to cells expressing Ptp10D. We used co-immunoprecipitation and peptide binding to show that the cytoplasmic domain (ICD) of Sas binds to dArc1 and mammalian Arc. dArc1 and Arc are related to retrotransposon Gag proteins. They form virus-like capsids which encapsulate Arc and other mRNAs and are transported between cells via EVs. The Sas ICD contains a motif required for dArc1 binding that is shared by the mammalian and Drosophila amyloid precursor protein (APP) orthologs, and the APP ICD also binds to mammalian Arc. Sas facilitates delivery of dArc1 capsids bearing dArc1 mRNA into distant Ptp10D-expressing recipient cells in vivo.


Assuntos
Proteínas de Drosophila , Vesículas Extracelulares , Animais , Ligantes , Vesículas Extracelulares/metabolismo , Drosophila/genética , Proteínas de Membrana/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , RNA Mensageiro/metabolismo , Mamíferos/genética
6.
Exp Neurol ; 366: 114433, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37156332

RESUMO

Proximity to telomeres (i) and high adenine and thymine (A + T) content (ii) are two factors associated with high mutation rates in human chromosomes. We have previously shown that >100 human genes when mutated to cause congenital hydrocephalus (CH) meet either factor (i) or (ii) at 91% matching, while two factors are poorly satisfied in human genes associated with familial Parkinson's disease (fPD) at 59%. Using the sets of mouse, rat, and human chromosomes, we found that 7 genes associated with CH were located on the X chromosome of mice, rats, and humans. However, genes associated with fPD were in different autosomes depending on species. While the contribution of proximity to telomeres in the autosome was comparable in CH and fPD, high A + T content played a pivotal contribution in X-linked CH (43% in all three species) than in fPD (6% in rodents or 13% in humans). Low A + T content found in fPD cases suggests that PARK family genes harbor roughly 3 times higher chances of methylations in CpG sites or epigenetic changes than X-linked genes.


Assuntos
Hidrocefalia , Doença de Parkinson , Camundongos , Ratos , Humanos , Animais , Doença de Parkinson/genética , Timina , Genes Ligados ao Cromossomo X , Telômero/genética , Hidrocefalia/genética , Mutação
7.
PLoS One ; 18(4): e0283470, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37104389

RESUMO

Mutations of protein kinases and cytokines are common and can cause cancer and other diseases. However, our understanding of the mutability in these genes remains rudimentary. Therefore, given previously known factors which are associated with high mutation rates, we analyzed how many genes encoding druggable kinases match (i) proximity to telomeres or (ii) high A+T content. We extracted this genomic information using the National Institute of Health Genome Data Viewer. First, among 129 druggable human kinase genes studied, 106 genes satisfied either factors (i) or (ii), resulting in an 82% match. Moreover, a similar 85% match rate was found in 73 genes encoding pro-inflammatory cytokines of multisystem inflammatory syndrome in children. Based on these promising matching rates, we further compared these two factors utilizing 20 de novo mutations of mice exposed to space-like ionizing radiation, in order to determine if these seemingly random mutations were similarly predictable with this strategy. However, only 10 of these 20 murine genetic loci met (i) or (ii), leading to only a 50% match. When compared with the mechanisms of top-selling FDA approved drugs, this data suggests that matching rate analysis on druggable targets is feasible to systematically prioritize the relative mutability-and therefore therapeutic potential-of the novel candidates.


Assuntos
Citocinas , Neoplasias , Criança , Humanos , Animais , Camundongos , Citocinas/genética , Citocinas/uso terapêutico , Genômica/métodos , Mutação , Neoplasias/genética , Telômero/genética
8.
Front Genet ; 13: 936151, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36406122

RESUMO

Symptoms of normal pressure hydrocephalus (NPH) and Alzheimer's disease (AD) are somewhat similar, and it is common to misdiagnose these two conditions. Although there are fluid markers detectable in humans with NPH and AD, determining which biomarker is optimal in representing genetic characteristics consistent throughout species is poorly understood. Here, we hypothesize that NPH can be differentiated from AD with mRNA biomarkers of unvaried proximity to telomeres. We examined human caudate nucleus tissue samples for the expression of transient receptor potential cation channel subfamily V member 4 (TRPV4) and amyloid precursor protein (APP). Using the genome data viewer, we analyzed the mutability of TRPV4 and other genes in mice, rats, and humans through matching nucleotides of six genes of interest and one house keeping gene with two factors associated with high mutation rate: 1) proximity to telomeres or 2) high adenine and thymine (A + T) content. We found that TRPV4 and microtubule associated protein tau (MAPT) mRNA were elevated in NPH. In AD, mRNA expression of TRPV4 was unaltered unlike APP and other genes. In mice, rats, and humans, the nucleotide size of TRPV4 did not vary, while in other genes, the sizes were inconsistent. Proximity to telomeres in TRPV4 was <50 Mb across species. Our analyses reveal that TRPV4 gene size and mutability are conserved across three species, suggesting that TRPV4 can be a potential link in the pathophysiology of chronic hydrocephalus in aged humans (>65 years) and laboratory rodents at comparable ages.

9.
Acta Astronaut ; 201: 576-579, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36157710

RESUMO

In response to the COVID-19 pandemic, NASA Jet Propulsion Laboratory (JPL) engineers had embarked on an ambitious project to design a reliable, easy-to-use, and low-cost ventilator that was made of readily available parts to address the unexpected global shortage of these lifesaving devices. After successfully designing and building the VITAL (Ventilator Intervention Technology Accessible Locally) ventilator in record time, FDA Emergency Use Authorization (EUA) was obtained and then the license to manufacture and sell these ventilators was made available to select companies through a competitive process. STARK Industries, LLC (STARK), located in Columbus, OH, USA, was one of only eight U.S. companies to be selected to receive this worldwide license. Motivated by its mission to improve human health and well-being through innovated medical technologies, STARK accepted the challenge of further developing the VITAL technology and manufacturing the ventilators in large quantities and making them available to those in need around the world. To this end, Spiritus Medical, Inc (Spiritus) was spun off from STARK to focus on the ventilator business. Through collaborative efforts with various corporate, academic, governmental, and non-profit partners, Spiritus was able to successfully begin manufacturing and selling its ventilators. Due to its low-cost nature and its straightforward design, this ventilator is ideal for use in developing countries where ventilators are in short supply and affordability is a major consideration. This is a story of how NASA's ingenuity, based on space-based know-how and experience, was used to rapidly design this innovative ventilator. And by forging partnerships with highly qualified and motivated partners such as STARK and Spiritus, NASA has succeeded in translating this work into technology that could potentially save thousands of lives in the fight against the COVID-19 pandemic.

10.
ACS Appl Mater Interfaces ; 14(34): 38541-38549, 2022 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-35984038

RESUMO

Poly(dimethylsiloxane) (PDMS) is a commonly used polymer in organ-on-a-chip devices and microphysiological systems. However, due to its hydrophobicity and permeability, it absorbs drug compounds, preventing accurate drug screening applications. Here, we developed an effective and facile method to prevent the absorption of drugs by utilizing a PDMS-PEG block copolymer additive and drug pretreatment. First, we incorporated a PDMS-PEG block copolymer into PDMS to address its inherent hydrophobicity. Next, we addressed the permeability of PDMS by eliminating the concentration gradient via pretreatment of the PDMS with the drug prior to experimentally testing drug absorption. The combined use of a PDMS-PEG block copolymer with drug pretreatment resulted in a mean reduction of drug absorption by 91.6% in the optimal condition. Finally, we demonstrated that the proposed method can be applied to prevent drug absorption in a PDMS-based cardiac microphysiological system, enabling more accurate drug studies.


Assuntos
Dimetilpolisiloxanos , Polímeros , Avaliação Pré-Clínica de Medicamentos , Interações Hidrofóbicas e Hidrofílicas , Permeabilidade
11.
Nat Commun ; 13(1): 3404, 2022 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-35725739

RESUMO

Worldwide, there are nearly 10 million new cases of dementia annually, of which Alzheimer's disease (AD) is the most common. New measures are needed to improve the diagnosis of individuals with cognitive impairment due to various etiologies. Here, we report a deep learning framework that accomplishes multiple diagnostic steps in successive fashion to identify persons with normal cognition (NC), mild cognitive impairment (MCI), AD, and non-AD dementias (nADD). We demonstrate a range of models capable of accepting flexible combinations of routinely collected clinical information, including demographics, medical history, neuropsychological testing, neuroimaging, and functional assessments. We then show that these frameworks compare favorably with the diagnostic accuracy of practicing neurologists and neuroradiologists. Lastly, we apply interpretability methods in computer vision to show that disease-specific patterns detected by our models track distinct patterns of degenerative changes throughout the brain and correspond closely with the presence of neuropathological lesions on autopsy. Our work demonstrates methodologies for validating computational predictions with established standards of medical diagnosis.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Aprendizado Profundo , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/psicologia , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/patologia , Progressão da Doença , Humanos , Neuroimagem/métodos
12.
Biomedicines ; 10(3)2022 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-35327396

RESUMO

Mutations of ion channels and G-protein-coupled receptors (GPCRs) are not uncommon and can lead to cardiovascular diseases. Given previously reported multiple factors associated with high mutation rates, we sorted the relative mutability of multiple human genes by (i) proximity to telomeres and/or (ii) high adenine and thymine (A+T) content. We extracted genomic information using the genome data viewer and examined the mutability of 118 ion channel and 143 GPCR genes based on their association with factors (i) and (ii). We then assessed these two factors with 31 genes encoding ion channels or GPCRs that are targeted by the United States Food and Drug Administration (FDA)-approved drugs. Out of the 118 ion channel genes studied, 80 met either factor (i) or (ii), resulting in a 68% match. In contrast, a 78% match was found for the 143 GPCR genes. We also found that the GPCR genes (n = 20) targeted by FDA-approved drugs have a relatively lower mutability than those genes encoding ion channels (n = 11), where targeted genes encoding GPCRs were shorter in length. The result of this study suggests that the use of matching rate analysis on factor-druggable genome is feasible to systematically compare the relative mutability of GPCRs and ion channels. The analysis on chromosomes by two factors identified a unique characteristic of GPCRs, which have a significant relationship between their nucleotide sizes and proximity to telomeres, unlike most genetic loci susceptible to human diseases.

13.
Am J Physiol Cell Physiol ; 322(3): C567-C580, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35171699

RESUMO

Skeletal muscle atrophy is a well-known consequence of spaceflight. Because of the potential significant impact of muscle atrophy and muscle dysfunction on astronauts and their mission, a thorough understanding of the mechanisms of this atrophy and the development of effective countermeasures is critical. Spaceflight-induced muscle atrophy is similar to atrophy seen in many terrestrial conditions, and therefore our understanding of this form of atrophy may also contribute to the treatment of atrophy in humans on Earth. The unique environmental features humans encounter in space include the weightlessness of microgravity, space radiation, and the distinctive aspects of living in a spacecraft. The disuse and unloading of muscles in microgravity are likely the most significant factors that mediate spaceflight-induced muscle atrophy and have been extensively studied and reviewed. However, there are numerous other direct and indirect effects on skeletal muscle that may be contributing factors to the muscle atrophy and dysfunction seen as a result of spaceflight. This review offers a novel perspective on the issue of muscle atrophy in space by providing a comprehensive overview of the unique aspects of the spaceflight environment and the various ways in which they can lead to muscle atrophy. We systematically review the potential contributions of these different mechanisms of spaceflight-induced atrophy and include findings from both actual spaceflight and ground-based models of spaceflight in humans, animals, and in vitro studies.


Assuntos
Voo Espacial , Ausência de Peso , Animais , Músculo Esquelético/patologia , Atrofia Muscular/etiologia , Atrofia Muscular/patologia , Ausência de Peso/efeitos adversos
14.
Aerosp Med Hum Perform ; 92(8): 650-669, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34503618

RESUMO

AbstractINTRODUCTION: For over 50 yr, investigators have studied the physiological adaptations of the human system during short- and long-duration spaceflight exposures. Much of the knowledge gained in developing health countermeasures for astronauts onboard the International Space Station demonstrate terrestrial applications. To date, a systematic process for translating these space applications to terrestrial human health has yet to be defined.METHODS: In the summer of 2017, a team of 38 international scientists launched the Bellagio ll Summit Initiative. The goals of the Summit were: 1) To identify space medicine findings and countermeasures with highest probability for future terrestrial applications; and 2) To develop a roadmap for translation of these countermeasures to future terrestrial application. The team reviewed public domain literature, NASA databases, and evidence books within the framework of the five-stage National Institutes of Health (NIH) translation science model, and the NASA two-stage translation model. Teams then analyzed and discussed interdisciplinary findings to determine the most significant evidence-based countermeasures sufficiently developed for terrestrial application.RESULTS: Teams identified published human spaceflight research and applied translational science models to define mature products for terrestrial clinical practice.CONCLUSIONS: The Bellagio ll Summit identified a snapshot of space medicine research and mature science with the highest probability of translation and developed a Roadmap of terrestrial application from space medicine-derived countermeasures. These evidence-based findings can provide guidance regarding the terrestrial applications of best practices, countermeasures, and clinical protocols currently used in spaceflight.Sides MB, Johnston SL III, Sirek A, Lee PH, Blue RS, Antonsen EL, Basner M, Douglas GL, Epstein A, Flynn-Evans EE, Gallagher MB, Hayes J, Lee SMC, Lockley SW, Monseur B, Nelson NG, Sargsyan A, Smith SM, Stenger MB, Stepanek J, Zwart SR; Bellagio II Team. Bellagio II report: terrestrial applications of space medicine research. Aerosp Med Hum Perform. 2021; 92(8):650669.


Assuntos
Medicina Aeroespacial , Voo Espacial , Astronautas , Humanos , Fatores de Tempo
15.
Int J Mol Sci ; 22(10)2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064609

RESUMO

Monogenic hypertension is rare and caused by genetic mutations, but whether factors associated with mutations are disease-specific remains uncertain. Given two factors associated with high mutation rates, we tested how many previously known genes match with (i) proximity to telomeres or (ii) high adenine and thymine content in cardiovascular diseases (CVDs) related to vascular stiffening. We extracted genomic information using a genome data viewer. In human chromosomes, 64 of 79 genetic loci involving >25 rare mutations and single nucleotide polymorphisms satisfied (i) or (ii), resulting in an 81% matching rate. However, this high matching rate was no longer observed as we checked the two factors in genes associated with essential hypertension (EH), thoracic aortic aneurysm (TAA), and congenital heart disease (CHD), resulting in matching rates of 53%, 70%, and 75%, respectively. A matching of telomere proximity or high adenine and thymine content projects the list of loci involving rare mutations of monogenic hypertension better than those of other CVDs, likely due to adoption of rigorous criteria for true-positive signals. Our data suggest that the factor-disease matching rate is an accurate tool that can explain deleterious mutations of monogenic hypertension at a >80% match-unlike the relatively lower matching rates found in human genes of EH, TAA, CHD, and familial Parkinson's disease.


Assuntos
Doenças Cardiovasculares/genética , Predisposição Genética para Doença , Mutação , Doenças do Sistema Nervoso/genética , Polimorfismo de Nucleotídeo Único , Telômero/genética , Adenina/metabolismo , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Humanos , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/patologia , Timina/metabolismo
16.
Cell Biosci ; 11(1): 115, 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34183055

RESUMO

Heart disease remains the leading cause of mortality globally, so further investigation is required to identify its underlying mechanisms and potential targets for treatment and prevention. Mitsugumin 53 (MG53), also known as TRIM72, is a TRIM family protein that was found to be involved in cell membrane repair and primarily found in striated muscle. Its role in skeletal muscle regeneration and myogenesis has been well documented. However, accumulating evidence suggests that MG53 has a potentially protective role in heart tissue, including in ischemia/reperfusion injury of the heart, cardiomyocyte membrane injury repair, and atrial fibrosis. This review summarizes the regulatory role of MG53 in cardiac tissues, current debates regarding MG53 in diabetes and diabetic cardiomyopathy, as well as highlights potential clinical applications of MG53 in treating cardiac pathologies.

17.
Front Physiol ; 11: 583393, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33240103

RESUMO

Since its identification in 2009, multiple studies have indicated the importance of MG53 in muscle physiology. The protein is produced in striated muscles but has physiologic implications reaching beyond the confines of striated muscles. Roles in muscle regeneration, calcium homeostasis, excitation-contraction coupling, myogenesis, and the mitochondria highlight the protein's wide-reaching impact. Numerous therapeutic applications could potentially emerge from these physiologic roles. This review summarizes the current literature regarding the role of MG53 in the skeletal muscle. Therapeutic applications are discussed.

18.
J Thorac Cardiovasc Surg ; 159(1): 61, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30826098
20.
J Thorac Cardiovasc Surg ; 159(3): e213-e214, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31627946
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