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1.
Front Neurosci ; 18: 1305939, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38784099

RESUMEN

The development of innovative non-invasive neuroimaging methods and biomarkers is critical for studying brain disease. Imaging of cerebrospinal fluid (CSF) pulsatility may inform the brain fluid dynamics involved in clearance of cerebral metabolic waste. In this work, we developed a methodology to characterize the frequency and spatial localization of whole brain CSF pulsations in humans. Using 7 Tesla (T) human magnetic resonance imaging (MRI) and ultrafast echo-planar imaging (EPI), in-vivo images were obtained to capture pulsations of the CSF signal. Physiological data were simultaneously collected and compared with the 7 T MR data. The primary components of signal pulsations were identified using spectral analysis, with the most evident frequency bands identified around 0.3, 1.2, and 2.4 Hz. These pulsations were mapped spatially and temporally onto the MR image domain and temporally onto the physiological measures of electrocardiogram and respiration. We identified peaks in CSF pulsations that were distinct from peaks in grey matter and white matter regions. This methodology may provide novel in vivo biomarkers of disrupted brain fluid dynamics.

2.
Curr Med Imaging ; 2024 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-38415483

RESUMEN

OBJECTIVE: We aimed to differentiate granulosa cell tumors (GCT) from other ovarian sex-cord tumors (OSCs) based on feature analysis of the tumor body on MR imaging. METHODS: We retrospectively enrolled 27 patients with pathologically proven sex-cord tumours (14 GSTs, 8 fibromas, 4 fibrothecomas, and 1 sclerosing stromal tumour) from our institution. All MRI examinations were performed at least one month prior to surgery. MR image features were recorded by two radiologists with consensus readings. Histogram analysis was performed using FeAture Explorer software. The differences in histogram parameters between GCT (38.1 ± 14.6 years) and OSC (43.7 ± 18.0 years) groups were compared. Fourteen randomly selected cellular-type myomas who also underwent MRI in our hospital were considered as the control group. The intra-operator consistency of ADC value was evaluated across measurements twice. RESULTS: The repeatability of conventional ADC measurements on the tumor body was good. The values of ADC-mean, ADC-min, and ADC-max significantly differed across three groups (p < 0.001). The histogram variance on DWI, histogram percentage on T2WI, and ADC min showed the best discriminative performance in determining GCTs from other OSCs with an area under the receiver operator curve (AUC) of 0.997, 0.882, and 0.795, respectively. The histogram variance on DWI yielded a sensitivity of 92.3%, a specificity of 100%, and an accuracy of 96.6% in discriminating GSTs from other OSCs. CONCLUSION: In the present study, feature analysis of tumor body MR imaging has helped to differentiate GST from OSC with better performance than conventional ADC measurements.

3.
Diabetes ; 73(4): 604-610, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38211578

RESUMEN

White matter hyperintensity (WMH) lesions on brain MRI images are surrogate markers of cerebral small vessel disease. Longitudinal studies examining the association between diabetes and WMH progression have yielded mixed results. Thus, in this study, we investigated the association between HbA1c, a biomarker for the presence and severity of hyperglycemia, and longitudinal WMH change after adjusting for known risk factors for WMH progression. We recruited 64 participants from South Korean memory clinics to undergo brain MRI at the baseline and a 2-year follow-up. We found the following. First, higher HbA1c was associated with greater global WMH volume (WMHV) changes after adjusting for known risk factors (ß = 7.7 × 10-4; P = 0.025). Second, the association between baseline WMHV and WMHV progression was only significant at diabetic levels of HbA1c (P < 0.05, when HbA1c >6.51%), and non-apolipoprotein E (APOE) ε4 carriers had a stronger association between HbA1c and WMHV progression (ß = -2.59 × 10-3; P = 0.004). Third, associations of WMHV progression with HbA1c were particularly apparent for deep WMHV change (ß = 7.17 × 10-4; P < 0.01) compared with periventricular WMHV change and, for frontal (ß = 5.00 × 10-4; P < 0.001) and parietal (ß = 1.53 × 10-4; P < 0.05) lobes, WMHV change compared with occipital and temporal WMHV change. In conclusion, higher HbA1c levels were associated with greater 2-year WMHV progression, especially in non-APOE ε4 participants or those with diabetic levels of HbA1c. These findings demonstrate that diabetes may potentially exacerbate cerebrovascular and white matter disease.


Asunto(s)
Diabetes Mellitus , Sustancia Blanca , Humanos , Hemoglobina Glucada , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Imagen por Resonancia Magnética/métodos , Estudios Longitudinales , Biomarcadores , Diabetes Mellitus/patología
4.
Am J Obstet Gynecol ; 230(3): 342.e1-342.e8, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37939982

RESUMEN

BACKGROUND: Identifying risk factors for Alzheimer disease in women is important as women compose two-thirds of individuals with Alzheimer disease. Previous work links vasomotor symptoms, the cardinal menopausal symptom, with poor memory performance and alterations in brain structure, function, and connectivity. These associations are evident when vasomotor symptoms are monitored objectively with ambulatory skin conductance monitors. OBJECTIVE: This study aimed to determine whether vasomotor symptoms are associated with Alzheimer disease biomarkers. STUDY DESIGN: Between 2017 and 2020, the MsBrain study enrolled 274 community-dwelling women aged 45 to 67 years who had a uterus and at least 1 ovary and were late perimenopausal or postmenopausal status. The key exclusion criteria included neurologic disorder, surgical menopause, and recent use of hormonal or nonhormonal vasomotor symptom treatment. Women underwent 24 hours of ambulatory skin conductance monitoring to assess vasomotor symptoms. Plasma concentrations of Alzheimer disease biomarkers, including amyloid ß 42-to-amyloid ß 40 ratio, phosphorylated tau (181 and 231), glial fibrillary acidic protein, and neurofilament light, were measured using a single-molecule array (Simoa) technology. Associations between vasomotor symptoms and Alzheimer disease biomarkers were assessed via linear regression models adjusted for age, race and ethnicity, education, body mass index, and apolipoprotein E4 status. Additional models adjusted for estradiol and sleep. RESULTS: A total of 248 (mean age, 59.06 years; 81% White; 99% postmenopausal status) of enrolled MsBrain participants contributed data. Objectively assessed vasomotor symptoms occurring during sleep were associated with significantly lower amyloid ß 42/amyloid ß 40, (beta, -.0010 [standard error, .0004]; P=.018; multivariable), suggestive of greater brain amyloid ß pathology. The findings remained significant after additional adjustments for estradiol and sleep. CONCLUSION: Nighttime vasomotor symptoms may be a marker of women at risk of Alzheimer disease. It is yet unknown if these associations are causal.


Asunto(s)
Enfermedad de Alzheimer , Menopausia , Femenino , Humanos , Persona de Mediana Edad , Sofocos , Péptidos beta-Amiloides , Sudoración , Biomarcadores , Estradiol
5.
Alzheimers Dement ; 20(2): 914-924, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37817668

RESUMEN

INTRODUCTION: Compared to males, females have an accelerated trajectory of cognitive decline in Alzheimer's disease (AD). The neurobiological factors underlying the more rapid cognitive decline in AD in females remain unclear. This study explored how sex-dependent alterations in hippocampal connectivity over 2 years are associated with cerebrovascular and amyloid pathologies in normal aging. METHODS: Thirty-three females and 21 males 65 to 93 years of age with no cognitive impairment performed a face-name associative memory functional magnetic resonance imaging (fMRI) task with a 2-year follow-up. We acquired baseline carbon 11-labeled Pittsburgh compound B ([11 C]PiB) positron emission tomography (PET) and T2-weighted fluid-attenuated inversion recovery (T2-FLAIR) MRI to quantify amyloid ß (Aß) burden and white matter hyperintensity (WMH) volume, respectively. RESULTS: Males had increased hippocampal-prefrontal connectivity over 2 years, associated with greater Aß burden. Females had increased bilateral hippocampal functional connectivity, associated with greater WMH volume. DISCUSSION: These findings suggest sex-dependent compensatory mechanisms in the memory network in the presence of cerebrovascular and AD pathologies and may explain the accelerated trajectory of cognitive decline in females.


Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Masculino , Femenino , Humanos , Péptidos beta-Amiloides/metabolismo , Encéfalo/patología , Enfermedad de Alzheimer/patología , Amiloide , Envejecimiento , Disfunción Cognitiva/patología , Tomografía de Emisión de Positrones , Imagen por Resonancia Magnética , Hipocampo/patología
6.
medRxiv ; 2023 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-38105931

RESUMEN

Development of innovative non-invasive neuroimaging methods and biomarkers are critical for studying brain disease. In this work, we have developed a methodology to characterize the frequency responses and spatial localization of oscillations and movements of cerebrospinal fluid (CSF) flow in the human brain. Using 7 Tesla human MRI and ultrafast echo-planar imaging (EPI), in-vivo images were obtained to capture CSF oscillations and movements. Physiological data was simultaneously collected and correlated with the 7T MR data. The primary components of CSF oscillations were identified using spectral analysis (with frequency bands identified around 0.3Hz, 1.2Hz and 2.4Hz) and were mapped spatially and temporally onto the MR image domain and temporally onto the physiological domain. The developed methodology shows a good consistency and repeatability (standard deviation of 0.052 and 0.078 for 0.3Hz and 1.2Hz bands respectively) in-vivo for potential brain dynamics and CSF flow and clearance studies.

7.
JAMA Netw Open ; 6(11): e2341388, 2023 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-37917057

RESUMEN

Importance: Posttraumatic stress disorder (PTSD), cardiovascular disease (CVD), and Alzheimer disease are major public health issues, particularly for women. The implications of PTSD for cardiovascular and brain health for women is poorly understood. Objective: To assess whether PTSD symptoms among midlife women are associated with carotid intima media thickness (IMT), an indicator of carotid atherosclerosis; brain white matter hyperintensity volume (WMHV), an indicator of brain small vessel disease; and cognitive performance and to test a modifying role of the APOEε4 genotype. Design, Setting, and Participants: In this cross-sectional study, participants were enrolled between 2016 to 2021 and completed questionnaires (PTSD Checklist-Civilian Version), physical measures, phlebotomy, neuropsychological testing, a carotid ultrasonographic examination, and 3-Tesla brain magnetic resonance imaging. Participants included community-based women ages 45 to 67 years without a history of CVD, stroke, or dementia. Data were analyzed from July 2022 to September 2023. Exposures: PTSD symptoms. Main Outcomes and Measures: Outcomes of interest were associations of PTSD symptoms with carotid IMT, brain WMHV, and cognition, assessed in linear regression models. Interactions by APOEε4 were tested. Covariates included age, race and ethnicity, education, and CVD risk factors. Results: Among 274 participants (mean [SD] age, 59.03 [4.34] years; 6 Asian participants [2.2%]; 48 Black participants [17.5%]; 215 White participants [78.5%]; 5 multiracial participants [1.8%]), 64 participants (24.71%) were APOEε4 genotype carriers. Higher PTSD symptoms were associated with greater carotid IMT (multivariable ß = 0.07 [95% CI, 0.01 to 0.13]; P = .03). Associations of PTSD symptoms with neurocognitive outcomes significantly varied by APOEε4 status. Among women with APOEε4, PTSD symptoms were associated with greater whole-brain WMHV (ß = 0.96 [95% CI, 0.30 to 1.63]; P = .009), periventricular WMHV (ß = 0.90 [95% CI, 0.24 to 1.56]; P = .02), deep WMHV (ß = 1.21 [95% CI, 0.23 to 2.20]; P = .01), and frontal WMHV (ß = 1.25 [95% CI, 0.05 to 2.45]; P = .04), as well as with poorer cognition, specifically attention and working memory (ß = -3.37 [95% CI, -6.12 to -0.62]; P = .02), semantic fluency (ß = -6.01 [95% CI, -10.70 to -1.31]; P = .01), perceptual speed (ß = -12.73 [95% CI, -20.71 to -4.75]; P = .002), and processing speed (ß = -11.05 [95% CI, -17.80 to -4.30]; P = .002) in multivariable models. Conclusions and Relevance: In this cross-sectional study of midlife women, greater PTSD symptoms were associated with higher carotid atherosclerosis and, among women who were APOEε4 carriers, greater brain small vessel disease and poorer cognitive performance. These findings point to the adverse implications of PTSD symptoms for cardiovascular and neurocognitive health among women in midlife, particularly for women who are APOEε4 carriers.


Asunto(s)
Enfermedades Cardiovasculares , Enfermedades de las Arterias Carótidas , Trastornos por Estrés Postraumático , Accidente Cerebrovascular , Femenino , Humanos , Persona de Mediana Edad , Trastornos por Estrés Postraumático/epidemiología , Grosor Intima-Media Carotídeo , Estudios Transversales , Encéfalo/diagnóstico por imagen , Enfermedades Cardiovasculares/epidemiología
8.
Dalton Trans ; 52(27): 9414-9422, 2023 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-37358388

RESUMEN

Based on N-B bonds, a novel strategy was developed for improving the energetic performance of tetrazoles. By employing the amino neighboring group participation, the azolyl borane compound 7 was selectively constructed, which exhibited excellent stability in water and air. This strategy solved the acidity problem of tetrazole as well as increasing the heat of detonation and combustion by 25% and 36%, respectively. Through laser ignition experiments, it also improved the combustion performance of tetrazoles. In DSC experiments, thermal decomposition temperatures of N-B covalent compounds were elevated as well. In an electrostatic potential calculation and sensitivity test, N-B covalent compounds exhibited good sensitivity (IS > 40 J and FS > 360 N). Through TG-DSC-FTIR-MS and in situ IR experiments, decomposition products were investigated to determine the next optimization stage for heat of detonation. It offered a significant potential for development to incorporate the N-B bond into nitrogen-rich compounds.

9.
Neuroimage ; 275: 120147, 2023 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-37156449

RESUMEN

In older adults without dementia, White Matter Hyperintensities (WMH) in MRI have been shown to be highly associated with cerebral amyloid deposition, measured by the Pittsburgh compound B (PiB) PET. However, the relation to age, sex, and education in explaining this association is not well understood. We use the voxel counts of regional WMH, age, one-hot encoded sex, and education to predict the regional PiB using a multilayer perceptron with only rectilinear activations using mean squared error. We then develop a novel, robust metric to understand the relevance of each input variable for prediction. Our observations indicate that sex is the most relevant predictor of PiB and that WMH is not relevant for prediction. These results indicate that there is a sex-specific risk architecture for Aß deposition.


Asunto(s)
Enfermedad de Alzheimer , Tomografía de Emisión de Positrones , Masculino , Femenino , Humanos , Anciano , Tomografía de Emisión de Positrones/métodos , Imagen por Resonancia Magnética , Compuestos de Anilina , Péptidos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo
12.
Alzheimers Dement ; 19(7): 3129-3137, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-36722746

RESUMEN

INTRODUCTION: Carotid atherosclerosis may be associated with brain white matter hyperintensities (WMH). Few studies consider women at midlife, a critical time for women's cardiovascular and brain health. We tested the hypothesis that higher carotid intima media thickness (IMT) would be associated with greater WMH volume (WMHV) among midlife women. We explored interactions by apolipoprotein E (APOE) ε4 status. METHODS: Two hundred thirty-nine women aged 45 to 67 underwent carotid artery ultrasound, phlebotomy, and magnetic resonance imaging (MRI). One hundred seventy participants had undergone an ultrasound 5 years earlier. RESULTS: Higher IMT was associated with greater whole brain (B[standard error (SE)] = 0.77 [.31], P = 0.01; multivariable) and periventricular (B[SE] = 0.80 [.30], P = 0.008; multivariable) WMHV. Associations were observed for IMT assessed contemporaneously with the MRI and 5 years prior to the MRI. Associations were strongest for APOE ε4-positive women. DISCUSSION: Among midlife women, higher IMT was associated with greater WMHV. Vascular risk is critical to midlife brain health, particularly for APOE ε4-positive women.


Asunto(s)
Enfermedades de las Arterias Carótidas , Sustancia Blanca , Humanos , Femenino , Grosor Intima-Media Carotídeo , Apolipoproteína E4 , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Factores de Riesgo , Enfermedades de las Arterias Carótidas/patología
13.
Neurology ; 100(2): e133-e141, 2023 01 10.
Artículo en Inglés | MEDLINE | ID: mdl-36224031

RESUMEN

BACKGROUND AND OBJECTIVES: The menopause transition is increasingly recognized as a time of importance for women's brain health. A growing body of work indicates that the classic menopausal symptom, vasomotor symptom (VMS), may be associated with poorer cardiovascular health. Other work links VMS to poorer cognition. We investigate whether VMS, when rigorously assessed using physiologic measures, are associated with greater white matter hyperintensity volume (WMHV) among midlife women. We consider a range of potential explanatory factors in these associations and explore whether VMS are associated with the spatial distribution of WMHV. METHODS: Women aged 45-67 years and free of hormone therapy underwent 24 hours of physiologic VMS monitoring (sternal skin conductance), actigraphy assessment of sleep, physical measures, phlebotomy, and 3 Tesla neuroimaging. Associations between VMS (24-hour, wake, and sleep VMS, with wake and sleep intervals defined by actigraphy) and whole brain WMHV were considered in linear regression models adjusted for age, race, education, smoking, body mass index, blood pressure, insulin resistance, and lipids. Secondary models considered WMHV in specific brain regions (deep, periventricular, frontal, temporal, parietal, and occipital) and additional covariates including sleep. RESULTS: The study sample included 226 women. Physiologically assessed VMS were associated with greater whole brain WMHV in multivariable models, with the strongest associations observed for sleep VMS (24-hour VMS, B[SE] = 0.095 [0.045], p = 0.032; Wake VMS, B[SE] = 0.078 [0.046], p = 0.089, Sleep VMS, B[SE] = 0.173 [0.060], p = 0.004). Associations were not accounted for by additional covariates including actigraphy-assessed sleep (wake after sleep onset). When considering the spatial distribution of WMHV, sleep VMS were associated with both deep WMHV, periventricular WMHV, and frontal lobe WMHV. DISCUSSION: VMS, particularly VMS occurring during sleep, were associated with greater WMHV. Identification of female-specific midlife markers of poor brain health later in life is critical to identify women who warrant early intervention and prevention. VMS have the potential to serve as female-specific midlife markers of brain health in women.


Asunto(s)
Sustancia Blanca , Femenino , Humanos , Encéfalo/diagnóstico por imagen , Menopausia/fisiología , Polisomnografía , Sustancia Blanca/diagnóstico por imagen , Salud de la Mujer , Persona de Mediana Edad , Anciano
14.
Am J Geriatr Psychiatry ; 31(2): 112-123, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36274019

RESUMEN

OBJECTIVE: Small Vessel Disease (SVD) is known to be associated with higher AD risk, but its relationship to amyloidosis in the progression of AD is unclear. In this cross-sectional study of cognitively normal older adults, we explored the interactive effects of SVD and amyloid-beta (Aß) pathology on hippocampal functional connectivity during an associative encoding task and on hippocampal volume. METHODS: This study included 61 cognitively normal older adults (age range: 65-93 years, age mean ± standard deviation: 75.8 ± 6.4, 41 [67.2%] female). PiB PET, T2-weighted FLAIR, T1-weighted and face-name fMRI images were acquired on each participant to evaluate brain Aß, white matter hyperintensities (WMH+/- status), gray matter density, and hippocampal functional connectivity. RESULTS: We found that, in WMH (+) older adults greater Aß burden was associated with greater hippocampal local connectivity (i.e., hippocampal-parahippocampal connectivity) and lower gray matter density in medial temporal lobe (MTL), whereas in WMH (-) older adults greater Aß burden was associated with greater hippocampal distal connectivity (i.e., hippocampal-prefrontal connectivity) and no changes in MTL gray matter density. Moreover, greater hippocampal local connectivity was associated with MTL atrophy. CONCLUSION: These observations support a hippocampal excitotoxicity model linking SVD to neurodegeneration in preclinical AD. This may explain how SVD may accelerate the progression from Aß positivity to neurodegeneration, and subsequent AD.


Asunto(s)
Enfermedad de Alzheimer , Hipocampo , Humanos , Femenino , Anciano , Anciano de 80 o más Años , Masculino , Estudios Transversales , Hipocampo/diagnóstico por imagen , Hipocampo/patología , Encéfalo/metabolismo , Péptidos beta-Amiloides/metabolismo , Imagen por Resonancia Magnética , Atrofia/patología , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología
15.
Artículo en Inglés | MEDLINE | ID: mdl-36498262

RESUMEN

Cognitive impairment in older adults is a major public concern for Kazakhstan's aging population. We aimed to (1) administer a neuropsychological test battery (NTB) in domains relevant to aging-associated cognitive impairment in a sample of adults aged 60+ without dementia in Almaty, Kazakhstan; (2) investigate the associations between demographic factors and test performance; and (3) provide information on the distribution of NTB scores as preliminary local normative data relevant for this population. A cross-sectional evaluation of 276 participants aged 60+ in Almaty, Kazakhstan, was conducted using cognitive instruments including tests of memory, attention, language, executive functions, visuospatial abilities, and processing speed. Multiple linear regression analyses were used to examine the association of demographic factors with neuropsychological test performance. The results from the regression analysis showed that those who are younger, have more years of education, are women, and are of Russian ethnicity had significantly better performance. The current study illustrated (1) the feasibility of administering the NTB to older adults in the general population in Kazakhstan; (2) the preliminary local normative neuropsychological measures; and (3) their independent associations with age, education, gender, and ethnicity. The findings are a platform for future research on dementia and cognitive impairment in older adults in Kazakhstan.


Asunto(s)
Disfunción Cognitiva , Demencia , Humanos , Femenino , Anciano , Masculino , Vida Independiente , Estudios Transversales , Pruebas Neuropsicológicas , Función Ejecutiva , Disfunción Cognitiva/epidemiología , Cognición
16.
Nanomaterials (Basel) ; 12(22)2022 Nov 11.
Artículo en Inglés | MEDLINE | ID: mdl-36432259

RESUMEN

High-performance composites with a resin matrix are urgently required for electronic packaging due to their low dielectric constant, outstanding high temperature resistance, excellent corrosion resistance, light weight and easy molding. In this work, hollow-glass-microsphere (HGM)-filled fluorinated-phthalonitrile (PBDP) composites, with filler contents ranging from 0 to 35.0 vol.%, were prepared in order to modify the dielectric properties of the phthalonitrile. Scanning electron microscopy (SEM) observations indicate that the modified HGM particles were uniformly dispersed in the matrix. The PBDP/27.5HGM-NH2 composite demonstrates a low dielectric constant of 1.85 at 12 GHz. The 5% thermogravimetric temperature (T5) of composites with silanized HGM filler (481-486 °C) is higher than the minimum packaging-material requirements (450 °C). In addition, the heat-resistance index (THRI) of PBDP/HGM-NH2 composites reached as high as 268 °C. the storage modulus of PBDP/HGM-NH2 composites were significantly increased to 1283 MPa at 400 °C, an increase by 50%, in comparison to that of PBDP phthalonitrile resin (857 MPa). The excellent dielectric and thermal properties of the present composites may pave a way for comprehensive applications in electronic packaging and thermal management for energy systems.

17.
Nat Commun ; 13(1): 6951, 2022 11 14.
Artículo en Inglés | MEDLINE | ID: mdl-36376293

RESUMEN

Immune checkpoint blockade therapies targeting the PD-L1/PD-1 axis have demonstrated clear clinical benefits. Improved understanding of the underlying regulatory mechanisms might contribute new insights into immunotherapy. Here, we identify transmembrane and ubiquitin-like domain-containing protein 1 (TMUB1) as a modulator of PD-L1 post-translational modifications in tumor cells. Mechanistically, TMUB1 competes with HECT, UBA and WWE domain-containing protein 1 (HUWE1), a E3 ubiquitin ligase, to interact with PD-L1 and inhibit its polyubiquitination at K281 in the endoplasmic reticulum. Moreover, TMUB1 enhances PD-L1 N-glycosylation and stability by recruiting STT3A, thereby promoting PD-L1 maturation and tumor immune evasion. TMUB1 protein levels correlate with PD-L1 expression in human tumor tissue, with high expression being associated with poor patient survival rates. A synthetic peptide engineered to compete with TMUB1 significantly promotes antitumor immunity and suppresses tumor growth in mice. These findings identify TMUB1 as a promising immunotherapeutic target.


Asunto(s)
Antígeno B7-H1 , Neoplasias , Animales , Humanos , Ratones , Antígeno B7-H1/metabolismo , Glicosilación , Inmunoterapia , Neoplasias/genética , Neoplasias/terapia , Escape del Tumor , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación
18.
Polymers (Basel) ; 14(19)2022 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-36236092

RESUMEN

In this study, a novel phthalonitrile monomer containing a pyridazine ring, 3,6-bis[3-(3,4-dicyanophenoxy)phenoxy]pyridazine (BCPD) with a low melting point (74 °C) and wide processing window (178 °C), was prepared by a nucleophilic substitution reaction. The molecular structure of the BCPD monomer was identified by Fourier transform infrared spectroscopy (FTIR), and nuclear magnetic resonance spectroscopy (NMR). Poly(BCPD) resins were derived from the formulations by curing at 350 and 370 °C. The thermoset that was post-cured at 370 °C demonstrated outstanding high heat-resistant (glass transition temperature (Tg) > 400 °C, 5% weight loss temperature (T5%) = 501 °C, Yc at 900 °C > 74%) and was flame-retardant (limiting oxygen index (LOI) = 48)). Further, the poly(BCPD) resin simultaneously exhibited a superior storage modulus, which could reach up to 3.8 Gpa at room temperature. Excellent processability and heat resistance were found for phthalonitrile thermosets containing the pyridazine ring, indicating poly(BCPD) resin could be potentially applied as high-temperature structural composite matrices.

19.
Mol Psychiatry ; 27(12): 5235-5243, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35974140

RESUMEN

We previously developed a novel machine-learning-based brain age model that was sensitive to amyloid. We aimed to independently validate it and to demonstrate its utility using independent clinical data. We recruited 650 participants from South Korean memory clinics to undergo magnetic resonance imaging and clinical assessments. We employed a pretrained brain age model that used data from an independent set of largely Caucasian individuals (n = 757) who had no or relatively low levels of amyloid as confirmed by positron emission tomography (PET). We investigated the association between brain age residual and cognitive decline. We found that our pretrained brain age model was able to reliably estimate brain age (mean absolute error = 5.68 years, r(650) = 0.47, age range = 49-89 year) in the sample with 71 participants with subjective cognitive decline (SCD), 375 with mild cognitive impairment (MCI), and 204 with dementia. Greater brain age was associated with greater amyloid and worse cognitive function [Odds Ratio, (95% Confidence Interval {CI}): 1.28 (1.06-1.55), p = 0.030 for amyloid PET positivity; 2.52 (1.76-3.61), p < 0.001 for dementia]. Baseline brain age residual was predictive of future cognitive worsening even after adjusting for apolipoprotein E e4 and amyloid status [Hazard Ratio, (95% CI): 1.94 (1.33-2.81), p = 0.001 for total 336 follow-up sample; 2.31 (1.44-3.71), p = 0.001 for 284 subsample with baseline Clinical Dementia Rating ≤ 0.5; 2.40 (1.43-4.03), p = 0.001 for 240 subsample with baseline SCD or MCI]. In independent data set, these results replicate our previous findings using this model, which was able to delineate significant differences in brain age according to the diagnostic stages of dementia as well as amyloid deposition status. Brain age models may offer benefits in discriminating and tracking cognitive impairment in older adults.


Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Anciano , Persona de Mediana Edad , Anciano de 80 o más Años , Preescolar , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Cognición , Tomografía de Emisión de Positrones/métodos , Imagen por Resonancia Magnética , Apolipoproteína E4
20.
J Clin Exp Neuropsychol ; 44(2): 134-145, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35786160

RESUMEN

INTRODUCTION: Our study aimed to understand the independent and combined effects of cocaine dependence and HIV status across aspects of verbal memory. METHOD: Our sample consisted of a total of 102 individuals: 28 individuals living with HIV and cocaine dependence (HIV+/CD), 28 individuals who are HIV-negative with cocaine dependence (HIV-/CD), 20 individuals living with HIV without cocaine dependence (HIV+/ND), and 26 individuals who are HIV-negative without cocaine dependence (HIV-/ND). We utilized the Hopkins Verbal Learning Test-Revised Version (HVLT-R) to assess components of verbal memory, including encoding, recall, and recognition. A 2 (HIV: Yes/No) × 2 (Cocaine: Yes/No) MANCOVA on Total and Delayed Recall while controlling for premorbid intelligence was conducted. We used a Kruskal-Wallis H test to examine retrieval and recognition. RESULTS: The combination of HIV and cocaine dependence amplified deficits on Total Recall. We found comparably poor performance across Delayed Recall between all three clinical groups. People living with HIV without cocaine dependence demonstrated intact recognition, whereas those with cocaine dependence had poor recognition. CONCLUSIONS: HIV and cocaine both impacted verbal memory. However, there are potential subtle differences in the role cocaine versus HIV has on the memory process. People living with HIV without cocaine dependence recognized significantly more words than they could freely recall. In contrast, cocaine dependence impacted recognition in HIV and non-HIV groups. These performance patterns suggest HIV may be associated with retrieval deficits, whereas cocaine dependence may be associated with encoding deficits. Further research assessing these specific components of the memory process will help clarify these potential differences.


Asunto(s)
Trastornos Relacionados con Cocaína , Cocaína , Cocaína/farmacología , Trastornos Relacionados con Cocaína/complicaciones , Humanos , Memoria , Trastornos de la Memoria/complicaciones , Trastornos de la Memoria/etiología , Recuerdo Mental , Pruebas Neuropsicológicas , Aprendizaje Verbal
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