The Induction of EMT and Activation of Adipose Stem Cells in Correlation with the Secretion of LTBP-1 in Mammary Cells

This work is part of an ongoing study that investigates the upregulation of LTBP-1 in mammary epithelial cells as well as the differentiation of breast adipose stem cells (BASCs) in the presence of TGF-β1. Through immunofluorescence imaging, LTBP-1 is shown to co-localize with fibronectin fibrils in adipose stem cells. Previous work from our lab has shown that blocking fibronectin fibril formation can inhibit Epithelial-Mesenchymal Transition. Thus, targeting of fibronectin assembly could be a potent new therapeutic in cancer treatment. In the current work, we focus on the pharmacodynamics of a FN assembly inhibitor derived from the protein Adhesin F1 (refered to as FUD). FN Fibril area was quantified in samples with different FUD dosages to determine the optimal concentration. The optimal dosage for this inhibitor was obtained for both mammary epithelial cells and breast adipose stem cells through image processing. Additionally, toxicity studies were performed using MTT assays. Results suggest that in both the mammary epithelial cells and the breast adipose stem cells, there is a range of dosing for which FN fibril formation is blocked but toxicity is low

Security Verification of Low-Trust Architectures

Low-trust architectures work on, from the viewpoint of software, always-encrypted data, and significantly reduce the amount of hardware trust to a small software-free enclave component. In this paper, we perform a complete formal verification of a specific low-trust architecture, the Sequestered Encryption (SE) architecture, to show that the design is secure against direct data disclosures and digital side channels for all possible programs. We first define the security requirements of the ISA of SE low-trust architecture. Looking upwards, this ISA serves as an abstraction of the hardware for the software, and is used to show how any program comprising these instructions cannot leak information, including through digital side channels. Looking downwards this ISA is a specification for the hardware, and is used to define the proof obligations for any RTL implementation arising from the ISA-level security requirements. These cover both functional and digital side-channel leakage. Next, we show how these proof obligations can be successfully discharged using commercial formal verification tools. We demonstrate the efficacy of our RTL security verification technique for seven different correct and buggy implementations of the SE architecture.Comment: 19 pages with appendi

Treatment With an Angiopoietin-1 Mimetic Peptide Improves Cognitive Outcome in Rats With Vascular Dementia

BACKGROUND AND PURPOSE: Vascular dementia (VaD) is a complex neurodegenerative disease affecting cognition and memory. There is a lack of approved pharmacological treatments specifically for VaD. In this study, we investigate the therapeutic effects of AV-001, a Tie2 receptor agonist, in middle-aged rats subjected to a multiple microinfarct (MMI) model of VaD. METHODS: Male, 10-12 month-old, Wistar rats were employed. The following experimental groups were used: Sham, MMI, MMI+1 μg/Kg AV-001, MMI+3 μg/Kg AV-001, MMI+6 μg/Kg AV-001. AV-001 treatment was initiated at 1 day after MMI and administered once daily via intraperitoneal injection. An investigator blinded to the experimental groups conducted a battery of neuro-cognitive tests including modified neurological severity score (mNSS) test, novel object recognition test, novel odor recognition test, three chamber social interaction test, and Morris water maze test. Rats were sacrificed at 6 weeks after MMI. RESULTS: There was no mortality observed after 1, 3, or 6 μg/Kg AV-001 treatment in middle-aged rats subjected to MMI. AV-001 treatment (1, 3, or 6 μg/Kg) does not significantly alter blood pressure or heart rate at 6 weeks after MMI compared to baseline values or the MMI control group. Treatment of MMI with 1 or 3 μg/Kg AV-001 treatment does not significantly alter body weight compared to Sham or MMI control group. While 6 μg/Kg AV-001 treated group exhibit significantly lower body weight compared to Sham and MMI control group, the weight loss is evident starting at 1 day after MMI when treatment was initiated and is not significantly different compared to its baseline values at day 0 or day 1 after MMI. AV-001 treatment significantly decreases serum alanine aminotransferase, serum creatinine, and serum troponin I levels compared to the MMI control group; however, all values are within normal range. MMI induces mild neurological deficits in middle-aged rats indicated by low mNSS scores (\u3c6 on a scale of 0-18). Compared to control MMI group, 1 μg/Kg AV-001 treatment group did not exhibit significantly different mNSS scores, while 3 and 6 μg/Kg AV-001 treatment induced significantly worse mNSS scores on days 21-42 and 14-42 after MMI, respectively. MMI in middle-aged rats induces significant cognitive impairment including short-term memory loss, long-term memory loss, reduced preference for social novelty and impaired spatial learning and memory compared to sham control rats. Rats treated with 1 μg/Kg AV-001 exhibit significantly improved short-term and long-term memory, increased preference for social novelty, and improved spatial learning and memory compared to MMI rats. Treatment with 3 μg/Kg AV-001 improves short-term memory and preference for social novelty but does not improve long-term memory or spatial learning and memory compared to MMI rats. Treatment with 6 μg/Kg AV-001 improves only long-term memory compared to MMI rats. Thus, 1 μg/Kg AV-001 treatment was selected as an optimal dose. Treatment of middle-aged rats subjected to MMI with 1 μg/Kg AV-001 significantly increases axon density, myelin density and myelin thickness in the corpus callosum, as well as increases synaptic protein expression, neuronal branching and dendritic spine density in the cortex, oligodendrocytes and oligodendrocyte progenitor cell number in the cortex and striatum and promotes neurogenesis in the subventricular zone compared to control MMI rats. CONCLUSIONS: In this study, we present AV-001 as a novel therapeutic agent to improve cognitive function and reduce white matter injury in middle aged-rats subjected to a MMI model of VaD. Treatment of MMI with 1 μg/Kg AV-001 significantly improves cognitive function, and increases axon density, remyelination and neuroplasticity in the brain of middle-aged rats

Regional AT-8 reactive tau species correlate with intracellular Aβ levels in cases of low AD neuropathologic change

The amyloid cascade hypothesis states that Aβ aggregates induce pathological changes in tau, leading to neurofibrillary tangles (NFTs) and cell death. A caveat with this hypothesis is the spatio-temporal divide between plaques and NFTs. This has been addressed by the inclusion of soluble Aβ and tau species in the revised amyloid cascade hypothesis. Nevertheless, despite the potential for non-plaque Aβ to contribute to tau pathology, few studies have examined relative correlative strengths between total Aβ, plaque Aβ and intracellular Aβ with tau pathology within a single tissue cohort. Employing frozen and fixed frontal cortex grey and white matter tissue from non-AD controls (Con; n = 39) and Alzheimer’s disease (AD) cases (n = 21), biochemical and immunohistochemical (IHC) measures of Aβ and AT-8 phosphorylated tau were assessed. Biochemical native-state dot blots from crude tissue lysates demonstrated robust correlations between total Aβ and AT-8 tau, when considered as a combined cohort (Con and AD) and when as Con and AD cases, separately. In contrast, no associations between Aβ plaques and AT-8 were reported when using IHC measurements in either Con or AD cases. However, when intracellular Aβ was measured via the Aβ specific antibody MOAB-2, a correlative relationship with AT-8 tau was reported in non-AD controls but not in AD cases. Collectively the data suggests that accumulating intracellular Aβ may influence AT-8 pathology, early in AD-related neuropathological change. Despite the lower levels of phospho-tau and Aβ in controls, the robust correlative relationships observed suggest a physiological association of Aβ production and tau phosphorylation, which may be modified during disease. This study is supportive of a revised amyloid cascade hypothesis and demonstrates regional associative relationships between tau pathology and intracellular Aβ, but not extracellular Aβ plaques

Regional AT-8 reactive tau species correlate with intracellular Aβ levels in cases of low AD neuropathologic change

The amyloid cascade hypothesis states that Aβ aggregates induce pathological changes in tau, leading to neurofibrillary tangles (NFTs) and cell death. A caveat with this hypothesis is the spatio-temporal divide between plaques and NFTs. This has been addressed by the inclusion of soluble Aβ and tau species in the revised amyloid cascade hypothesis. Nevertheless, despite the potential for non-plaque Aβ to contribute to tau pathology, few studies have examined relative correlative strengths between total Aβ, plaque Aβ and intracellular Aβ with tau pathology within a single tissue cohort. Employing frozen and fixed frontal cortex grey and white matter tissue from non-AD controls (Con; n = 39) and Alzheimer’s disease (AD) cases (n = 21), biochemical and immunohistochemical (IHC) measures of Aβ and AT-8 phosphorylated tau were assessed. Biochemical native-state dot blots from crude tissue lysates demonstrated robust correlations between total Aβ and AT-8 tau, when considered as a combined cohort (Con and AD) and when as Con and AD cases, separately. In contrast, no associations between Aβ plaques and AT-8 were reported when using IHC measurements in either Con or AD cases. However, when intracellular Aβ was measured via the Aβ specific antibody MOAB-2, a correlative relationship with AT-8 tau was reported in non-AD controls but not in AD cases. Collectively the data suggests that accumulating intracellular Aβ may influence AT-8 pathology, early in AD-related neuropathological change. Despite the lower levels of phospho-tau and Aβ in controls, the robust correlative relationships observed suggest a physiological association of Aβ production and tau phosphorylation, which may be modified during disease. This study is supportive of a revised amyloid cascade hypothesis and demonstrates regional associative relationships between tau pathology and intracellular Aβ, but not extracellular Aβ plaques

Sharing culture in a tech world: Grandparent–grandchild cultural exchanges over video chat.

Grandparents who were separated from their infant grandchildren during COVID-19 sought other ways to connect, including video chat. Video chat supports learning, and its features (e.g., contingent responsiveness) may allow for cultural exchange. However, technological problems may disrupt these exchanges. In a semi-naturalistic, longitudinal study, 47 families submitted up to three video chats and surveys. Families were predominantly White/Caucasian, highly-educated, and lived between 1 and 2700 miles apart. Multilevel models were used to predict the proportion of the sessions devoted to exchanging culture (e.g., holidays, parenting advice) and managing tech problems. Culture exchange did not change as a function of infant age, video chat experience, or when encountering tech problems. Although only marginally statistically significant, culture exchange increased as distance increased. Tech problems changed as a function of tech talk. A qualitative analysis revealed that cultural transmission occurred via a culture of care and sharing of information across video chat, that families adapted their behaviors to the new technology, and that technology disruptions rarely interfered with the flow of information. These findings demonstrate the ability to share culture when physically separated and in the presence of tech disruptions. Further, this study supports previous work on the emerging culture of video chat. Families adapted to being separated, and grandparents and infants successfully communicated through a new modality. Because video chat supports family relationships, equitable access to high-speed internet should be a priority to enable more families to use it

Post-mortem AT-8 reactive tau species correlate with non-plaque Aβ levels in the frontal cortex of non-AD and AD brains

The amyloid cascade hypothesis states that Aβ and its aggregates induce pathological changes in tau, leading to formation of neurofibrillary tangles (NFTs) and cell death. A caveat with this hypothesis is the temporo-spatial divide between plaques and NFTs. This has been addressed by the inclusion of soluble species of Aβ and tau in the revised amyloid cascade hypothesis, however, the demonstration of a correlative relationship between Aβ and tau burden in post-mortem human tissue has remained elusive. Employing frozen and fixed frontal cortex grey and associated white matter tissue from non-AD controls (Con; n=39) and Alzheimer’s diseases (AD) cases (n=21), biochemical and immunohistochemical measures of Aβ and AT-8 phosphorylated tau were assessed. Native-state dot-blot from crude tissue lysates demonstrated robust correlations between intraregional Aβ and AT-8 tau, such increases in Aβ immunoreactivity conferred increases in AT-8 immunoreactivity, both when considered across the entire cohort as well as separately in Con and AD cases. In contrast, no such association between Aβ plaques and AT-8 were reported when using immunohistochemical measurements. However, when using the non-amyloid precursor protein cross reactive MOAB-2, antibody to measure intracellular Aβ within a subset of cases, a similar correlative relationship with AT-8 tau as that observed in biochemical analysis was observed. Collectively our data suggests that accumulating intracellular Aβ may influence AT-8 pathology. Despite the markedly lower levels of phospho-tau in non-AD controls correlative relationships between AT-8 phospho-tau and Aβ as measured in both biochemical and immunohistochemical assays were more robust in non-AD controls, suggesting a physiological association of Aβ production and tau phosphorylation, at least within the frontal cortex. Such interactions between regional Aβ load and phospho-tau load may become modified with disease potentially, as a consequence of interregional tau seed propagation, and thus may diminish the linear relationship observed between Aβ and phospho-tau in non-AD controls. This study provides evidence supportive of the revised amyloid cascade hypothesis, and demonstrates an associative relationship between AT-8 tau pathology and intracellular Aβ but not extracellular Aβ plaques

Post-mortem AT-8 reactive tau species correlate with non-plaque Aβ levels in the frontal cortex of non-AD and AD brains

The amyloid cascade hypothesis states that Aβ and its aggregates induce pathological changes in tau, leading to formation of neurofibrillary tangles (NFTs) and cell death. A caveat with this hypothesis is the temporo-spatial divide between plaques and NFTs. This has been addressed by the inclusion of soluble species of Aβ and tau in the revised amyloid cascade hypothesis, however, the demonstration of a correlative relationship between Aβ and tau burden in post-mortem human tissue has remained elusive. Employing frozen and fixed frontal cortex grey and associated white matter tissue from non-AD controls (Con; n=39) and Alzheimer’s diseases (AD) cases (n=21), biochemical and immunohistochemical measures of Aβ and AT-8 phosphorylated tau were assessed. Native-state dot-blot from crude tissue lysates demonstrated robust correlations between intraregional Aβ and AT-8 tau, such increases in Aβ immunoreactivity conferred increases in AT-8 immunoreactivity, both when considered across the entire cohort as well as separately in Con and AD cases. In contrast, no such association between Aβ plaques and AT-8 were reported when using immunohistochemical measurements. However, when using the non-amyloid precursor protein cross reactive MOAB-2, antibody to measure intracellular Aβ within a subset of cases, a similar correlative relationship with AT-8 tau as that observed in biochemical analysis was observed. Collectively our data suggests that accumulating intracellular Aβ may influence AT-8 pathology. Despite the markedly lower levels of phospho-tau in non-AD controls correlative relationships between AT-8 phospho-tau and Aβ as measured in both biochemical and immunohistochemical assays were more robust in non-AD controls, suggesting a physiological association of Aβ production and tau phosphorylation, at least within the frontal cortex. Such interactions between regional Aβ load and phospho-tau load may become modified with disease potentially, as a consequence of interregional tau seed propagation, and thus may diminish the linear relationship observed between Aβ and phospho-tau in non-AD controls. This study provides evidence supportive of the revised amyloid cascade hypothesis, and demonstrates an associative relationship between AT-8 tau pathology and intracellular Aβ but not extracellular Aβ plaques

Pregnant women's perspectives about maternal immunization in Latin America

Background: Maternal immunization rates and vaccine uptake in Latin America vary from country to country. This variability stems from factors related to pregnant women, vaccine recommendations from healthcare providers and the health system. The aim of this paper is to describe women's knowledge and attitudes to maternal immunziation, and barriers to access and vaccination related decision-making processes in Latin American countries. Methods: We conducted focus group discussions (FGD) with pregnant women in five middle-income countries: Argentina, Brazil, Honduras, Mexico and Peru, between July 2016 and July 2018. The FGDs were conducted by trained qualitative researchers in diverse clinics located in the capital cities of these countries. Results: A total of 162 pregnant women participated in the FGDs. In general, participants were aware of the recommendation to receive vaccines during pregnancy but lacked knowledge regarding the diseases prevented by these vaccines. Pregnant women expressed a desire for clearer and more detailed communication on maternal vaccines by their healthcare professionals instead of relying on other sources of information such as the internet. Overall, participants had positive attitudes towards maternal immunization and were open to receiving vaccines in pregnancy based on general trust they have in recommendations made by their healthcare providers. The main obstacles pregnant women said they encounter were mainly centered around their clinical experience: long waiting times, vaccine shortages, and impolite behavior of healthcare providers or clinical staff. Conclusion: Important advances have been made in Latin America to promote maternal immunization. Results from this study show that an important aspect that remains to be addressed, and is crucial in improving vaccine uptake in pregnancy, is women's clinical experience. We recommend pregnant women to be treated as a priority population for providing immunization and related healthcare education. It is imperative to train healthcare providers in health communication so they can effectively communicate with pregnant women regarding maternal vaccines and can fill knowledge gaps that otherwise might be covered by unreliable sources dispensing inaccurate information.Fil: Fauzia Malik, A.. University of Yale. School of Medicine; Estados UnidosFil: Belizan, María. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Gutierrez, Mariana. University of Emory; Estados UnidosFil: Vilajeliu, Alba. Pan American Health Organization; Estados UnidosFil: Sanclemente, Lauren N.. University of Emory; Estados UnidosFil: Gonzalez Casanova, Ines. Indiana University; Estados Unidos. University of Emory; Estados UnidosFil: Jones, Daniel Eduardo. Instituto de Efectividad Clínica y Sanitaria; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Omer, Saad. University of Yale; Estados Unidos. University of Yale. School of Medicine; Estados UnidosFil: Maria Ropero, Alba. Pan American Health Organization; Estados UnidosFil: Alonso, Juan Pedro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto de Efectividad Clínica y Sanitaria; Argentin

Health care providers perspectives about maternal immunization in Latin America

Background: Antenatal care providers have a key role in providing appropriate information and immunization recommendations to improve pregnant women's vaccine uptake. The objective of this study is to describe health care providers' perspectives and experience regarding the implementation of maternal immunization programs in Latin America. Methods: We conducted 33 in-depth interviews of health care providers from Argentina, Brazil, Honduras, Mexico, and Peru (6–7 per country). Qualitative data analysis was conducted using a combination of both manual techniques and the computer software program NVivo. We identified and coded main themes related to maternal immunization. Results: The main themes identified in this analysis were practices related to maternal immunization, knowledge and training, resource availability and interactions with pregnant women. Healthcare providers knew that recommendations exists but some did not know their content; they expressed concerns about insufficient training. Providers from all five countries expressed the need for additional human resources and supplies. They also expressed a desire for women to be more proactive and ask more questions during the health visits. Conclusion: This is the first multi-country study assessing the perspectives of health care providers about maternal immunization practices at the facility level in Latin America. Recommendations based on the results from this study include implementing additional trainings around maternal immunization, especially targeting obstetricians and midwives. These trainings should be conducted in coordination with improvements to supply chain and other structural issues.Fil: Malik, Fauzia A.. University of Yale; Estados UnidosFil: Alonso, Juan Pedro. Instituto de Efectividad Clínica y Sanitaria; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Sanclemente, Lauren N.. University of Emory; Estados UnidosFil: Vilajeliu, Alba. Organización Panamericana de la Salud; Estados UnidosFil: Gutierrez, Mariana. University of Emory; Estados UnidosFil: Gonzalez Casanova, Ines. University of Emory; Estados Unidos. Indiana University; Estados UnidosFil: Jones, Daniel Eduardo. Instituto de Efectividad Clínica y Sanitaria; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Omer, Saad. University of Yale; Estados UnidosFil: Ropero, Alba-Maria. Organización Panamericana de la Salud; Estados UnidosFil: Belizán, María Melina Eleonora. Instituto de Efectividad Clínica y Sanitaria; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin