Screening ToxCast™ Phase I Chemicals in a Mouse Embryonic Stem Cell Adherent Cell Differentiation and Cytotoxicity (ACDC) Assay

EPA Science Inventory

An Adherent Cell Differentiation and Cytotoxicity (ACDC) in vitro assay with mouse embryonic stem cells was used to screen the ToxCast Phase I chemical library for effects on cellular differentiation and cell number. The U.S. Environmental Protection Agency (EPA) established the ...

Naringin protects human adipose-derived mesenchymal stem cells against hydrogen peroxide-induced inhibition of osteogenic differentiation.

PubMed

Wang, Lei; Zhang, Yu-Ge; Wang, Xiu-Mei; Ma, Long-Fei; Zhang, Yuan-Min

2015-12-05

Extensive evidence indicates that oxidative stress plays a pivotal role in the development of osteoporosis. We show that naringin, a natural antioxidant and anti-inflammatory compound, effectively protects human adipose-derived mesenchymal stem cells (hADMSCs) against hydrogen peroxide (H2O2)-induced inhibition of osteogenic differentiation. Naringin increased viability of hAMDSCs and attenuated H2O2-induced cytotoxicity. Naringin also reversed H2O2-induced oxidative stress. Oxidative stress induced by H2O2 inhibits osteogenic differentiation by decreasing alkaline phosphatase (ALP) activity, calcium content and mRNA expression levels of osteogenesis marker genes RUNX2 and OSX in hADMSCs. However, addition of naringin leads to a significant recovery, suggesting the protective effects of naringin against H2O2-induced inhibition of osteogenic differentiation. Furthermore, the H2O2-induced decrease of protein expressions of β-catenin and clyclin D1, two important transcriptional regulators of Wnt-signaling, was successfully rescued by naringin treatment. Also, in the presence of Wnt inhibitor DKK-1, naringin is no longer effective in stimulating ALP activity, increasing calcium content and mRNA expression levels of RUNX2 and OSX in H2O2-exposed hADMSCs. These data clearly demonstrates that naringin protects hADMSCs against oxidative stress-induced inhibition of osteogenic differentiation, which may involve Wnt signaling pathway. Our work suggests that naringin may be a useful addition to the treatment armamentarium for osteoporosis and activation of Wnt signaling may represent attractive therapeutic strategy for the treatment of degenerative disease of bone tissue. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Ethnic density and depressive symptoms among African Americans: threshold and differential effects across social and demographic subgroups.

PubMed

Bécares, Laia; Nazroo, James; Jackson, James

2014-12-01

We examined the association between Black ethnic density and depressive symptoms among African Americans. We sought to ascertain whether a threshold exists in the association between Black ethnic density and an important mental health outcome, and to identify differential effects of this association across social, economic, and demographic subpopulations. We analyzed the African American sample (n = 3570) from the National Survey of American Life, which we geocoded to the 2000 US Census. We determined the threshold with a multivariable regression spline model. We examined differential effects of ethnic density with random-effects multilevel linear regressions stratified by sociodemographic characteristics. The protective association between Black ethnic density and depressive symptoms changed direction, becoming a detrimental effect, when ethnic density reached 85%. Black ethnic density was protective for lower socioeconomic positions and detrimental for the better-off categories. The masking effects of area deprivation were stronger in the highest levels of Black ethnic density. Addressing racism, racial discrimination, economic deprivation, and poor services-the main drivers differentiating ethnic density from residential segregation-will help to ensure that the racial/ethnic composition of a neighborhood is not a risk factor for poor mental health.

Ethnic Density and Depressive Symptoms Among African Americans: Threshold and Differential Effects Across Social and Demographic Subgroups

PubMed Central

Nazroo, James; Jackson, James

2014-01-01

Objectives. We examined the association between Black ethnic density and depressive symptoms among African Americans. We sought to ascertain whether a threshold exists in the association between Black ethnic density and an important mental health outcome, and to identify differential effects of this association across social, economic, and demographic subpopulations. Methods. We analyzed the African American sample (n = 3570) from the National Survey of American Life, which we geocoded to the 2000 US Census. We determined the threshold with a multivariable regression spline model. We examined differential effects of ethnic density with random-effects multilevel linear regressions stratified by sociodemographic characteristics. Results. The protective association between Black ethnic density and depressive symptoms changed direction, becoming a detrimental effect, when ethnic density reached 85%. Black ethnic density was protective for lower socioeconomic positions and detrimental for the better-off categories. The masking effects of area deprivation were stronger in the highest levels of Black ethnic density. Conclusions. Addressing racism, racial discrimination, economic deprivation, and poor services—the main drivers differentiating ethnic density from residential segregation—will help to ensure that the racial/ethnic composition of a neighborhood is not a risk factor for poor mental health. PMID:25322307

Genistein and resveratrol: mammary cancer chemoprevention and mechanisms of action in the rat.

PubMed

Whitsett, Timothy G; Lamartiniere, Coral A

2006-12-01

The environment, including diet, plays a critical role in a woman's subsequent risk of breast cancer. Two dietary polyphenols that have received attention from the health and research communities for their ability to protect against breast cancer are: genistein, a component of soy; and resveratrol, a phytoalexin found in red grapes and red wine. We and others have shown that both genistein and resveratrol can protect against mammary cancer in rodents. The timing of exposure to genistein appears critical for its mammary protective effects. It has been reported that genistein early in life causes enhanced mammary gland differentiation, alterations in cell proliferation and apoptosis, and upregulation of tumor-suppressor genes. With resveratrol in the diet, changes in cell proliferation and apoptosis in terminal ductal structures of the mammary gland might help to explain its protective effects. We conclude that genistein and resveratrol can protect against breast cancer by regulating important mammary growth and differentiation pathways.

Vitamin D3 contributes to enhanced osteogenic differentiation of MSCs under oxidative stress condition via activating the endogenous antioxidant system.

PubMed

Zhou, J; Wang, F; Ma, Y; Wei, F

2018-06-02

The anti-oxidative effects of vitamin D3 (Vd3) on mesenchymal stem cells (MSCs) have not been studied before. The present study suggested that Vd3 could not only promote the osteogenic differentiation of MSCs under normal condition but also partly protect it from oxidative stress damage by activating the endogenous antioxidant system. Evolving evidence proved that oxidative stress caused by reactive oxygen species (ROS) overproduction might lead to bone loss. Vd3, a commonly used osteogenic induction drug, was proved to exhibit potent anti-oxidative effects on other cell types. The present study aims to investigate the protective effects of Vd3 on oxidative stress-induced dysfunctions of MSCs, as well as its underlying mechanisms. The H 2 O 2 was used as exogenous reactive oxygen species (ROS). The influence of ROS and anti-oxidative protection of Vd3 on MSCs were analyzed too. Multi-techniques were used to assess the beneficial effects of Vd3 on MSCs under oxidative stress condition. The results demonstrated that Vd3 could significantly attenuate the H 2 O 2 -induced cell injury of MSCs via Sirt1/FoxO1 signaling pathway, and reduced the H 2 O 2 exposure-induced intracellular oxidative stress status of MSCs. What's more, the H 2 O 2 exposure resulted in the decreased osteogenic differentiation of MSCs, as evidenced by decreased alkaline phosphatase activity, calcium deposition level, and osteogenic differentiation gene mRNA levels, but the injury was restored via Vd3 administration. The results suggested that Vd3 could not only promote the osteogenic differentiation of osteoblastic cells under normal condition but also partly protect the cell from oxidative stress damage by activating endogenous antioxidant system. The study shed light on the new roles of Vd3 in bone modeling and remodeling regulation.

Application of Phasor Measurement Units for Protection of Distribution Networks with High Penetration of Photovoltaic Sources

NASA Astrophysics Data System (ADS)

Meskin, Matin

The rate of the integration of distributed generation (DG) units to the distribution level to meet the growth in demand increases as a reasonable replacement for costly network expansion. This integration brings many advantages to the consumers and power grids, as well as giving rise to more challenges in relation to protection and control. Recent research has brought to light the negative effects of DG units on short circuit currents and overcurrent (OC) protection systems in distribution networks. Change in the direction of fault current flow, increment or decrement of fault current magnitude, blindness of protection, feeder sympathy trip, nuisance trip of interrupting devices, and the disruption of coordination between protective devices are some potential impacts of DG unit integration. Among other types of DG units, the integration of renewable energy resources into the electric grid has seen a vast improvement in recent years. In particular, the interconnection of photovoltaic (PV) sources to the medium voltage (MV) distribution networks has experienced a rapid increase in the last decade. In this work, the effect of PV source on conventional OC relays in MV distribution networks is shown. It is indicated that the PV output fluctuation, due to changes in solar radiation, causes the magnitude and direction of the current to change haphazardly. These variations may result in the poor operation of OC relays as the main protective devices in the MV distribution networks. In other words, due to the bi-directional power flow characteristic and the fluctuation of current magnitude occurring in the presence of PV sources, a specific setting of OC relays is difficult to realize. Therefore, OC relays may operate in normal conditions. To improve the OC relay operation, a voltage-dependent-overcurrent protection is proposed. Although, this new method prevents the OC relay from maloperation, its ability to detect earth faults and high impedance faults is poor. Thus, a comprehensive protective system is suggested at the end of the dissertation. The proposed method is based on the application of the phasor measurement unit (PMU) and the differential protection method. All of the current magnitudes and angles are collected by PMU and are sent to the phasor data concentrator (PDC), where a differential protection algorithm is applied to these data. If any fault is detected, the trip will be sent back to the corresponding circuit breakers across the network. Higher selectivity, sensitivity, and faster operation in the differential protection are superior to those of other protection schemes. Differential protection operates as unit protection, which means that it operates only when there is a fault in the protection zone. It does not function for faults occurring out of zone. Therefore, no coordination is required between differential protections across the power system. Moreover, the misoperation of this protective scheme is less likely as compared to other protection methods.

Melatonin protects bone marrow mesenchymal stem cells against iron overload-induced aberrant differentiation and senescence.

PubMed

Yang, Fan; Yang, Lei; Li, Yuan; Yan, Gege; Feng, Chao; Liu, Tianyi; Gong, Rui; Yuan, Ye; Wang, Ning; Idiiatullina, Elina; Bikkuzin, Timur; Pavlov, Valentin; Li, Yang; Dong, Chaorun; Wang, Dawei; Cao, Yang; Han, Zhenbo; Zhang, Lai; Huang, Qi; Ding, Fengzhi; Bi, Zhengang; Cai, Benzhi

2017-10-01

Bone marrow mesenchymal stem cells (BMSCs) are an expandable population of stem cells which can differentiate into osteoblasts, chondrocytes and adipocytes. Dysfunction of BMSCs in response to pathological stimuli contributes to bone diseases. Melatonin, a hormone secreted from pineal gland, has been proved to be an important mediator in bone formation and mineralization. The aim of this study was to investigate whether melatonin protected against iron overload-induced dysfunction of BMSCs and its underlying mechanisms. Here, we found that iron overload induced by ferric ammonium citrate (FAC) caused irregularly morphological changes and markedly reduced the viability in BMSCs. Consistently, osteogenic differentiation of BMSCs was significantly inhibited by iron overload, but melatonin treatment rescued osteogenic differentiation of BMSCs. Furthermore, exposure to FAC led to the senescence in BMSCs, which was attenuated by melatonin as well. Meanwhile, melatonin was able to counter the reduction in cell proliferation by iron overload in BMSCs. In addition, protective effects of melatonin on iron overload-induced dysfunction of BMSCs were abolished by its inhibitor luzindole. Also, melatonin protected BMSCs against iron overload-induced ROS accumulation and membrane potential depolarization. Further study uncovered that melatonin inhibited the upregulation of p53, ERK and p38 protein expressions in BMSCs with iron overload. Collectively, melatonin plays a protective role in iron overload-induced osteogenic differentiation dysfunction and senescence through blocking ROS accumulation and p53/ERK/p38 activation. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Alpha-adrenergic blocker mediated osteoblastic stem cell differentiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Choi, Yoon Jung; Lee, Jue Yeon; Research Center, Nano Intelligent Biomedical Engineering Corporation

Highlights: Black-Right-Pointing-Pointer Doxazocin directly up-regulated bone metabolism at a low dose. Black-Right-Pointing-Pointer Doxazocin induced osteoblastic stem cell differentiation without affecting cell proliferation. Black-Right-Pointing-Pointer This osteogenic stem cell differentiation is mediated by ERK-signal dependent pathway. -- Abstract: Recent researches have indicated a role for antihypertensive drugs including alpha- or beta-blockers in the prevention of bone loss. Some epidemiological studies reported the protective effects of those agents on fracture risk. However, there is limited information on the association with those agents especially at the mechanism of action. In the present study, we investigated the effects of doxazosin, an alpha-blocker that is clinicallymore » used for the treatment of benign prostatic hyperplasia (BPH) along with antihypertensive medication, on the osteogenic stem cell differentiation. We found that doxazosin increased osteogenic differentiation of human mesenchymal stem cells, detected by Alizarin red S staining and calcein. Doxazosin not only induced expression of alkaline phosphatase, type I collagen, osteopontin, and osteocalcin, it also resulted in increased phosphorylation of extracellular signal-regulated kinase (ERK1/2), a MAP kinase involved in osteoblastic differentiation. Treatment with U0126, a MAP kinase inhibitor, significantly blocked doxazosin-induced osteoblastic differentiation. Unrelated to activation of osteogenic differentiation by doxazosin, we found that there were no significant changes in adipogenic differentiation or in the expression of adipose-specific genes, including peroxisome proliferator-activated receptor {gamma}, aP2, or LPL. In this report, we suggest that doxazosin has the ability to increase osteogenic cell differentiation via ERK1/2 activation in osteogenic differentiation of adult stem cells, which supports the protective effects of antihypertensive drug on fracture risk and according to our data doxazosin might be useful for application in the field of bone metabolism.« less

Partitioning-based mechanisms under personalized differential privacy.

PubMed

Li, Haoran; Xiong, Li; Ji, Zhanglong; Jiang, Xiaoqian

2017-05-01

Differential privacy has recently emerged in private statistical aggregate analysis as one of the strongest privacy guarantees. A limitation of the model is that it provides the same privacy protection for all individuals in the database. However, it is common that data owners may have different privacy preferences for their data. Consequently, a global differential privacy parameter may provide excessive privacy protection for some users, while insufficient for others. In this paper, we propose two partitioning-based mechanisms, privacy-aware and utility-based partitioning, to handle personalized differential privacy parameters for each individual in a dataset while maximizing utility of the differentially private computation. The privacy-aware partitioning is to minimize the privacy budget waste, while utility-based partitioning is to maximize the utility for a given aggregate analysis. We also develop a t -round partitioning to take full advantage of remaining privacy budgets. Extensive experiments using real datasets show the effectiveness of our partitioning mechanisms.

Partitioning-based mechanisms under personalized differential privacy

PubMed Central

Li, Haoran; Xiong, Li; Ji, Zhanglong; Jiang, Xiaoqian

2017-01-01

Differential privacy has recently emerged in private statistical aggregate analysis as one of the strongest privacy guarantees. A limitation of the model is that it provides the same privacy protection for all individuals in the database. However, it is common that data owners may have different privacy preferences for their data. Consequently, a global differential privacy parameter may provide excessive privacy protection for some users, while insufficient for others. In this paper, we propose two partitioning-based mechanisms, privacy-aware and utility-based partitioning, to handle personalized differential privacy parameters for each individual in a dataset while maximizing utility of the differentially private computation. The privacy-aware partitioning is to minimize the privacy budget waste, while utility-based partitioning is to maximize the utility for a given aggregate analysis. We also develop a t-round partitioning to take full advantage of remaining privacy budgets. Extensive experiments using real datasets show the effectiveness of our partitioning mechanisms. PMID:28932827

Performance analysis of microcomputer based differential protection of UHV lines under selective phase switching

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bhatti, A.A.

1990-04-01

This paper examines the effects of primary and secondary fault quantities as well s of mutual couplings of neighboring circuits on the sensitivity of operation and threshold settings of a microcomputer based differential protection of UHV lines under selective phase switching. Microcomputer based selective phase switching allows the disconnection of minimum number of phases involved in a fault and requires the autoreclosing of these phases immediately after the extinction of secondary arc. During a primary fault a heavy current contribution to the healthy phases tends to cause an unwanted tripping. Faulty phases physically disconnected constitute an isolated fault which beingmore » coupled to the system affects the current and voltage levels of the healthy phases still retained in the system and may cause an unwanted tripping. The microcomputer based differential protection, appears to have poor performance when applied to uncompensated lines employing selective pole switching.« less

Buffering boys and boosting girls: The protective and promotive effects of Early Head Start for children’s expressive language in the context of parenting stress

PubMed Central

Vallotton, C. D.; Harewood, T.; Ayoub, C. A.; Pan, B.; Mastergeorge, A. M.; Brophy-Herb, H.

2011-01-01

Children’s characteristics, including gender, influence their development by eliciting differential responses from their environments, and by influencing differential responses to their environments. Parenting-related stress, associated with poverty environments, negatively influences children’s language, likely through its impact on parent-child interactions, but may impact boys’ and girls’ development differently. Early intervention represents one tool for supporting development in at-risk toddlers, but gender-differences in effects of intervention are rarely described. The current studies assessed the effects of Early Head Start (EHS) on children’s productive vocabulary in the context of parenting stress and examined gender differences in program effects on vocbulary. Data were from the national EHS Research and Evaluation (EHSRE) study (Study 1, N = 3,001), and from a dataset associated with one EHSRE site (Study 2, N = 146) where additional data on productive vocabulary were collected. Study 1 found that at 24 months of age, the EHS program protected girls’ productive vocabulary from the negative effects of parenting stress, but had little impact on boys’ vocabulary. In Study 2, the local EHS site promoted girls’ vocabulary development over time from 14 to 36 months despite the negative effects of parenting stress, and protected boys’ vocabulary from the negative parenting stress effects. These results suggest differential ways in which at-risk toddlers are affected by early intervention. PMID:23166405

Has the Copayment Ceiling Improved Financial Protection in the Korean National Health Insurance System? Evidence From the 2009 Policy Change.

PubMed

Lee, Tae-Jin; Cheong, Chelim

2017-11-01

To relieve the financial burden faced by households, the Korean National Health Insurance (NHI) system introduced a "copayment ceiling," which evolved into a differential ceiling in 2009, with the copayment ceiling depending on patients' income. This study aimed to examine the effect of the differential copayment ceiling on financial protection and healthcare utilization, particularly focusing on whether its effects varied across different income groups. This study obtained data from the Korea Health Panel. The number of households included in the analysis was 6555 in 2008, 5859 in 2009, 5539 in 2010, and 5372 in 2011. To assess the effects of the differential copayment ceiling on utilization, out-of-pocket (OOP) payments, and catastrophic payments, various random-effects models were applied. Utilization was measured as treatment days, while catastrophic payments were defined as OOP payments exceeding 10% of household income. Among the right-hand side variables were the interaction terms of the new policy with income levels, as well as a set of household characteristics. The differential copayment ceiling contributed to increased utilization regardless of income levels both in all patients and in cancer patients. However, the new policy did not seem to reduce significantly the incidence of catastrophic payments among cancer patients, and even increased the incidence among all patients. The limited effect of the differential ceiling can be attributed to a high proportion of direct payments for services not covered by the NHI, as well as the relatively small number of households benefiting from the differential ceilings; these considerations warrant a better policy design.

TolC plays a crucial role in immune protection conferred by Edwardsiella tarda whole-cell vaccines.

PubMed

Wang, Chao; Peng, Bo; Li, Hui; Peng, Xuan-Xian

2016-07-12

Although vaccines developed from live organisms have better efficacy than those developed from dead organisms, the mechanisms underlying this differential efficacy remain unexplored. In this study, we combined sub-immunoproteomics with immune challenge to investigate the action of the outer membrane proteome in the immune protection conferred by four Edwardsiella tarda whole-cell vaccines prepared via different treatments and to identify protective immunogens that play a key role in this immune protection. Thirteen spots representing five outer membrane proteins and one cytoplasmic protein were identified, and it was found that their abundance was altered in relation with the immune protective abilities of the four vaccines. Among these proteins, TolC and OmpA were found to be the key immunogens conferring the first and second highest degrees of protection, respectively. TolC was detected in the two effective vaccines (live and inactivated-30-F). The total antiserum and anti-OmpA titers were higher for the two effective vaccines than for the two ineffective vaccines (inactivated-80-F and inactivated-100). Further evidence demonstrated that the live and inactivated-30-F vaccines demonstrated stronger abilities to induce CD8+ and CD4+ T cell differentiation than the other two evaluated vaccines. Our results indicate that the outer membrane proteome changes dramatically following different treatments, which contributes to the effectiveness of whole-cell vaccines.

Targeted social protection in a pastoralist economy: case study from Kenya.

PubMed

Janzen, S A; Jensen, N D; Mude, A G

2016-11-01

Social protection programmes are designed to help vulnerable populations - including pastoralists - maintain a basic level of well-being, manage risk, and cope with negative shocks. Theory suggests that differential targeting according to poverty status can increase the reach and effectiveness of budgeted social protection programmes. Chronically poor households benefit most from social protection designed to help them meet their basic needs and make vital investments necessary to graduate from poverty. Vulnerable non-destitute households benefit from protection against costly temporary shocks, but do not necessarily need regular assistance. Welfare gains occur when a comprehensive social protection programme considers the needs of both types of households. The authors use evidence-based understanding of poverty dynamics in the pastoralist-based economy of northern Kenya's arid and semi-arid lands as a case study to discuss and compare the observed impacts of two different social protection schemes on heterogeneous pastoralist households: a targeted, unconditional, cash-transfer programme designed to support the poorest, and an index-based livestock insurance programme, which acts as a productive 'safety net' to help stem a descent into poverty and increase resilience. Both types of social protection scheme have been shown to decrease poverty, improve food security and protect child health. However, the behavioural response for asset accumulation varies with the type of protection and the household's unique situation. Poor households that receive cash transfers retain and accumulate assets quickly. Insured households, who are typically vulnerable yet not destitute, protect existing herds and invest more in the livestock they already own. The authors argue that differential targeting increases programme efficiency, and discuss Kenya's current approach to implementing differentially targeted social protection.

Victoria's Child FIRST and IFS differential response system: progress and issues.

PubMed

Lonne, Bob; Brown, Gerry; Wagner, Ingrid; Gillespie, Kerri

2015-01-01

Differential response has long been utilized by statutory child protection systems in Australia. This article describes the advent and history of Victoria's differential response system, with a particular focus on the Child FIRST and IFS programme. This program entails a partnership arrangement between the Department of Human Services child protection services and community-based, not-for-profit agencies to provide a diverse range of early intervention and prevention services. The findings of a recent external service system evaluation, a judicial inquiry, and the large-scale Child and Family Services Outcomes Survey of parents/carers perspectives of their service experiences are used to critically examine the effectiveness of this differential response approach. Service-user perspectives of the health and wellbeing of children and families are identified, as well as the recognized implementation issues posing significant challenges for the goal of an integrated partnership system. The need for ongoing reform agendas is highlighted along with the policy, program and structural tensions that exist in differential response systems, which are reliant upon partnerships and shared responsibilities for protecting children and assisting vulnerable families. Suggestions are made for utilizing robust research and evaluation that gives voice to service users and promotes their rights and interests. Copyright © 2014 Elsevier Ltd. All rights reserved.

Pulsed electromagnetic fields promote survival and neuronal differentiation of human BM-MSCs.

PubMed

Urnukhsaikhan, Enerelt; Cho, Hyunjin; Mishig-Ochir, Tsogbadrakh; Seo, Young-Kwon; Park, Jung-Kueg

2016-04-15

Pulsed electromagnetic fields (PEMF) are known to affect biological properties such as differentiation, regulation of transcription factor and cell proliferation. However, the cell-protective effect of PEMF exposure is largely unknown. The aim of this study is to understand the mechanisms underlying PEMF-mediated suppression of apoptosis and promotion of survival, including PEMF-induced neuronal differentiation. Treatment of induced human BM-MSCs with PEMF increased the expression of neural markers such as NF-L, NeuroD1 and Tau. Moreover, treatment of induced human BM-MSCs with PEMF greatly decreased cell death in a dose- and time-dependent manner. There is evidence that Akt and Ras are involved in neuronal survival and protection. Activation of Akt and Ras results in the regulation of survival proteins such as Bad and Bcl-xL. Thus, the Akt/Ras signaling pathway may be a desirable target for enhancing cell survival and treatment of neurological disease. Our analyses indicated that PEMF exposure dramatically increased the activity of Akt, Rsk, Creb, Erk, Bcl-xL and Bad via phosphorylation. PEMF-dependent cell protection was reversed by pretreatment with LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K). Our data suggest that the PI3K/Akt/Bad signaling pathway may be a possible mechanism for the cell-protective effects of PEMF. Copyright © 2016 Elsevier Inc. All rights reserved.

Has the Copayment Ceiling Improved Financial Protection in the Korean National Health Insurance System? Evidence From the 2009 Policy Change

PubMed Central

2017-01-01

Objectives To relieve the financial burden faced by households, the Korean National Health Insurance (NHI) system introduced a “copayment ceiling,” which evolved into a differential ceiling in 2009, with the copayment ceiling depending on patients’ income. This study aimed to examine the effect of the differential copayment ceiling on financial protection and healthcare utilization, particularly focusing on whether its effects varied across different income groups. Methods This study obtained data from the Korea Health Panel. The number of households included in the analysis was 6555 in 2008, 5859 in 2009, 5539 in 2010, and 5372 in 2011. To assess the effects of the differential copayment ceiling on utilization, out-of-pocket (OOP) payments, and catastrophic payments, various random-effects models were applied. Utilization was measured as treatment days, while catastrophic payments were defined as OOP payments exceeding 10% of household income. Among the right-hand side variables were the interaction terms of the new policy with income levels, as well as a set of household characteristics. Results The differential copayment ceiling contributed to increased utilization regardless of income levels both in all patients and in cancer patients. However, the new policy did not seem to reduce significantly the incidence of catastrophic payments among cancer patients, and even increased the incidence among all patients. Conclusions The limited effect of the differential ceiling can be attributed to a high proportion of direct payments for services not covered by the NHI, as well as the relatively small number of households benefiting from the differential ceilings; these considerations warrant a better policy design. PMID:29207446

Melatonin antagonizes interleukin-18-mediated inhibition on neural stem cell proliferation and differentiation.

PubMed

Li, Zheng; Li, Xingye; Chan, Matthew T V; Wu, William Ka Kei; Tan, DunXian; Shen, Jianxiong

2017-09-01

Neural stem cells (NSCs) are self-renewing, pluripotent and undifferentiated cells which have the potential to differentiate into neurons, oligodendrocytes and astrocytes. NSC therapy for tissue regeneration, thus, gains popularity. However, the low survivals rate of the transplanted cell impedes its utilities. In this study, we tested whether melatonin, a potent antioxidant, could promote the NSC proliferation and neuronal differentiation, especially, in the presence of the pro-inflammatory cytokine interleukin-18 (IL-18). Our results showed that melatonin per se indeed exhibited beneficial effects on NSCs and IL-18 inhibited NSC proliferation, neurosphere formation and their differentiation into neurons. All inhibitory effects of IL-18 on NSCs were significantly reduced by melatonin treatment. Moreover, melatonin application increased the production of both brain-derived and glial cell-derived neurotrophic factors (BDNF, GDNF) in IL-18-stimulated NSCs. It was observed that inhibition of BDNF or GDNF hindered the protective effects of melatonin on NSCs. A potentially protective mechanism of melatonin on the inhibition of NSC's differentiation caused IL-18 may attribute to the up-regulation of these two major neurotrophic factors, BNDF and GNDF. The findings indicate that melatonin may play an important role promoting the survival of NSCs in neuroinflammatory diseases. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Taurine suppresses osteoblastic differentiation of aortic valve interstitial cells induced by beta-glycerophosphate disodium, dexamethasone and ascorbic acid via the ERK pathway.

PubMed

Feng, Xiang; Li, Jian-ming; Liao, Xiao-bo; Hu, Ye-rong; Shang, Bao-peng; Zhang, Zhi-yuan; Yuan, Ling-qing; Xie, Hui; Sheng, Zhi-feng; Tang, Hao; Zhang, Wei; Gu, Lu; Zhou, Xin-min

2012-10-01

Aortic valve calcification (AVC) is an active process characterized by osteoblastic differentiation of the aortic valve interstitial cells (AVICs). Taurine is a free β-amino acid and plays important physiological roles including protective effect of cardiovascular events. To evaluate the possible role of taurine in AVC, we isolated human AVICs from patients with type A dissection without leaflet disease. We demonstrated that the cultured AVICs express SM α-actin, vimentin and taurine transporter (TAUT), but not CD31, SM-myosin or desmin. We also established the osteoblastic differentiation model of the AVICs induced by pro-calcific medium (PCM) containing β-glycerophosphate disodium, dexamethasone and ascorbic acid in vitro. The results showed that taurine attenuated the PCM-induced osteoblastic differentiation of AVICs by decreasing the alkaline phosphate (ALP) activity/expression and the expression of the core binding factor α1 (Cbfα1) in a dose-dependent manner (reaching the maximum protective effect at 10 mM), and taurine (10 mM) inhibited the mineralization level of AVICs in the form of calcium content significantly. Furthermore, taurine activated the extracellular signal-regulated protein kinase (ERK) pathway via TAUT, and the inhibitor of ERK (PD98059) abolished the effect of taurine on both ALP activity/expression and Cbfα1 expression. These results suggested that taurine could inhibit osteoblastic differentiation of AVIC via the ERK pathway.

Responding to information about children in adversity: ten years of a differential response model in Western Australia.

PubMed

Harries, Maria; Cant, Rosemary L; Bilson, Andy; Thorpe, David

2015-01-01

This article uses a comprehensive database about children in adversity collected over the 16-year period from 1990 to 2005 in the state of Western Australia. The focus of this interrogation is the effect of major changes in responses to information about children brought to the attention of the Western Australian statutory authority in a 10-year period during this 16 years. The initiative for these changes was termed New Directions, and its associated policy and practice changes were aimed at differentiating information expressing concerns about children and families from allegations of child maltreatment. They emphasized the provision of supportive and empowering services to families experiencing difficulties - a form of differential response to children in adversity. The article covers the period leading up to the policy and practice change and the 10 years during which these changes were implemented. It examines some effects of the new policy and comments on whether the changes resulted in missed opportunities to protect children from harm, which in turn, might have led to higher rates of re-reporting. The authors present an overall picture of the nature of the information accepted by the statutory authority and how the interpretation of that information might have affected subsequent outcomes for children. In doing so, it shows that the policy and consequential practice changes associated with a differential response mechanism had long lasting positive effects that, despite dire warnings, did not compromise the protection of the small group of children identified as requiring protective interventions. Copyright © 2014 Elsevier Ltd. All rights reserved.

Buffering Boys and Boosting Girls: The Protective and Promotive Effects of Early Head Start for Children's Expressive Language in the Context of Parenting Stress

ERIC Educational Resources Information Center

Vallotton, C. D.; Harewood, T.; Ayoub, C. A.; Pan, B.; Mastergeorge, A. M.; Brophy-Herb, H.

2012-01-01

Children's characteristics, including gender, influence their development by eliciting differential responses from their environments, and by influencing differential responses to their environments. Parenting-related stress, associated with poverty environments, negatively influences children's language, likely through its impact on parent-child…

Time to Akt: Superior tumor-reactive T cells for adoptive immunotherapy.

PubMed

van der Waart, Anniek B; Hobo, Willemijn; Dolstra, Harry

2015-05-01

T cells are crucial players in the protection against cancer, and can be used in adoptive cell therapy to prevent or treat relapse. However, their state of differentiation determines their effectiveness, with early memory cells being the most favorable. Here, we discuss restraining of differentiation to engineer the ultimate tumor-reactive T cell.

Cytotoxicity and osteogenic potential of silicate calcium cements as potential protective materials for pulpal revascularization.

PubMed

Bortoluzzi, Eduardo A; Niu, Li-Na; Palani, Chithra D; El-Awady, Ahmed R; Hammond, Barry D; Pei, Dan-Dan; Tian, Fu-Cong; Cutler, Christopher W; Pashley, David H; Tay, Franklin R

2015-12-01

In pulpal revascularization, a protective material is placed coronal to the blood clot to prevent recontamination and to facilitate osteogenic differentiation of mesenchymal stem cells to produce new dental tissues. Although mineral trioxide aggregate (MTA) has been the material of choice for clot protection, it is easily displaced into the clot during condensation. The present study evaluated the effects of recently introduced calcium silicate cements (Biodentine and TheraCal LC) on the viability and osteogenic differentiation of human dental pulp stem cells (hDPSCs) by comparing with MTA Angelus. Cell viability was assessed using XTT assay and flow cytometry. The osteogenic potential of hDPSCs exposed to calcium silicate cements was examined using qRT-PCR for osteogenic gene expressions, alkaline phosphatase enzyme activity, Alizarin red S staining and transmission electron microscopy of extracellular calcium deposits. Parametric statistical methods were employed for analyses of significant difference among groups, with α=0.05. The cytotoxic effects of Biodentine and TheraCal LC on hDPSCs were time- and concentration-dependent. Osteogenic differentiation of hDPSCs was enhanced after exposure to Biodentine that was depleted of its cytotoxic components. This effect was less readily observed in hDPSCs exposed to TheraCal LC, although both cements supported extracellular mineralization better than the positive control (zinc oxide-eugenol-based cement). A favorable tissue response is anticipated to occur with the use of Biodentine as a blood clot-protecting material for pulpal revascularization. Further investigations with the use of in vivo animal models are required to validate the potential adverse biological effects of TheraCal LC on hDPSCs. Copyright © 2015 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

Cytotoxicity and Osteogenic Potential of Silicate Calcium Cements as Potential Protective Materials for Pulpal Revascularization

PubMed Central

Bortoluzzi, Eduardo A.; Niu, Li-na; Palani, Chithra D.; El-Awady, Ahmed R.; Hammond, Barry D.; Pei, Dan-dan; Tian, Fu-cong; Cutler, Christopher W.; Pashley, David H.; Tay, Franklin R.

2016-01-01

Objectives In pulpal revascularization, a protective material is placed coronal to the blood clot to prevent recontamination and to facilitate osteogenic differentiation of mesenchynal stem cells to produce new dental tissues. Although mineral trioxide aggregate (MTA) has been the material of choice for clot protection, it is easily displaced into the clot during condensation. The present study evaluated the effects of recently-introduced calcium silicate cements (Biodentine and TheraCal LC) on the viability and osteogenic differentiation of human dental pulp stem cells (hDPSCs) by comparing with MTA Angelus. Methods Cell viability was assessed using XTT assay and flow cytometry. The osteogenic potential of hDPSCs exposed to calcium silicate cements was examined using qRT-PCR for osteogeic gene expressions, alkaline phosphatase enzyme activity, Alizarin red S staining and transmission electron microscopy of extracellular calcium deposits. Parametric statistical methods were employed for analyses of significant difference among groups, with α=0.05. Results The cytotoxic effects of Biodentine and TheraCal LC on hDPSCs were time- and concentration-dependent. Osteogenic differentiation of hDPSCs was enhanced after exposure to Biodentine that was depleted of its cytotoxic components. This effect was less readily observed in hDPSCs exposed to TheraCal LC, although both cements supported extracelluar mineralization better than the positive control (zinc oxide-eugenol–based cement). Significance A favorable tissue response is anticipated to occur with the use of Biodentine as a blood clot-protecting material for pulpal revascularizaiton. Further investigations with the use of in vivo animal models are required to validate the potential adverse biological effects of TheraCal LC on hDPSCs. PMID:26494267

In vivo regulation of colonic cell proliferation, differentiation, apoptosis, and P27Kip1 by dietary fish oil and butyrate in rats.

PubMed

Hong, Mee Young; Turner, Nancy D; Murphy, Mary E; Carroll, Raymond J; Chapkin, Robert S; Lupton, Joanne R

2015-11-01

We have shown that dietary fish oil is protective against experimentally induced colon cancer, and the protective effect is enhanced by coadministration of pectin. However, the underlying mechanisms have not been fully elucidated. We hypothesized that fish oil with butyrate, a pectin fermentation product, protects against colon cancer initiation by decreasing cell proliferation and increasing differentiation and apoptosis through a p27(Kip1)-mediated mechanism. Rats were provided diets of corn or fish oil, with/without butyrate, and terminated 12, 24, or 48 hours after azoxymethane (AOM) injection. Proliferation (Ki-67), differentiation (Dolichos Biflorus Agglutinin), apoptosis (TUNEL), and p27(Kip1) (cell-cycle mediator) were measured in the same cell within crypts in order to examine the coordination of cell cycle as a function of diet. DNA damage (N(7)-methylguanine) was determined by quantitative IHC analysis. Dietary fish oil decreased DNA damage by 19% (P = 0.001) and proliferation by 50% (P = 0.003) and increased differentiation by 56% (P = 0.039) compared with corn oil. When combined with butyrate, fish oil enhanced apoptosis 24 hours after AOM injection compared with a corn oil/butyrate diet (P = 0.039). There was an inverse relationship between crypt height and apoptosis in the fish oil/butyrate group (r = -0.53, P = 0.040). The corn oil/butyrate group showed a positive correlation between p27(Kip1) expression and proliferation (r = 0.61, P = 0.035). These results indicate the in vivo effect of butyrate on apoptosis and proliferation is dependent on dietary lipid source. These results demonstrate the presence of an early coordinated colonocyte response by which fish oil and butyrate protects against colon tumorigenesis. ©2015 American Association for Cancer Research.

Puerarin protects differentiated PC12 cells from H₂O₂-induced apoptosis through the PI3K/Akt signalling pathway.

PubMed

Zhang, Qin; Huang, Wei-Dong; Lv, Xue-Ying; Yang, Yun-Mei

2012-05-01

Oxidative stress has been implicated as a major mechanism underlying the pathogenesis of neurodegenerative disorders. ROS (reactive oxygen species) can cause cell death via apoptosis. NGF (nerve growth factor) differentiated rat PC12 cells have been extensively used to study the differentiation and apoptosis of neurons. This study has investigated the protective effects of puerarin in H2O2-induced apoptosis of differentiated PC12 cells, and the possible molecular mechanisms involved. Differentiated PC12 cells were incubated with 700 μM H2O2 in the absence or presence of different doses of puerarin (4, 8 and 16 μM). Apoptosis was assessed by MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay, TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) analysis and Annexin V-PI (propidium iodide) double staining flow cytometry. Protein levels of phospho-Akt and phospho-BAD (Bcl-2/Bcl-XL-antagonist, causing cell death) were assayed by Western blotting. After stimulation with H2O2 for 18 h, the viability of differentiated PC12 cells decreased significantly and a large number of cells underwent apoptosis. Differentiated PC12 cells were rescued from H2O2-induced apoptosis at different concentrations of puerarin in a dose-dependent manner. This was through increased production of phospho-Akt and phospho-BAD, an effect that could be reversed by wortmannin, an inhibitor of PI3K (phosphoinositide 3-kinase). The results suggest that puerarin may have neuroprotective effect through activation of the PI3K/Akt signalling pathway.

Differential protection of Cry1Fa toxin against Spodoptera frugiperda larval gut proteases by cadherin orthologs correlates with increased synergism.

PubMed

Rahman, Khalidur; Abdullah, Mohd Amir F; Ambati, Suresh; Taylor, Milton D; Adang, Michael J

2012-01-01

The Cry proteins produced by Bacillus thuringiensis (Bt) are the most widely used biopesticides effective against a range of crop pests and disease vectors. Like chemical pesticides, development of resistance is the primary threat to the long-term efficacy of Bt toxins. Recently discovered cadherin-based Bt Cry synergists showed the potential to augment resistance management by improving efficacy of Cry toxins. However, the mode of action of Bt Cry synergists is thus far unclear. Here we elucidate the mechanism of cadherin-based Cry toxin synergism utilizing two cadherin peptides, Spodoptera frugiperda Cad (SfCad) and Manduca sexta Cad (MsCad), which differentially enhance Cry1Fa toxicity to Spodoptera frugiperda neonates. We show that differential SfCad- and MsCad-mediated protection of Cry1Fa toxin in the Spodoptera frugiperda midgut correlates with differential Cry1Fa toxicity enhancement. Both peptides exhibited high affinity for Cry1Fa toxin and an increased rate of Cry1Fa-induced pore formation in S. frugiperda. However, only SfCad bound the S. frugiperda brush border membrane vesicle and more effectively prolonged the stability of Cry1Fa toxin in the gut, explaining higher Cry1Fa enhancement by this peptide. This study shows that cadherin fragments may enhance B. thuringiensis toxicity by at least two different mechanisms or a combination thereof: (i) protection of Cry toxin from protease degradation in the insect midgut and (ii) enhancement of pore-forming ability of Cry toxin.

The IL23R R381Q Gene Variant Protects against Immune-Mediated Diseases by Impairing IL-23-Induced Th17 Effector Response in Humans

PubMed Central

Di Meglio, Paola; Di Cesare, Antonella; Laggner, Ute; Chu, Chung-Ching; Napolitano, Luca; Villanova, Federica; Tosi, Isabella; Capon, Francesca; Trembath, Richard C.; Peris, Ketty; Nestle, Frank O.

2011-01-01

IL-23 and Th17 cells are key players in tissue immunosurveillance and are implicated in human immune-mediated diseases. Genome-wide association studies have shown that the IL23R R381Q gene variant protects against psoriasis, Crohn's disease and ankylosing spondylitis. We investigated the immunological consequences of the protective IL23R R381Q gene variant in healthy donors. The IL23R R381Q gene variant had no major effect on Th17 cell differentiation as the frequency of circulating Th17 cells was similar in carriers of the IL23R protective (A) and common (G) allele. Accordingly, Th17 cells generated from A and G donors produced similar amounts of Th17 cytokines. However, IL-23-mediated Th17 cell effector function was impaired, as Th17 cells from A allele carriers had significantly reduced IL-23-induced IL-17A production and STAT3 phosphorylation compared to G allele carriers. Our functional analysis of a human disease-associated gene variant demonstrates that IL23R R381Q exerts its protective effects through selective attenuation of IL-23-induced Th17 cell effector function without interfering with Th17 differentiation, and highlights its importance in the protection against IL-23-induced tissue pathologies. PMID:21364948

The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans.

PubMed

Di Meglio, Paola; Di Cesare, Antonella; Laggner, Ute; Chu, Chung-Ching; Napolitano, Luca; Villanova, Federica; Tosi, Isabella; Capon, Francesca; Trembath, Richard C; Peris, Ketty; Nestle, Frank O

2011-02-22

IL-23 and Th17 cells are key players in tissue immunosurveillance and are implicated in human immune-mediated diseases. Genome-wide association studies have shown that the IL23R R381Q gene variant protects against psoriasis, Crohn's disease and ankylosing spondylitis. We investigated the immunological consequences of the protective IL23R R381Q gene variant in healthy donors. The IL23R R381Q gene variant had no major effect on Th17 cell differentiation as the frequency of circulating Th17 cells was similar in carriers of the IL23R protective (A) and common (G) allele. Accordingly, Th17 cells generated from A and G donors produced similar amounts of Th17 cytokines. However, IL-23-mediated Th17 cell effector function was impaired, as Th17 cells from A allele carriers had significantly reduced IL-23-induced IL-17A production and STAT3 phosphorylation compared to G allele carriers. Our functional analysis of a human disease-associated gene variant demonstrates that IL23R R381Q exerts its protective effects through selective attenuation of IL-23-induced Th17 cell effector function without interfering with Th17 differentiation, and highlights its importance in the protection against IL-23-induced tissue pathologies.

Impact analysis of tap switch out of step for converter transformer

NASA Astrophysics Data System (ADS)

Hong-yue, ZHANG; Zhen-hua, ZHANG; Zhang-xue, XIONG; Gao-wang, YU

2017-06-01

AC transformer load regulation is mainly used to adjust the load side voltage level, improve the quality of power supply, the voltage range is relatively narrow. In DC system, converter transformer is the core equipment of AC and DC power converter and inverter. converter transformer tap adjustment can maintain the normal operation of the converter in small angle range control, the absorption of reactive power, economic operation, valve less stress, valve damping circuit loss, AC / DC harmonic component is also smaller. In this way, the tap switch action is more frequent, and a large range of the tap switch adjustment is required. Converter transformer with a more load voltage regulation switch, the voltage regulation range of the switch is generally 20~30%, the adjustment of each file is 1%~2%. Recently it is often found that the tap switch of Converter Transformers is out of step in Converter station. In this paper, it is analyzed in detail the impact of tap switch out of step for differential protection, overexcitation protection and zero sequence over current protection. Analysis results show that: the tap switch out of step has no effect on the differential protection and the overexcitation protection including the tap switch. But the tap switch out of step has effect on zero sequence overcurrent protection of out of step star-angle converter transformer. The zero sequence overcurrent protection will trip when the tap switch out of step is greater than 3 for out of step star-angle converter transformer.

Differential association of socio-economic status with gender- and age-defined suicidal ideation among adult and elderly individuals in South Korea.

PubMed

Lee, Hoo-Yeon; Hahm, Myung-Il; Park, Eun-Cheol

2013-11-30

South Korea has the highest suicide rate among countries in the Organisation for Economic Co-operation and Development (OECD), with a rising trend that contrasts with the trend in most other OECD countries. This study assessed differential associations of socio-demographic factors with suicidal ideation in South Korea. We used five waves of data from the 2010 Korea National Health and Nutrition Examination Survey. Study subjects included 5803 men and women aged >25 years. We analysed weighted percentages with consideration of the complex survey sample design and unequal weights. Surveylogistic regressions were applied. Protective effects against suicidal ideation were found for higher household income, higher educational attainment, and being married. Functional limitations and depressive symptoms were risk factors for suicidal ideation. However, these significant factors may exert different effects on vulnerability for suicidal ideation among different genders and age groups. Thus, household income was mainly protective for women and subjects aged 25-44 years, and educational attainment was protective for individuals aged >65 years. Our findings suggest the need for extended social protection policies for the less privileged population and special strategies for different groups. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Adipose tissue-derived stem cell secreted IGF-1 protects myoblasts from the negative effect of myostatin.

PubMed

Gehmert, Sebastian; Wenzel, Carina; Loibl, Markus; Brockhoff, Gero; Huber, Michaela; Krutsch, Werner; Nerlich, Michael; Gosau, Martin; Klein, Silvan; Schreml, Stephan; Prantl, Lukas; Gehmert, Sanga

2014-01-01

Myostatin, a TGF-β family member, is associated with inhibition of muscle growth and differentiation and might interact with the IGF-1 signaling pathway. Since IGF-1 is secreted at a bioactive level by adipose tissue-derived mesenchymal stem cells (ASCs), these cells (ASCs) provide a therapeutic option for Duchenne Muscular Dystrophy (DMD). But the protective effect of stem cell secreted IGF-1 on myoblast under high level of myostatin remains unclear. In the present study murine myoblasts were exposed to myostatin under presence of ASCs conditioned medium and investigated for proliferation and apoptosis. The protective effect of IGF-1 was further examined by using IGF-1 neutralizing and receptor antibodies as well as gene silencing RNAi technology. MyoD expression was detected to identify impact of IGF-1 on myoblasts differentiation when exposed to myostatin. IGF-1 was accountable for 43.6% of the antiapoptotic impact and 48.8% for the proliferative effect of ASCs conditioned medium. Furthermore, IGF-1 restored mRNA and protein MyoD expression of myoblasts under risk. Beside fusion and transdifferentiation the beneficial effect of ASCs is mediated by paracrine secreted cytokines, particularly IGF-1. The present study underlines the potential of ASCs as a therapeutic option for Duchenne muscular dystrophy and other dystrophic muscle diseases.

c-FLIP is involved in erythropoietin-mediated protection of erythroid-differentiated cells from TNF-alpha-induced apoptosis.

PubMed

Vittori, Daniela; Vota, Daiana; Callero, Mariana; Chamorro, María E; Nesse, Alcira

2010-05-04

The TNF-alpha (tumour necrosis factor) affects a wide range of biological activities, such as cell proliferation and apoptosis. Cell life or death responses to this cytokine might depend on cell conditions. This study focused on the modulation of factors that would affect the sensitivity of erythroid-differentiated cells to TNF-alpha. Hemin-differentiated K562 cells showed higher sensitivity to TNF-induced apoptosis than undifferentiated cells. At the same time, hemin-induced erythroid differentiation reduced c-FLIP (cellular FLICE-inhibitory protein) expression. However, this negative effect was prevented by prior treatment with Epo (erythropoietin), which allowed the cell line to maintain c-FLIP levels. On the other hand, erythroid-differentiated UT-7 cells - dependent on Epo for survival - showed resistance to TNF-alpha pro-apoptotic action. Only after the inhibition of PI3K (phosphatidylinositol-3 kinase)-mediated pathways, which was accompanied by negative c-FLIP modulation and increased erythroid differentiation, were UT-7 cells sensitive to TNF-alpha-triggered apoptosis. In summary, erythroid differentiation might deregulate the balance between growth promotion and death signals induced by TNF-alpha, depending on cell type and environmental conditions. The role of c-FLIP seemed to be critical in the protection of erythroid-differentiated cells from apoptosis or in the determination of their sensitivity to TNF-mediated programmed cell death. Epo, which for the first time was found to be involved in the prevention of c-FLIP down-regulation, proved to have an anti-apoptotic effect against the pro-inflammatory factor. The identification of signals related to cell life/death switching would have significant implications in the control of proliferative diseases and would contribute to the understanding of mechanisms underlying the anaemia associated with inflammatory processes.

Differential effect of rebamipide on transmembrane mucin biosynthesis in stratified ocular surface epithelial cells.

PubMed

Uchino, Yuichi; Woodward, Ashley M; Argüeso, Pablo

2016-12-01

Mucins are a group of highly glycosylated glycoproteins responsible for the protection of wet-surfaced epithelia. Recent data indicate that transmembrane mucins differ in their contribution to the protective function of the ocular surface, with MUC16 being the most effective barrier on the apical surface glycocalyx. Here, we investigated the role of the mucoprotective drug rebamipide in the regulation of transmembrane mucin biosynthesis using stratified cultures of human corneal and conjunctival epithelial cells. We find that the addition of rebamipide to corneal, but not conjunctival, epithelial cells increased MUC16 protein biosynthesis. Rebamipide did not affect the levels of MUC1, 4 and 20 compared to control. In these experiments, rebamipide had no effect on the expression levels of Notch intracellular domains, suggesting that the rebamipide-induced increase in MUC16 biosynthesis in differentiated corneal cultures is not regulated by Notch signaling. Overall these findings indicate that rebamipide induces the differential upregulation of MUC16 in stratified cultures of human corneal epithelial cells, which may have implications to the proper restoration of barrier function in ocular surface disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

Epitope-cavities generated by molecularly imprinted films measure the coincident response to anthrax protective antigen and its segments.

PubMed

Tai, Dar-Fu; Jhang, Ming-Hong; Chen, Guan-Yu; Wang, Sue-Chen; Lu, Kuo-Hao; Lee, Yu-Der; Liu, Hsin-Tzu

2010-03-15

A molecularly imprinted film was fabricated, in the presence of epitope-peptides, onto a quartz crystal microbalance (QCM) chip. These five peptides are known linear or conformational epitopes of the anthrax protective antigen PA(83). Imprinting resulted in an epitope-cavity with affinity for the corresponding template. With the use of a basic monomer, the binding-effect was further enhanced increasing the affinity to nanomolar levels. The affinities of the peptide to their corresponding molecularly induced polymers (MIPs) were more closely related to the molecular weight of the analyte than to the number of residues. All epitope-cavities differentiated their epitope region on the protective antigen PA(83) as well as the corresponding furin cleavage fragments PA(63) and PA(20). The QCM chip differential response to the protective antigen fragment was observed in the picomolar range, thus demonstrating a method to manipulate protein on the surface with defined orientation.

Cannabidiol Exposure During Neuronal Differentiation Sensitizes Cells Against Redox-Active Neurotoxins.

PubMed

Schönhofen, Patrícia; de Medeiros, Liana M; Bristot, Ivi Juliana; Lopes, Fernanda M; De Bastiani, Marco A; Kapczinski, Flávio; Crippa, José Alexandre S; Castro, Mauro Antônio A; Parsons, Richard B; Klamt, Fábio

2015-08-01

Cannabidiol (CBD), one of the most abundant Cannabis sativa-derived compounds, has been implicated with neuroprotective effect in several human pathologies. Until now, no undesired side effects have been associated with CBD. In this study, we evaluated CBD's neuroprotective effect in terminal differentiation (mature) and during neuronal differentiation (neuronal developmental toxicity model) of the human neuroblastoma SH-SY5Y cell line. A dose-response curve was performed to establish a sublethal dose of CBD with antioxidant activity (2.5 μM). In terminally differentiated SH-SY5Y cells, incubation with 2.5 μM CBD was unable to protect cells against the neurotoxic effect of glycolaldehyde, methylglyoxal, 6-hydroxydopamine, and hydrogen peroxide (H2O2). Moreover, no difference in antioxidant potential and neurite density was observed. When SH-SY5Y cells undergoing neuronal differentiation were exposed to CBD, no differences in antioxidant potential and neurite density were observed. However, CBD potentiated the neurotoxicity induced by all redox-active drugs tested. Our data indicate that 2.5 μM of CBD, the higher dose tolerated by differentiated SH-SY5Y neuronal cells, does not provide neuroprotection for terminally differentiated cells and shows, for the first time, that exposure of CBD during neuronal differentiation could sensitize immature cells to future challenges with neurotoxins.

The Effect of Agmatine on Expression of IL-1β and TLX Which Promotes Neuronal Differentiation in Lipopolysaccharide-Treated Neural Progenitors.

PubMed

Song, Juhyun; Kumar, Bokara Kiran; Kang, Somang; Park, Kyung Ah; Lee, Won Taek; Lee, Jong Eun

2013-12-01

Differentiation of neural progenitor cells (NPCs) is important for protecting neural cells and brain tissue during inflammation. Interleukin-1 beta (IL-1β) is the most common pro- inflammatory cytokine in brain inflammation, and increased IL-1β levels can decrease the proliferation of NPCs. We aimed to investigate whether agmatine (Agm), a primary polyamine that protects neural cells, could trigger differentiation of NPCs by activating IL-1β in vitro. The cortex of ICR mouse embryos (E14) was dissociated to culture NPCs. NPCs were stimulated by lipopolysaccharide (LPS). After 6 days, protein expression of stem cell markers and differentiation signal factors was confirmed by using western blot analysis. Also, immunocytochemistry was used to confirm the cell fate. Agm treatment activated NPC differentiation significantly more than in the control group, which was evident by the increased expression of a neuronal marker, MAP2, in the LPS-induced, Agm-treated group. Differentiation of LPS-induced, Agm-treated NPCs was regulated by the MAPK pathway and is thought to be related to IL-1β activation and decreased expression of TLX, a transcription factor that regulates NPC differentiation. Our results reveal that Agm can promote NPC differentiation to neural stem cells by modulating IL-1β expression under inflammatory condition, and they suggest that Agm may be a novel therapeutic strategy for neuroinflammatory diseases.

Protection relay of phase-shifting device with thyristor switch for high voltage power transmission lines

NASA Astrophysics Data System (ADS)

Lachugin, V. F.; Panfilov, D. I.; Akhmetov, I. M.; Astashev, M. G.; Shevelev, A. V.

2014-12-01

Problems of functioning of differential current protection systems of phase shifting devices (PSD) with mechanically changed coefficient of transformation of shunt transformer are analyzed. Requirements for devices of protection of PSD with thyristor switch are formulated. Based on use of nonlinear models of series-wound and shunt transformers of PSD modes of operation of major protection during PSD, switching to zero load operation and to operation under load and during short circuit operation were studied for testing PSD with failures. Use of the principle of duplicating by devices of differential current protection (with realization of functions of breaking) of failures of separate pares of PSD with thyristor switch was substantiated. To ensure protection sensitivity to the shunt transformer winding short circuit, in particular, to a short circuit that is not implemented in the current differential protection for PSD with mechanical switch, the differential current protection reacting to the amount of primary ampere-turns of high-voltage and low-voltage winding of this transformer was designed. Studies have shown that the use of differential current cutoff instead of overcurrent protection for the shunt transformer wndings allows one to provide the sensitivity during thyristor failure with the formation of a short circuit. The results of simulation mode for the PSD with switch thyristor designed to be installed as switching point of Voskhod-Tatarskaya-Barabinsk 220 kV transmission line point out the efficiency of the developed solutions that ensure reliable functioning of the PSD.

Differential Protection of Cry1Fa Toxin against Spodoptera frugiperda Larval Gut Proteases by Cadherin Orthologs Correlates with Increased Synergism

PubMed Central

Rahman, Khalidur; Abdullah, Mohd Amir F.; Ambati, Suresh; Taylor, Milton D.

2012-01-01

The Cry proteins produced by Bacillus thuringiensis (Bt) are the most widely used biopesticides effective against a range of crop pests and disease vectors. Like chemical pesticides, development of resistance is the primary threat to the long-term efficacy of Bt toxins. Recently discovered cadherin-based Bt Cry synergists showed the potential to augment resistance management by improving efficacy of Cry toxins. However, the mode of action of Bt Cry synergists is thus far unclear. Here we elucidate the mechanism of cadherin-based Cry toxin synergism utilizing two cadherin peptides, Spodoptera frugiperda Cad (SfCad) and Manduca sexta Cad (MsCad), which differentially enhance Cry1Fa toxicity to Spodoptera frugiperda neonates. We show that differential SfCad- and MsCad-mediated protection of Cry1Fa toxin in the Spodoptera frugiperda midgut correlates with differential Cry1Fa toxicity enhancement. Both peptides exhibited high affinity for Cry1Fa toxin and an increased rate of Cry1Fa-induced pore formation in S. frugiperda. However, only SfCad bound the S. frugiperda brush border membrane vesicle and more effectively prolonged the stability of Cry1Fa toxin in the gut, explaining higher Cry1Fa enhancement by this peptide. This study shows that cadherin fragments may enhance B. thuringiensis toxicity by at least two different mechanisms or a combination thereof: (i) protection of Cry toxin from protease degradation in the insect midgut and (ii) enhancement of pore-forming ability of Cry toxin. PMID:22081566

Histone deacetylase inhibitors reduce differentiating osteoblast-mediated protection of acute myeloid leukemia cells from cytarabine

PubMed Central

Sterner, Rosalie M.; Kremer, Kimberly N.; Al-Kali, Aref; Patnaik, Mrinal M.; Gangat, Naseema; Litzow, Mark R.; Kaufmann, Scott H.; Westendorf, Jennifer J.; van Wijnen, Andre J.; Hedin, Karen E.

2017-01-01

The bone marrow microenvironment protects acute myeloid leukemia (AML) cells during chemotherapy and is a major factor in relapse. Here, we examined which type(s) of bone marrow cells are responsible for the relapse of AML following treatment with cytarabine (Ara-C), and we identified a means to inhibit this protection. To determine the protective cell type(s), AML cells were treated with Ara-C, and AML cell survival in the presence or absence of osteoblast lineage cells was assessed. Cultured AML cells and patient bone marrow isolates were each significantly protected from Ara-C-induced apoptosis by co-culture with differentiating osteoblasts. Moreover, pretreating differentiating osteoblasts with the histone deacetylase inhibitors (HDACi) vorinostat and panobinostat abrogated the ability of the differentiating osteoblasts to protect AML cells. Together, our results indicate that differentiating osteoblasts have the potential to promote residual AML in the bone marrow following standard chemotherapy and act via a mechanism requiring HDACi-sensitive gene expression. Using HDACi to target the leukemic microenvironment in combination with Ara-C could potentially improve treatment of AML. Moreover, other strategies for manipulating bone marrow osteoblasts may also help eradicate AML cells and reduce relapse. PMID:29212250

Differentiating pathway-based toxicity from non-specific effects in high throughput data: A foundation for prioritizing targets for AOP development.

EPA Science Inventory

The Environmental Protection Agency has implemented a high throughput screening program, ToxCast, to quickly evaluate large numbers of chemicals for their effects on hundreds of different biological targets. To understand how these measurements relate to adverse effects in an or...

The Effect of IQ Level on the Degree of Cognitive Deterioration Experienced during Acute Hypoglycemia in Normal Humans.

ERIC Educational Resources Information Center

Gold, Ann E.; And Others

1995-01-01

Whether IQ level exerts a differential effect on the impairment of cognitive performance induced during acute hypoglycemia was studied for 24 nondiabetic adults. At various levels of hypoglycemia, no overall effect of IQ on deterioration was noted. Higher IQ did not apparently protect against adverse effects. (SLD)

Histone Deacetylase Inhibitors Target the Leukemic Microenvironment by Enhancing a Nherf1-Protein Phosphatase 1α-TAZ Signaling Pathway in Osteoblasts*

PubMed Central

Kremer, Kimberly N.; Dudakovic, Amel; Hess, Allan D.; Smith, B. Douglas; Karp, Judith E.; Kaufmann, Scott H.; Westendorf, Jennifer J.; van Wijnen, Andre J.; Hedin, Karen E.

2015-01-01

Disrupting the protective signals provided by the bone marrow microenvironment will be critical for more effective combination drug therapies for acute myeloid leukemia (AML). Cells of the osteoblast lineage that reside in the endosteal niche have been implicated in promoting survival of AML cells. Here, we investigated how to prevent this protective interaction. We previously showed that SDF-1, a chemokine abundant in the bone marrow, induces apoptosis of AML cells, unless the leukemic cells receive protective signals provided by differentiating osteoblasts (8, 10). We now identify a novel signaling pathway in differentiating osteoblasts that can be manipulated to disrupt the osteoblast-mediated protection of AML cells. Treating differentiating osteoblasts with histone deacetylase inhibitors (HDACi) abrogated their ability to protect co-cultured AML cells from SDF-1-induced apoptosis. HDACi prominently up-regulated expression of the Nherf1 scaffold protein, which played a major role in preventing osteoblast-mediated protection of AML cells. Protein phosphatase-1α (PP1α) was identified as a novel Nherf1 interacting protein that acts as the downstream mediator of this response by promoting nuclear localization of the TAZ transcriptional modulator. Moreover, independent activation of either PP1α or TAZ was sufficient to prevent osteoblast-mediated protection of AML cells even in the absence of HDACi. Together, these results indicate that HDACi target the AML microenvironment by enhancing activation of the Nherf1-PP1α-TAZ pathway in osteoblasts. Selective drug targeting of this osteoblast signaling pathway may improve treatments of AML by rendering leukemic cells in the bone marrow more susceptible to apoptosis. PMID:26491017

Biological Activities of Oleanolic Acid Derivatives from Calendula officinalis Seeds.

PubMed

Zaki, Ahmed; Ashour, Ahmed; Mira, Amira; Kishikawa, Asuka; Nakagawa, Toshinori; Zhu, Qinchang; Shimizu, Kuniyoshi

2016-05-01

Phytochemical examination of butanol fraction of Calendula officinalis seeds led to the isolation of two compounds identified as 28-O-β-D-glucopyranosyl-oleanolic acid 3-O-β-D-glucopyranosyl (1→3)-β-D-glucopyranosiduronic acid (CS1) and oleanolic acid 3-O-β-D-glucopyranosyl (1→3)-β-D-glucopyranosiduronic acid (CS2). Biological evaluation was carried out for these two compounds such as melanin biosynthesis inhibitory, hyaluronic acid production activities, anti obesity using lipase inhibition and adipocyte differentiation as well as evaluation of the protective effect against hydrogen peroxide induced neurotoxicity in neuro-2A cells. The results showed that, compound CS2 has a melanin biosynthesis stimulatory activity; however, compound CS1 has a potent stimulatory effect for the production of hyaluronic acid on normal human dermal fibroblast from adult (NHDF-Ad). Both compounds did not show any inhibitory effect on both lipase and adipocyte differentiation. Compound CS2 could protect neuro-2A cells and increased cell viability against H2 O2 . These activities (melanin biosynthesis stimulatory and protective effect against H2 O2 of CS2 and hyaluronic acid productive activities of these triterpene derivatives) have been reported for the first time. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Sun Protection; A risk management approach

NASA Astrophysics Data System (ADS)

Diffey, Brian

2017-10-01

Sun Protection differentiates itself from other texts by adopting a risk-management approach to determine whether, how, and in what circumstances, harm might be caused, and to explore the feasibility of various strategies in controlling exposure to solar UV radiation. This multi-disciplinary book covers topics from climatology through human exposure to sunlight, as well as biological and clinical effects of UV radiation to physical and chemical strategies for photoprotection.

Investigation of a redox-sensitive predictive model of mouse embryonic stem cells differentiation using quantitative nuclease protection assays and glutathione redox status

EPA Science Inventory

Investigation of a redox-sensitive predictive model of mouse embryonic stem cell differentiation via quantitative nuclease protection assays and glutathione redox status Chandler KJ,Hansen JM, Knudsen T,and Hunter ES 1. U.S. Environmental Protection Agency, Research Triangl...

Ecological Values amid Local Interests: Natural Resource Conservation, Social Differentiation, and Human Survival in Honduras

ERIC Educational Resources Information Center

Gareau, Brian J.

2007-01-01

Local peoples living in protected areas often have a different understanding about their natural space than do non-local groups that promote and declare such areas "protected." By designing protected areas without local involvement, or understandings of local social differentiation and power, natural resources management schemes will…

MicroRNA-7 Promotes Glycolysis to Protect against 1-Methyl-4-phenylpyridinium-induced Cell Death.

PubMed

Chaudhuri, Amrita Datta; Kabaria, Savan; Choi, Doo Chul; Mouradian, M Maral; Junn, Eunsung

2015-05-08

Parkinson disease is associated with decreased activity of the mitochondrial electron transport chain. This defect can be recapitulated in vitro by challenging dopaminergic cells with 1-methyl-4-phenylpyridinium (MPP(+)), a neurotoxin that inhibits complex I of electron transport chain. Consequently, oxidative phosphorylation is blocked, and cells become dependent on glycolysis for ATP production. Therefore, increasing the rate of glycolysis might help cells to produce more ATP to meet their energy demands. In the present study, we show that microRNA-7, a non-coding RNA that protects dopaminergic neuronal cells against MPP(+)-induced cell death, promotes glycolysis in dopaminergic SH-SY5Y and differentiated human neural progenitor ReNcell VM cells, as evidenced by increased ATP production, glucose consumption, and lactic acid production. Through a series of experiments, we demonstrate that targeted repression of RelA by microRNA-7, as well as subsequent increase in the neuronal glucose transporter 3 (Glut3), underlies this glycolysis-promoting effect. Consistently, silencing Glut3 expression diminishes the protective effect of microRNA-7 against MPP(+). Further, microRNA-7 fails to prevent MPP(+)-induced cell death when SH-SY5Y cells are cultured in a low glucose medium, as well as when differentiated ReNcell VM cells or primary mouse neurons are treated with the hexokinase inhibitor, 2-deoxy-d-glucose, indicating that a functional glycolytic pathway is required for this protective effect. In conclusion, microRNA-7, by down-regulating RelA, augments Glut3 expression, promotes glycolysis, and subsequently prevents MPP(+)-induced cell death. This protective effect of microRNA-7 could be exploited to correct the defects in oxidative phosphorylation in Parkinson disease. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Cultural protective factors for community risks and substance use among rural African American adolescents.

PubMed

Nasim, Aashir; Fernander, Anita; Townsend, Tiffany G; Corona, Rosalie; Belgrave, Faye Z

2011-01-01

Relatively little attention has been afforded to protective factors for community-level risks among non-urban populations. This study examined the extent to which traditional cultural attitudes and behaviors of 137 African American adolescents (ages 12-17) from a rural community moderated the relationship between perceived community disorganization and substance use behaviors. Results from hierarchical linear regression revealed that traditional cultural attitudes and behaviors were differentially related to community disorganization and adolescent substance use. In terms of protective influences, religious beliefs and practices and traditional family practices moderated the effect of community disorganization on substance use. Specifically, religious beliefs and practices demonstrated a protective-stabilizing effect as community disorganization increased; traditional family practices demonstrated a protective but reactive effect. Attitudes of cultural mistrust increased youth's susceptibility to substance use as community disorganization worsened--vulnerable and reactive. The findings underscore the importance of examining the link between cultural and contextual factors in an attempt to understand the etiology of substance use among rural African American adolescents.

Allosteric and Orthosteric Activators of mGluR8 differentially affect the Chemotherapeutic-induced Human Neuroblastoma SH-SY5Y Cell Damage: The Impact of Cell Differentiation State.

PubMed

Jantas, Danuta; Grygier, Beata; Zatorska, Justyna; Lasoń, Władysław

2018-05-12

The participation of group III metabotropic glutamate receptors (mGluRs) in cancer growth and progression is still an understudied issue. Based on our recent data on high expression of mGluR8 in human neuroblastoma SH-SY5Y cells, in the present study we evaluated the effect of an mGluR8-specific positive allosteric modulator (PAM: AZ12216052) and orthosteric agonist ((S)-3,4-DCPG) on chemotherapeutic (doxorubicin, irinotecan or cisplatin)-evoked cell damage in undifferentiated (UN-) and retinoic acid-differentiated (RA-) SH-SY5Y cells. The data showed that AZ12216052 as well as a group III mGluR antagonist (UBP1112) but not (S)-3,4-DCPG partially inhibited the cell damage evoked by doxorubicin, irinotecan or cisplatin in UN-SH-SY5Y cells. In RA-SH-SY5Y, we observed only a modest protective effect of mGluR8 PAM. In contrast, both types of mGluR8 activators significantly enhanced toxic effects of doxorubicin and irinotecan in RA-SH-SY5Y cells. These data suggest that in undifferentiated neuroblastoma malignant cells, some mGluR8 modulators can decrease cytotoxic effects of chemotherapeutics which exclude them from the group of putative anti-cancer agents. On the other hand, in SH-SY5Y cells differentiated to a more mature neuron-like phenotype, i.e. nonmalignant cells, the mGluR8 activators can aggravate the chemotherapeutic neurotoxicity which is a well-known undesired effect of these drugs. Our pharmacological data add new observations to the unexplored field of research on the role of mGluR8 in cancer, pointing to complexity of response which could be mediated by particular types of mGluR8 ligands at least in neuroblastoma cells. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Examining the Differential Effectiveness of a Life Skills Program (IPSY) on Alcohol Use Trajectories in Early Adolescence

ERIC Educational Resources Information Center

Spaeth, Michael; Weichold, Karina; Silbereisen, Rainer K.; Wiesner, Margit

2010-01-01

Objective: This study investigated whether a universal school-based life skills program--IPSY (Information + Psychosocial Competence = Protection)--against substance misuse exerted the same effectiveness for young adolescents (10.5-13 years) from distinct alcohol use trajectories characterized by late childhood risk factors (temperament,…

Early diet has differential effects on the small intestine microbiome by region in neonatal piglets

USDA-ARS?s Scientific Manuscript database

Exclusive breast milk feeding is known to be protective against gastrointestinal disorders in newborn infants and may reduce the risk of allergies and upper respiratory tract infections well into childhood. Although the exact mechanism of these beneficial effects has not been identified, the gut mic...

Tuning the endothelial response: differential release of exocytic cargos from Weibel-Palade Bodies.

PubMed

Nightingale, Thomas D; McCormack, Jessica J; Grimes, William; Robinson, Christopher; Lopes da Silva, Mafalda; White, Ian J; Vaughan, Andrew; Cramer, Louise P; Cutler, Daniel F

2018-06-28

Endothelial cells harbour specialised storage organelles, Weibel-Palade Bodies (WPBs). Exocytosis of WPB content into the vascular lumen initiates primary haemostasis, mediated by Von Willebrands factor (VWF) and inflammation, mediated by several proteins including P-selectin. During full fusion, secretion of this large haemostatic protein and smaller pro-inflammatory proteins are thought to be inextricably linked. To determine if secretagogue-dependent differential release of WPB cargo occurs, and whether this is mediated by the formation of an actomyosin ring during exocytosis. We used VWF string analysis, leukocyte rolling assays, ELISA, spinning disk confocal microscopy, high-throughput confocal microscopy and inhibitor and siRNA treatments to demonstrate the existence of cellular machinery that allows differential release of WPB cargo proteins. Inhibition of the actomyosin ring differentially effects two processes regulated by WPB exocytosis; it perturbs VWF string formation but has no effect on leukocyte rolling. The efficiency of ring recruitment correlates with VWF release; the ratio of release of VWF to small cargoes decreases when ring recruitment is inhibited. The recruitment of the actin ring is time-dependent; fusion events occurring directly after stimulation are less likely to initiate haemostasis than later events, and is activated by PKC isoforms. Secretagogues differentially recruit the actomyosin ring, thus demonstrating one mechanism by which the pro-thrombotic effect of endothelial activation can be modulated. This potentially limits thrombosis whilst permitting a normal inflammatory response. These results have implications for the assessment of WPB fusion, cargo-content release and the treatment of patients with von Willebrand disease. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Hataedock treatment has preventive therapeutic effects for atopic dermatitis through skin barrier protection in Dermatophagoides farinae-induced NC/Nga mice.

PubMed

Cha, Ho-Yeol; Ahn, Sang-Hyun; Cheon, Jin-Hong; Park, Sun-Young; Kim, Kibong

2017-07-12

Hataedock treatment is traditionally used for the purpose of preventing the future skin disease by feeding herbal extracts to the newborn in traditional Chinese and Korean medicine. This study investigated the preventive therapeutic effects of Hataedock (HTD) treatment for atopic dermatitis (AD) through skin barrier protection in Dermatophagoides farinae-induced NC/Nga mice. To the HTD treatment group, the extract of Coptis japonica Makino and Glycyrrhiza uralensis Fischer, which analyzed with High Performance Liquid Chromatography (HPLC)-fingerprint for quality consistency, was administered orally to the 3-week-old mice before inducing AD. After that, Dermatophagoides farinae was applied except the control group to induce AD-like skin lesions. We confirmed the effects of HTD on morphological changes, protection of skin barrier, regulation of Th2 differentiation, inflammation regulation and induction of apoptosis through histochemistry, immunohistochemistry, and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. HTD effectively reduced edema, angiogenesis and skin lesion. HTD also increased the levels of liver X receptor (LXR) and filaggrin but decreased the level of protein kinase C (PKC) (p<0.01). The levels of interleukin-4 (IL-4), IL-13, signal transducer and activator of transcription-6 (STAT-6) and Cluster of differentiation 40 (CD40) were significantly reduced in the HTD treated group (p<0.01). HTD also suppressed the mast cell degranulation and the level of the high-affinity IgE receptor (FcɛRI), substance P, Matrix metalloproteinases-9 (MMP-9) and 5-hydroxytryptamine (5-HT) (p<0.01). The levels of inflammatory factors such as nuclear factor-kappaB (NF-κB) p65, phosphorylated IκB (p-IκB) and inducible nitric oxide synthase (iNOS) were also decreased (p<0.01). Apoptosis of inflammatory cells was also found to increase (p<0.01). Our results indicate that HTD effectively regulate the Th2 differentiation, mast cell activation and various inflammatory responses on AD-induced mice through protection of skin barrier. Therefore, HTD may have potential applications for alternative and preventive treatment in the management of AD. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Suppression of MicroRNA let-7a Expression by Agmatine Regulates Neural Stem Cell Differentiation

PubMed Central

Song, Juhyun; Oh, Yumi; Kim, Jong Youl; Cho, Kyoung Joo

2016-01-01

Purpose Neural stem cells (NSCs) effectively reverse some severe central nervous system (CNS) disorders, due to their ability to differentiate into neurons. Agmatine, a biogenic amine, has cellular protective effects and contributes to cellular proliferation and differentiation in the CNS. Recent studies have elucidated the function of microRNA let-7a (let-7a) as a regulator of cell differentiation with roles in regulating genes associated with CNS neurogenesis. Materials and Methods This study aimed to investigate whether agmatine modulates the expression of crucial regulators of NSC differentiation including DCX, TLX, c-Myc, and ERK by controlling let-7a expression. Results Our data suggest that high levels of let-7a promoted the expression of TLX and c-Myc, as well as repressed DCX and ERK expression. In addition, agmatine attenuated expression of TLX and increased expression of ERK by negatively regulating let-7a. Conclusion Our study therefore enhances the present understanding of the therapeutic potential of NSCs in CNS disorders. PMID:27593875

Suppression of MicroRNA let-7a Expression by Agmatine Regulates Neural Stem Cell Differentiation.

PubMed

Song, Juhyun; Oh, Yumi; Kim, Jong Youl; Cho, Kyoung Joo; Lee, Jong Eun

2016-11-01

Neural stem cells (NSCs) effectively reverse some severe central nervous system (CNS) disorders, due to their ability to differentiate into neurons. Agmatine, a biogenic amine, has cellular protective effects and contributes to cellular proliferation and differentiation in the CNS. Recent studies have elucidated the function of microRNA let-7a (let-7a) as a regulator of cell differentiation with roles in regulating genes associated with CNS neurogenesis. This study aimed to investigate whether agmatine modulates the expression of crucial regulators of NSC differentiation including DCX, TLX, c-Myc, and ERK by controlling let-7a expression. Our data suggest that high levels of let-7a promoted the expression of TLX and c-Myc, as well as repressed DCX and ERK expression. In addition, agmatine attenuated expression of TLX and increased expression of ERK by negatively regulating let-7a. Our study therefore enhances the present understanding of the therapeutic potential of NSCs in CNS disorders.

Protective effect of creatine against inhibition by methylglyoxal of mitochondrial respiration of cardiac cells.

PubMed Central

Roy, Soumya Sinha; Biswas, Swati; Ray, Manju; Ray, Subhankar

2003-01-01

Previous publications from our laboratory have shown that methylglyoxal inhibits mitochondrial respiration of malignant and cardiac cells, but it has no effect on mitochondrial respiration of other normal cells [Biswas, Ray, Misra, Dutta and Ray (1997) Biochem. J. 323, 343-348; Ray, Biswas and Ray (1997) Mol. Cell. Biochem. 171, 95-103]. However, this inhibitory effect of methylglyoxal is not significant in cardiac tissue slices. Moreover, post-mitochondrial supernatant (PMS) of cardiac cells could almost completely protect the mitochondrial respiration against the inhibitory effect of methylglyoxal. A systematic search indicated that creatine present in cardiac cells is responsible for this protective effect. Glutathione has also some protective effect. However, creatine phosphate, creatinine, urea, glutathione disulphide and beta-mercaptoethanol have no protective effect. The inhibitory and protective effects of methylglyoxal and creatine respectively on cardiac mitochondrial respiration were studied with various concentrations of both methylglyoxal and creatine. Interestingly, neither creatine nor glutathione have any protective effect on the inhibition by methylglyoxal on the mitochondrial respiration of Ehrlich ascites carcinoma cells. The creatine and glutathione contents of several PMS, which were tested for the possible protective effect, were measured. The activities of two important enzymes, namely glyoxalase I and creatine kinase, which act upon glutathione plus methylglyoxal and creatine respectively, were also measured in different PMS. Whether mitochondrial creatine kinase had any role in the protective effect of creatine had also been investigated using 1-fluoro-2,4-dinitrobenzene, an inhibitor of creatine kinase. The differential effect of creatine on mitochondria of cardiac and malignant cells has been discussed with reference to the therapeutic potential of methylglyoxal. PMID:12605598

Altered sensitivity to ellagic acid in neuroblastoma cells undergoing differentiation with 12-O-tetradecanoylphorbol-13-acetate and all-trans retinoic acid.

PubMed

Alfredsson, Christina Fjæraa; Rendel, Filip; Liang, Qui-Li; Sundström, Birgitta E; Nånberg, Eewa

2015-12-01

Ellagic acid has previously been reported to induce reduced proliferation and activation of apoptosis in several tumor cell lines including our own previous data from non-differentiated human neuroblastoma SH-SY5Y cells. The aim of this study was now to investigate if in vitro differentiation with the phorbol ester 12-O- tetradecanoylphorbol-13-acetate or the vitamin A derivative all-trans retinoic acid altered the sensitivity to ellagic acid in SH-SY5Y cells. The methods used were cell counting and LDH-assay for evaluation of cell number and cell death, flow cytometric analysis of SubG1- and TUNEL-analysis for apoptosis and western blot for expression of apoptosis-associated proteins. In vitro differentiation was shown to reduce the sensitivity to ellagic acid with respect to cell detachment, loss of viability and activation of apoptosis. The protective effect was phenotype-specific and most prominent in all-trans retinoic acid-differentiated cultures. Differentiation-dependent up-regulation of Bcl-2 and integrin expression is introduced as possible protective mechanisms. The presented data also point to a positive correlation between proliferative activity and sensitivity to ellagic-acid-induced cell detachment. In conclusion, the presented data emphasize the need to consider degree of neuronal differentiation and phenotype of neuroblastoma cells when discussing a potential pharmaceutical application of ellagic acid in tumor treatment. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Influence of 1α, 25-dihydroxyvitamin D3 [1, 25(OH)2D3] on the expression of Sox 9 and the transient receptor potential vanilloid 5/6 ion channels in equine articular chondrocytes.

PubMed

Hdud, Ismail M; Loughna, Paul T

2014-01-01

Sox 9 is a major marker of chondrocyte differentiation. When chondrocytes are cultured in vitro they progressively de-differentiate and this is associated with a decline in Sox 9 expression. The active form of vitamin D, 1, 25 (OH)2D3 has been shown to be protective of cartilage in both humans and animals. In this study equine articular chondrocytes were grown in culture and the effects of 1, 25 (OH)2D3 upon Sox 9 expression examined. The expression of the transient receptor potential vanilloid (TRPV) ion channels 5 and 6 in equine chondrocytes in vitro, we have previously shown, is inversely correlated with de-differentiation. The expression of these channels in response to 1, 25 (OH)2D3 administration was therefore also examined. The active form of vitamin D (1, 25 (OH)2D3) when administered to cultured equine chondrocytes at two different concentrations significantly increased the expression of Sox 9 at both. In contrast 1, 25 (OH)2D3 had no significant effect upon the expression of either TRPV 5 or 6 at either the protein or the mRNA level. The increased expression of Sox 9, in equine articular chondrocytes in vitro, in response to the active form of vitamin D suggests that this compound could be utilized to inhibit the progressive de-differentiation that is normally observed in these cells. It is also supportive of previous studies indicating that 1α, 25-dihydroxyvitamin D3 can have a protective effect upon cartilage in animals in vivo. The previously observed correlation between the degree of differentiation and the expression levels of TRPV 5/6 had suggested that these ion channels may have a direct involvement in, or be modulated by, the differentiation process in vitro. The data in the present study do not support this.

Population connectivity and the effectiveness of marine protected areas to protect vulnerable, exploited and endemic coral reef fishes at an endemic hotspot

NASA Astrophysics Data System (ADS)

van der Meer, M. H.; Berumen, M. L.; Hobbs, J.-P. A.; van Herwerden, L.

2015-06-01

Marine protected areas (MPAs) aim to mitigate anthropogenic impacts by conserving biodiversity and preventing overfishing. The effectiveness of MPAs depends on population connectivity patterns between protected and non-protected areas. Remote islands are endemism hotspots for coral reef fishes and provide rare examples of coral reefs with limited fishing pressure. This study explored population genetic connectivity across a network of protected and non-protected areas for the endemic wrasse, Coris bulbifrons, which is listed as "vulnerable" by the IUCN due to its small, decreasing geographic range and declining abundance. Mitochondrial DNA (mtDNA) and microsatellite DNA (msatDNA) markers were used to estimate historic and contemporary gene flow to determine the level of population self-replenishment and to measure genetic and genotypic diversity among all four locations in the species range (south-west Pacific Ocean)—Middleton Reef (MR), Elizabeth Reef (ER), Lord Howe Island (LHI) and Norfolk Island (NI). MPAs exist at MR and LHI and are limited or non-existent at ER and NI, respectively. There was no obvious differentiation in mtDNA among locations, however, msatDNA revealed differentiation between the most peripheral (NI) and all remaining locations (MR, ER and LHI). Despite high mtDNA connectivity ( M = 259-1,144), msatDNA connectivity was limited ( M = 3-9) with high self-replenishment (68-93 %) at all locations. NI is the least connected and heavily reliant on self-replenishment, and the absence of MPAs at NI needs to be rectified to ensure the persistence of endemic species at this location. Other endemic fishes exhibit similar patterns of high self-replenishment across the four locations, indicating that a single spatial management approach consisting of a MPA network protecting part of each location could provide reasonable protection for these species. Thus, the existing network of MPAs at this endemic hotspot appears adequate at some locations, but not at all.

Neurotoxicity of "ecstasy" and its metabolites in human dopaminergic differentiated SH-SY5Y cells.

PubMed

Ferreira, Patrícia Silva; Nogueira, Tiago Bernandes; Costa, Vera Marisa; Branco, Paula Sério; Ferreira, Luísa Maria; Fernandes, Eduarda; Bastos, Maria Lourdes; Meisel, Andreas; Carvalho, Félix; Capela, João Paulo

2013-02-04

"Ecstasy" (3,4-methylenedioxymethamphetamine or MDMA) is a widely abused recreational drug, reported to produce neurotoxic effects, both in laboratory animals and in humans. MDMA metabolites can be major contributors for MDMA neurotoxicity. This work studied the neurotoxicity of MDMA and its catechol metabolites, α-methyldopamine (α-MeDA) and N-methyl-α-methyldopamine (N-Me-α-MeDA) in human dopaminergic SH-SY5Y cells differentiated with retinoic acid and 12-O-tetradecanoyl-phorbol-13-acetate. Differentiation led to SH-SY5Y neurons with higher ability to accumulate dopamine and higher resistance towards dopamine neurotoxicity. MDMA catechol metabolites were neurotoxic to SH-SY5Y neurons, leading to caspase 3-independent cell death in a concentration- and time-dependent manner. MDMA did not show a concentration- and time-dependent death. Pre-treatment with the antioxidant and glutathione precursor, N-acetylcysteine (NAC), resulted in strong protection against the MDMA metabolites' neurotoxicity. Neither the superoxide radical scavenger, tiron, nor the inhibitor of the dopamine (DA) transporter, GBR 12909, prevented the metabolites' toxicity. Cells exposed to α-MeDA showed an increase in intracellular glutathione (GSH) levels, which, at the 48 h time-point, was not dependent in the activity increase of γ-glutamylcysteine synthetase (γ-GCS), revealing a possible transient effect. Importantly, pre-treatment with buthionine sulfoximine (BSO), an inhibitor of γ-GCS, prevented α-MeDA induced increase in GSH levels, but did not augment this metabolite cytotoxicity. Even so, BSO pre-treatment abolished NAC protective effects against α-MeDA neurotoxicity, which were, at least partially, due to GSH de novo synthesis. Inversely, pre-treatment of cells with BSO augmented N-Me-α-MeDA-induced neurotoxicity, but only slightly affected NAC neuroprotection. In conclusion, MDMA catechol metabolites promote differential toxic effects to differentiated dopaminergic human SH-SY5Y cells. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Aesculin modulates bone metabolism by suppressing receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis and transduction signals.

PubMed

Zhao, Xiao-Li; Chen, Lin-Feng; Wang, Zhen

2017-06-17

Aesculin (AES), a coumarin compound derived from Aesculus hippocasanum L, is reported to exert protective role against inflammatory diseases, gastric disease and cancer. However, direct effect of AES in bone metabolism is deficient. In this study, we examined the effects of AES on osteoclast (OC) differentiation in receptor activator of NF-κB ligand (RANKL)-induced RAW264.7 cells. AES inhibits the OC differentiation in both dose- and time-dependent manner within non-toxic concentrations, as analyzed by Tartrate Resistant Acid Phosphatase (TRAP) staining. The actin ring formation manifesting OC function is also decreased by AES. Moreover, expressions of osteoclastogenesis related genes Trap, Atp6v0d2, Cathepsin K and Mmp-9 are decreased upon AES treatment. Mechanistically, AES attenuates the activation of MAPKs and NF-κB activity upon RANKL induction, thus leading to the reduction of Nfatc1 mRNA expression. Moreover, AES inhibits Rank expression, and RANK overexpression markedly decreases AES's effect on OC differentiation and NF-κB activity. Consistently, AES protects against bone mass loss in the ovariectomized and dexamethasone treated rat osteoporosis model. Taken together, our data demonstrate that AES can modulate bone metabolism by suppressing osteoclastogenesis and related transduction signals. AES therefore could be a promising agent for the treatment of osteoporosis. Copyright © 2017 Elsevier Inc. All rights reserved.

Reliability Analysis of Differential Relay as Main Protection Transformer Using Fuzzy Logic Algorithm

NASA Astrophysics Data System (ADS)

Mulyadi, Y.; Sucita, T.; Sumarto; Alpani, M.

2018-02-01

Electricity supply demand is increasing every year. It makes PT. PLN (Persero) is required to provide optimal customer service and satisfaction. Optimal service depends on the performance of the equipment of the power system owned, especially the transformer. Power transformer is an electrical equipment that transforms electricity from high voltage to low voltage or vice versa. However, in the electrical power system, is inseparable from interference included in the transformer. But, the disturbance can be minimized by the protection system. The main protection transformer is differential relays. Differential relays working system using Kirchoff law where inflows equal outflows. If there are excessive currents that interfere then the relays will work. But, the relay can also experience decreased performance. Therefore, this final project aims to analyze the reliability of the differential relay on the transformer in three different substations. Referring to the standard applied by the transmission line protection officer, the differential relay shall have slope characteristics of 30% in the first slope and 80% in the second slope when using two slopes and 80% when using one slope with an instant time and the corresponding ratio. So, the results obtained on the Siemens differential release have a reliable slope characteristic with a value of 30 on the fuzzy logic system. In a while, ABB a differential relay is only 80% reliable because two experiments are not reliable. For the time, all the differential relays are instant with a value of 0.06 on the fuzzy logic system. For ratios, the differential relays ABB have a better value than others brand with a value of 151 on the fuzzy logic system.

Bone-derived mesenchymal stromal cells from HIV transgenic mice exhibit altered proliferation, differentiation capacity and paracrine functions along with impaired therapeutic potential in kidney injury

PubMed Central

Cheng, Kang; Rai, Partab; Lan, Xiqian; Plagov, Andrei; Malhotra, Ashwani; Gupta, Sanjeev; Singhal, Pravin C

2013-01-01

Mesenchymal stem cells (MSCs) secrete paracrine factors that could be cytoprotective and serve roles in immunoregulation during tissue injury. Although MSCs express HIV receptors, and co-receptors, and are susceptible to HIV infection, whether HIV-1 may affect biological properties of MSCs needs more study. We evaluated cellular proliferation, differentiation and paracrine functions of MSCs isolated from compact bones of healthy control mice and Tg26 HIV-1 transgenic mice. The ability of MSCs to protect against cisplatin toxicity was studied in cultured renal tubular cells as well as in intact mice. We successfully isolated MSCs from healthy mice and Tg26 HIV-1 transgenic mice and found the latter expressed viral Nef, Vpu, NL4-3 and Vif genes. The proliferation and differentiation of Tg26 HIV-1 MSCs was inferior to MSCs from healthy mice. Moreover, transplantation of Tg26 HIV-1 MSCs less effectively improved outcomes compared with healthy MSCs in mice with acute kidney injury. Also, Tg26 HIV-1 MSCs secreted multiple cytokines, but at significantly lower levels than healthy MSCs, which resulted in failure of conditioned medium from these MSCs to protect cultured renal tubular cells from cisplatin toxicity. Therefore, HIV-1 had adverse biological effects on MSCs extending to their proliferation, differentiation, function, and therapeutic potential. These findings will help in advancing mechanistical insight in renal injury and repair in the setting of HIV-1 infection. PMID:23806280

Protective Effects of a Rhodiola Crenulata Extract and Salidroside on Hippocampal Neurogenesis against Streptozotocin-Induced Neural Injury in the Rat

PubMed Central

Qu, Ze-qiang; Zhou, Yan; Zeng, Yuan-shan; Lin, Yu-kun; Li, Yan; Zhong, Zhi-qiang; Chan, Wood Yee

2012-01-01

Previously we have demonstrated that a Rhodiola crenulata extract (RCE), containing a potent antioxidant salidroside, promotes neurogenesis in the hippocampus of depressive rats. The current study was designed to further investigate the protective effect of the RCE on neurogenesis in a rat model of Alzheimer's disease (AD) induced by an intracerebroventricular injection of streptozotocin (STZ), and to determine whether this neuroprotective effect is induced by the antioxidative activity of salidroside. Our results showed that pretreatment with the RCE significantly improved the impaired neurogenesis and simultaneously reduced the oxidative stress in the hippocampus of AD rats. In vitro studies revealed that (1) exposure of neural stem cells (NSCs) from the hippocampus to STZ strikingly increased intracellular reactive oxygen species (ROS) levels, induced cell death and perturbed cell proliferation and differentiation, (2) hydrogen peroxide induced similar cellular activities as STZ, (3) pre-incubation of STZ-treated NSCs with catalase, an antioxidant, suppressed all these cellular activities induced by STZ, and (4) likewise, pre-incubation of STZ-treated NSCs with salidroside, also an antioxidant, suppressed all these activities as catalase: reduction of ROS levels and NSC death with simultaneous increases in proliferation and differentiation. Our findings indicated that the RCE improved the impaired hippocampal neurogenesis in the rat model of AD through protecting NSCs by its main ingredient salidroside which scavenged intracellular ROS. PMID:22235318

Effects of sulforaphane on neural stem cell proliferation and differentiation.

PubMed

Han, Zhenxian; Xu, Qian; Li, Changfu; Zhao, Hong

2017-03-01

Sulforaphane (SFN) is a natural organosulfur compound with anti-oxidant and anti-inflammation properties. The objective of this study is to investigate the effect of SFN on the proliferation and differentiation of neural stem cells (NSC). NSCs were exposed to SFN at the concentrations ranging from 0.25 to 10 µM. Cell viability was evaluated with MTT assay and lactate dehydogenase (LDH) release assay. The proliferation of NSCs was evaluated with neurosphere formation assay and Ki-67 staining. The level of Tuj-1 was evaluated with immunostaining and Western blot to assess NSC neuronal differentiation. The expression of key proteins in the Wnt signaling pathway, including β-catenin and cyclin D1, in response to SFN treatment or the Wnt inhibitor, DKK-1, was determined by Western blotting. No significant cytotoxicity was seen for SFN on NSCs with SFN at concentrations of less than 10 µM. On the contrary, SFN of low concentrations stimulated cell proliferation and prominently increased neurosphere formation and NSC differentiation to neurons. SFN treatment upregulated Wnt signaling in the NSCs, whereas DKK-1 attenuated the effects of SFN. SFN is a drug to promote NSC proliferation and neuronal differentiation when used at low concentrations. These protective effects are mediated by Wnt signaling pathway. © 2017 Wiley Periodicals, Inc.

Cytokines and the regulation of fungus-specific CD4 T cell differentiation

PubMed Central

Espinosa, Vanessa; Rivera, Amariliz

2011-01-01

CD4 T cells play important and non-redundant roles in protection against infection with diverse fungi. Distinct CD4 T cell subsets can mediate protection against fungal disease where Th1 and Th17 CD4 T cell subsets have been found to promote fungal clearance and protective immunity against diverse fungal pathogens. The differentiation of naïve CD4 T cells into Th1 or Th17 cells is crucially controlled by their interaction with dendritic cells and instructed by cytokines. IL-12 and IFN-γ promote Th1 differentiation while TGF-β, IL-6, IL-1, IL-21 and IL-23 promote Th17 differentiation and maintenance. The production of these cytokines by DCs is in turn regulated by innate receptors triggered in response to fungal infection. In this review we will discuss the contributions of cytokines found to influence fungus-specific CD4 T cell differentiation and their role in defense against fungal disease. We will also highlight the contributions of innate receptors involved in recognition of fungi and how they shape cytokine secretion and CD4 T cell differentiation. PMID:22133343

The impact of differential patterns of physical violence and stalking on mental health and help-seeking among women with protective orders.

PubMed

Logan, T K; Shannon, Lisa; Cole, Jennifer; Walker, Robert

2006-09-01

This study examined the severity of partner violence on women's mental health and help-seeking as well as perceptions of safety and protective-order effectiveness. Three groups based on partner violence victimization in the past year were compared: (a) women who reported experiencing moderate physical violence but no history of severe violence or stalking (n = 102), (b) women who experienced severe violence but no history of stalking (n = 142), and (c) women who experienced severe violence and stalking (n = 145). Results suggest that stalking has a unique impact on victims' mental health and perceived safety, and that protections afforded by protective orders may not be adequate for women experiencing stalking.

HGF and IGF-1 promote protective effects of allogeneic BMSC transplantation in rabbit model of acute myocardial infarction.

PubMed

Zhang, Guang-Wei; Gu, Tian-Xiang; Guan, Xiao-Yu; Sun, Xue-Jun; Qi, Xun; Li, Xue-Yuan; Wang, Xiao-Bing; Lv, Feng; Yu, Lei; Jiang, Da-Qing; Tang, Rui

2015-12-01

To explore effects of hepatocyte growth factor (HGF) combined with insulin-like growth factor 1 (IGF-1) on transplanted bone marrow mesenchymal stem cells (BMSCs), for treatment of acute myocardial ischaemia. After ligation of the left anterior descending artery, rabbits were divided into a Control group, a Factors group (HGF+IGF-1), a BMSC group and a Factors+BMSCs group. Allogenous BMSCs (1 × 10(7)) and/or control-released microspheres of 2 μg HGF+2 μg IGF-1 were intramyocardially injected into infarcted regions. Apoptosis and differentiation of implanted BMSCs, histological and morphological results, and cardiac remodelling and function were evaluated at different time points. In vitro, BMSCs were exposed to HGF, IGF-1 and both (50 ng/ml) and subsequently proliferation, migration, myocardial differentiation and apoptosis induced by hypoxia, were analysed. Four weeks post-operatively, the above indices were significantly improved in Factors+BMSCs group compared to the others (P < 0.01), although Factors and BMSCs group also showed better results than Control group (P < 0.05). In vitro, HGF promoted BMSC migration and differentiation into cardiomyocytes, but inhibited proliferation (P < 0.05), while IGF-1 increased proliferation and migration, and inhibited apoptosis induced by hypoxia (P < 0.05), but did not induce myocardial differentiation. Combination of HGF and IGF-1 significantly promoted BMSCs capacity for migration, differentiation and lack of apoptosis (P < 0.05). Combination of HGF and IGF-1 activated BMSCs complementarily, and controlled release of the two factors promoted protective potential of transplanted BMSCs to repair infarcted myocardium. This suggests a new strategy for cell therapies to overcome acute ischemic myocardial injury. © 2015 John Wiley & Sons Ltd.

Severe Malaria Infections Impair Germinal Center Responses by Inhibiting T Follicular Helper Cell Differentiation.

PubMed

Ryg-Cornejo, Victoria; Ioannidis, Lisa Julia; Ly, Ann; Chiu, Chris Yu; Tellier, Julie; Hill, Danika Lea; Preston, Simon Peter; Pellegrini, Marc; Yu, Di; Nutt, Stephen Laurence; Kallies, Axel; Hansen, Diana Silvia

2016-01-05

Naturally acquired immunity to malaria develops only after years of repeated exposure to Plasmodium parasites. Despite the key role antibodies play in protection, the cellular processes underlying the slow acquisition of immunity remain unknown. Using mouse models, we show that severe malaria infection inhibits the establishment of germinal centers (GCs) in the spleen. We demonstrate that infection induces high frequencies of T follicular helper (Tfh) cell precursors but results in impaired Tfh cell differentiation. Despite high expression of Bcl-6 and IL-21, precursor Tfh cells induced during infection displayed low levels of PD-1 and CXCR5 and co-expressed Th1-associated molecules such as T-bet and CXCR3. Blockade of the inflammatory cytokines TNF and IFN-γ or T-bet deletion restored Tfh cell differentiation and GC responses to infection. Thus, this study demonstrates that the same pro-inflammatory mediators that drive severe malaria pathology have detrimental effects on the induction of protective B cell responses. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Differentiating pathway-specific from nonspecific effects in high-throughput toxicity data: A foundation for prioritizing adverse outcome pathway development

EPA Science Inventory

The U.S. Environmental Protection Agency’s ToxCast program has screened thousands of chemicals for biological activity, primarily using high-throughput in vitro bioassays. Adverse outcome pathways (AOPs) offer a means to link pathway-specific biological activities with potential ...

The Influence of Thyroid-Stimulating Hormone and Thyroid-Stimulating Hormone Receptor Antibodies on Osteoclastogenesis

PubMed Central

Morshed, Syed; Latif, Rauf; Zaidi, Mone; Davies, Terry F.

2011-01-01

Background We have shown that thyroid-stimulating hormone (TSH) has a direct inhibitory effect on osteoclastic bone resorption and that TSH receptor (TSHR) null mice display osteoporosis. To determine the stage of osteoclast development at which TSH may exert its effect, we examined the influence of TSH and agonist TSHR antibodies (TSHR-Ab) on osteoclast differentiation from murine embryonic stem (ES) cells to gain insight into bone remodeling in hyperthyroid Graves' disease. Methods Osteoclast differentiation was initiated in murine ES cell cultures through exposure to macrophage colony stimulation factor, receptor activator of nuclear factor кB ligand, vitamin D, and dexamethasone. Results Tartrate resistant acid phosphatase (TRAP)-positive osteoclasts formed in ∼12 days. This coincided with the expected downregulation of known markers of self renewal and pluripotency (including Oct4, Sox2, and REX1). Both TSH and TSHR-Abs inhibited osteoclastogenesis as evidenced by decreased development of TRAP-positive cells (∼40%–50% reduction, p = 0.0047), and by decreased expression, in a concentration-dependent manner, of osteoclast differentiation markers (including the calcitonin receptor, TRAP, cathepsin K, matrix metallo-proteinase-9, and carbonic anhydrase II). Similar data were obtained using serum immunoglobulin-Gs (IgGs) from patients with hyperthyroid Graves' disease and known TSHR-Abs. TSHR stimulators inhibited tumor necrosis factor-alpha mRNA and protein expression, but increased the expression of osteoprotegerin (OPG), an antiosteoclastogenic human soluble receptor activator of nuclear factor кB ligand receptor. Neutralizing antibody to OPG reversed the inhibitory effect of TSH on osteoclast differentiation evidencing that the TSH effect was at least in part mediated by increased OPG. Conclusion These data establish ES-derived osteoclastogenesis as an effective model system to study the regulation of osteoclast differentiation in early development. The results support the observations that TSH has a bone protective action by negatively regulating osteoclastogenesis. Further, our results implicate TSHR-Abs in offering skeletal protection in hyperthyroid Graves' disease, even in the face of high thyroid hormone and low TSH levels. PMID:21745106

DIFFERENTIAL KILLING EFFECT IN JUTE BY X-RAYS AND RADIOISOTOPES

DOE Office of Scientific and Technical Information (OSTI.GOV)

Basu, R.K.

1962-01-01

Treatments with x rays and BETA rays from P/sup 32/ and S/sup 35/ on dry and pure line seeds of three varieties of Corchorus olitorius L. and two varieties of C. capsularis L. produced differential killing effect. 0ver the range of dosages applied treatments with P/sup 32/ and S/sup 35/ showed lesser killing effect than treatments with x rays. From the counts of survivals at maturity, the LD/sub 50/with x rays was found to lie between 64000 and r0000 r for the varieties of C. olitorius and between 80000 and 90000 r for the varieties of C. capsularis. While themore » usual relationship of decrease in survival with increase in dosage was established with x rays, treatments with P/sup 32/ and S/ sup 35/ often showed increased survival compared to the control. The differential killing effect of the three mutagens is discussed as a consequence of difference in ion density. The obscure effects of radioisotopes may be due to production of substances reacting in the form of stimulation or protective agents. The differential radiosensitivity of the two species may be due to difference in factors like seed size and thickness of seed coat, which influence the non- genetical effects of irradiation. (auth)« less

Differential renal effects of candesartan at high and ultra-high doses in diabetic mice–potential role of the ACE2/AT2R/Mas axis

PubMed Central

Callera, Glaucia E.; Antunes, Tayze T.; Correa, Jose W.; Moorman, Danielle; Gutsol, Alexey; He, Ying; Cat, Aurelie Nguyen Dinh; Briones, Ana M.; Montezano, Augusto C.; Burns, Kevin D.; Touyz, Rhian M.

2016-01-01

High doses of Ang II receptor (AT1R) blockers (ARBs) are renoprotective in diabetes. Underlying mechanisms remain unclear. We evaluated whether high/ultra-high doses of candesartan (ARB) up-regulate angiotensin-converting enzyme 2 (ACE2)/Ang II type 2 receptor (AT2R)/Mas receptor [protective axis of the of the renin–angiotensin system (RAS)] in diabetic mice. Systolic blood pressure (SBP), albuminuria and expression/activity of RAS components were assessed in diabetic db/db and control db/+ mice treated with increasing candesartan doses (intermediate, 1 mg/kg/d; high, 5 mg/kg/d; ultra-high, 25 and 75 mg/kg/d; 4 weeks). Lower doses candesartan did not influence SBP, but ultra-high doses reduced SBP in both groups. Plasma glucose and albuminuria were increased in db/db compared with db/+ mice. In diabetic mice treated with intermediate dose candesartan, renal tubular damage and albuminuria were ameliorated and expression of ACE2, AT2R and Mas and activity of ACE2 were increased, effects associated with reduced ERK1/2 phosphorylation, decreased fibrosis and renal protection. Ultra-high doses did not influence the ACE2/AT2R/Mas axis and promoted renal injury with increased renal ERK1/2 activation and exaggerated fibronectin expression in db/db mice. Our study demonstrates dose-related effects of candesartan in diabetic nephropathy: intermediate–high dose candesartan is renoprotective, whereas ultra-high dose candesartan induces renal damage. Molecular processes associated with these effects involve differential modulation of the ACE2/AT2R/Mas axis: intermediate–high dose candesartan up-regulating RAS protective components and attenuating pro-fibrotic processes, and ultra-high doses having opposite effects. These findings suggest novel mechanisms through the protective RAS axis, whereby candesartan may ameliorate diabetic nephropathy. Our findings also highlight potential injurious renal effects of ultra-high dose candesartan in diabetes. PMID:27612496

Differentiated protection method in passive optical networks based on OPEX

NASA Astrophysics Data System (ADS)

Zhang, Zhicheng; Guo, Wei; Jin, Yaohui; Sun, Weiqiang; Hu, Weisheng

2011-12-01

Reliable service delivery becomes more significant due to increased dependency on electronic services all over society and the growing importance of reliable service delivery. As the capability of PON increasing, both residential and business customers may be included in a PON. Meanwhile, OPEX have been proven to be a very important factor of the total cost for a telecommunication operator. Thus, in this paper, we present the partial protection PON architecture and compare the operational expenditures (OPEX) of fully duplicated protection and partly duplicated protection for ONUs with different distributed fiber length, reliability requirement and penalty cost per hour. At last, we propose a differentiated protection method to minimize OPEX.

Molecular Regulation of DNA Damage-Induced Apoptosis in Neurons of Cerebral Cortex

PubMed Central

Liu, Zhiping; Pipino, Jacqueline; Chestnut, Barry; Landek, Melissa A.

2009-01-01

Cerebral cortical neuron degeneration occurs in brain disorders manifesting throughout life, but the mechanisms are understood poorly. We used cultured embryonic mouse cortical neurons and an in vivo mouse model to study mechanisms of DNA damaged-induced apoptosis in immature and differentiated neurons. p53 drives apoptosis of immature and differentiated cortical neurons through its rapid and prominent activation stimulated by DNA strand breaks induced by topoisomerase-I and -II inhibition. Blocking p53-DNA transactivation with α-pifithrin protects immature neurons; blocking p53-mitochondrial functions with μ-pifithrin protects differentiated neurons. Mitochondrial death proteins are upregulated in apoptotic immature and differentiated neurons and have nonredundant proapoptotic functions; Bak is more dominant than Bax in differentiated neurons. p53 phosphorylation is mediated by ataxia telangiectasia mutated (ATM) kinase. ATM inactivation is antiapoptotic, particularly in differentiated neurons, whereas inhibition of c-Abl protects immature neurons but not differentiated neurons. Cell death protein expression patterns in mouse forebrain are mostly similar to cultured neurons. DNA damage induces prominent p53 activation and apoptosis in cerebral cortex in vivo. Thus, DNA strand breaks in cortical neurons induce rapid p53-mediated apoptosis through actions of upstream ATM and c-Abl kinases and downstream mitochondrial death proteins. This molecular network operates through variations depending on neuron maturity. PMID:18820287

Melatonin enhances neural stem cell differentiation and engraftment by increasing mitochondrial function.

PubMed

Mendivil-Perez, Miguel; Soto-Mercado, Viviana; Guerra-Librero, Ana; Fernandez-Gil, Beatriz I; Florido, Javier; Shen, Ying-Qiang; Tejada, Miguel A; Capilla-Gonzalez, Vivian; Rusanova, Iryna; Garcia-Verdugo, José M; Acuña-Castroviejo, Darío; López, Luis Carlos; Velez-Pardo, Carlos; Jimenez-Del-Rio, Marlene; Ferrer, José M; Escames, Germaine

2017-09-01

Neural stem cells (NSCs) are regarded as a promising therapeutic approach to protecting and restoring damaged neurons in neurodegenerative diseases (NDs) such as Parkinson's disease and Alzheimer's disease (PD and AD, respectively). However, new research suggests that NSC differentiation is required to make this strategy effective. Several studies have demonstrated that melatonin increases mature neuronal markers, which reflects NSC differentiation into neurons. Nevertheless, the possible involvement of mitochondria in the effects of melatonin during NSC differentiation has not yet been fully established. We therefore tested the impact of melatonin on NSC proliferation and differentiation in an attempt to determine whether these actions depend on modulating mitochondrial activity. We measured proliferation and differentiation markers, mitochondrial structural and functional parameters as well as oxidative stress indicators and also evaluated cell transplant engraftment. This enabled us to show that melatonin (25 μM) induces NSC differentiation into oligodendrocytes and neurons. These effects depend on increased mitochondrial mass/DNA/complexes, mitochondrial respiration, and membrane potential as well as ATP synthesis in NSCs. It is also interesting to note that melatonin prevented oxidative stress caused by high levels of mitochondrial activity. Finally, we found that melatonin enriches NSC engraftment in the ND mouse model following transplantation. We concluded that a combined therapy involving transplantation of NSCs pretreated with pharmacological doses of melatonin could efficiently restore neuronal cell populations in PD and AD mouse models depending on mitochondrial activity promotion. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Effect of Micro-RNA on Tenocytes and Tendon-Related Gene Expression: A Systematic Review.

PubMed

Dubin, Jeremy A; Greenberg, Daniel R; Iglinski-Benjamin, Kag C; Abrams, Geoffrey D

2018-06-06

The purpose of the review was to synthesize the current literature regarding the effect of miRNA on biological processes known to be involved in tendon and tenocyte development and homeostasis. Using multiple databases, a systematic review was performed with a customized search term crafted to identify any study examining micro-RNA in relation to tendon and/or tenocytes. Results were classified based on the following categories: gene expression, tenocyte development and differentiation, tendon tissue repair, and tenocyte senescence. A total of 3,112 potentially relevant studies were reviewed, and after exclusion criteria was applied, 15 investigations were included in the final analysis. There were 14 specific miRNA included in this review, with 11 studies reporting on tendon-related gene expression, five reporting on tendon development and/or tenocyte differentiation, six reporting on tendon tissue repair, and five reporting on tenocyte senescence. The miR-29 family was the most commonly reported micro-RNA in the investigation. We also report on a number of micro-RNA which are associated with both positive and negative effects on tendon homeostasis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Distinct Effects of Saracatinib on Memory CD8+ T-cell Differentiation

PubMed Central

Takai, Shinji; Sabzevari, Helen; Farsaci, Benedetto; Schlom, Jeffrey; Greiner, John W.

2012-01-01

Immunologic memory involving CD8+ T-cells is a hallmark of an adaptive antigen-specific immune response and comprises a critical component of protective immunity. Designing approaches that enhance long-term T-cell memory would, for the most part, fortify vaccines and enhance host protection against infectious diseases and, perhaps, cancer immunotherapy. A better understanding of the cellular programs involved in the antigen-specific T-cell response has led to new approaches that target the magnitude and quality of the memory T-cell response. Here we show that T-cells from T-cell receptor transgenic mice for the nucleoprotein of influenza virus NP68 exhibit the distinct phases priming, expansion, contraction, memory - of an antigen-specific T-cell response when exposed in vitro to the cognate peptide. Saracatinib, a specific inhibitor of Src family kinases, administered at low doses during the expansion or contraction phases, increased CD62Lhigh/CD44high central memory CD8+ T-cells and IFN-γ production, while suppressing immunity when added during the priming phase. These effects by saracatinib were not accompanied by the expected decline of Src family kinases, but were accompanied by Akt-mTOR suppression and/or mediated via another pathway. Increased central memory cells by saracatinib were recapitulated in mice using a poxvirus-based influenza vaccine, thus underscoring the importance of dose and timing of the inhibitor in the context of memory T-cell differentiation. Finally, vaccine plus saracatinib treatment showed better protection against tumor challenge. The immune-potentiating effects on CD8+ T-cells by a low dose of saracatinib might afford better protection from pathogen or cancer when combined with vaccine. PMID:22450814

Differential Effects of Ethanol on c-Jun N-Terminal Kinase, 14-3-3 Proteins, and Bax in Postnatal Day 4 and Postnatal Day 7 Rat Cerebellum

PubMed Central

Heaton, Marieta Barrow; Paiva, Michael; Kubovic, Stacey; Kotler, Alexandra; Rogozinski, Jonathan; Swanson, Eric; Madorsky, Vladimir; Posados, Michelle

2011-01-01

These studies investigated ethanol effects on upstream cellular elements and interactions which contribute to Bax-related apoptosis in neonatal rat cerebellum at ages of peak ethanol sensitivity (postnatal day 4 [P4]), compared to later ages of relative resistance (P7). Analyses were made of basal levels of the pro-apoptotic c-jun N-termimal kinase (JNK), Bax, and the 14-3-3 anchoring proteins, as well as the responsiveness of these substances to ethanol at P4 versus P7. Dimerization of Bax with 14-3-3 was also investigated at the two ages following ethanol treatment, a process which sequesters Bax in the cytosol, thus inhibiting its mitochondrial translocation and disruption of the mitochondrial membrane potential. Cultured cerebellar granule cells were used to examine the protective potential of JNK inhibition on ethanol-mediated cell death. Basal levels of JNK were significantly higher at P4 than P7, but no differences in the other proteins were found. Activated JNK, and cytosolic and mitochondrially-translocated Bax were increased in P4 but not P7 animals following ethanol exposure, while protective 14-3-3 proteins were increased only at P7. Ethanol treatment resulted in decreases in Bax:14-3-3 heterodimers at P4, but not at P7. Inhibition of JNK activity in vitro provided partial protection against ethanol neurotoxicity. Thus, differential temporal vulnerability to ethanol in this CNS region correlates with differences in both levels of apoptosis-related substances (e.g., JNK), and differential cellular responsiveness, favoring apoptosis at the most sensitive age and survival at the resistant age. The upstream elements contributing to this vulnerability can be targets for future therapeutic strategies. PMID:22169498

Timely and Needed Perspectives on Differential Response in Child Protective Services

ERIC Educational Resources Information Center

Ellett, Alberta J.

2013-01-01

This article is an invited commentary and analysis of the authors' completed systematic evaluation of Child Protective Services (CPS) differential response (DR) models. I write this commentary based on 25 years of public child welfare experience followed by 13 years as a social work professor and researcher. In their review of DR, the…

Effect of Chromatin Structure on the Extent and Distribution of DNA Double Strand Breaks Produced by Ionizing Radiation; Comparative Study of hESC and Differentiated Cells Lines.

PubMed

Venkatesh, Priyanka; Panyutin, Irina V; Remeeva, Evgenia; Neumann, Ronald D; Panyutin, Igor G

2016-01-02

Chromatin structure affects the extent of DNA damage and repair. Thus, it has been shown that heterochromatin is more protective against DNA double strand breaks (DSB) formation by ionizing radiation (IR); and that DNA DSB repair may proceed differently in hetero- and euchromatin regions. Human embryonic stem cells (hESC) have a more open chromatin structure than differentiated cells. Here, we study the effect of chromatin structure in hESC on initial DSB formation and subsequent DSB repair. DSB were scored by comet assay; and DSB repair was assessed by repair foci formation via 53BP1 antibody staining. We found that in hESC, heterochromatin is confined to distinct regions, while in differentiated cells it is distributed more evenly within the nuclei. The same dose of ionizing radiation produced considerably more DSB in hESC than in differentiated derivatives, normal human fibroblasts; and one cancer cell line. At the same time, the number of DNA repair foci were not statistically different among these cells. We showed that in hESC, DNA repair foci localized almost exclusively outside the heterochromatin regions. We also noticed that exposure to ionizing radiation resulted in an increase in heterochromatin marker H3K9me3 in cancer HT1080 cells, and to a lesser extent in IMR90 normal fibroblasts, but not in hESCs. These results demonstrate the importance of chromatin conformation for DNA protection and DNA damage repair; and indicate the difference of these processes in hESC.

Retinoic acid-loaded polymeric nanoparticles enhance vascular regulation of neural stem cell survival and differentiation after ischaemia

NASA Astrophysics Data System (ADS)

Ferreira, R.; Fonseca, M. C.; Santos, T.; Sargento-Freitas, J.; Tjeng, R.; Paiva, F.; Castelo-Branco, M.; Ferreira, L. S.; Bernardino, L.

2016-04-01

Stroke is one of the leading causes of death and disability worldwide. However, current therapies only reach a small percentage of patients and may cause serious side effects. We propose the therapeutic use of retinoic acid-loaded nanoparticles (RA-NP) to safely and efficiently repair the ischaemic brain by creating a favourable pro-angiogenic environment that enhances neurogenesis and neuronal restitution. Our data showed that RA-NP enhanced endothelial cell proliferation and tubule network formation and protected against ischaemia-induced death. To evaluate the effect of RA-NP on vascular regulation of neural stem cell (NSC) survival and differentiation, endothelial cell-conditioned media (EC-CM) were collected. EC-CM from healthy RA-NP-treated cells reduced NSC death and promoted proliferation while EC-CM from ischaemic RA-NP-treated cells decreased cell death, increased proliferation and neuronal differentiation. In parallel, human endothelial progenitor cells (hEPC), which are part of the endogenous repair response to vascular injury, were collected from ischaemic stroke patients. hEPC treated with RA-NP had significantly higher proliferation, which further highlights the therapeutic potential of this formulation. To conclude, RA-NP protected endothelial cells from ischaemic death and stimulated the release of pro-survival, proliferation-stimulating factors and differentiation cues for NSC. RA-NP were shown to be up to 83-fold more efficient than free RA and to enhance hEPC proliferation. These data serve as a stepping stone to use RA-NP as vasculotrophic and neurogenic agents for vascular disorders and neurodegenerative diseases with compromised vasculature.

Differential response of Aspen and Birch trees to heat stress under elevated carbon dioxide

Treesearch

Joseph N.T. Darbah; Thomas D. Sharkey; Carlo Calfapietra; David F. Karnosky

2010-01-01

The effect of high temperature on photosynthesis of isoprene-emitting (aspen) and non-isoprene-emitting (birch) trees were measured under elevated CO2 and ambient conditions. Aspen trees tolerated heat better than birch trees and elevated CO2 protected photosynthesis of both species against moderate heat stress. Elevated CO...

Differentiating pathway-specific from non-specific effects in high-throughput toxicity data: A foundation for prioritizing adverse outcome pathway development

EPA Science Inventory

The U.S. Environmental Protection Agency’s ToxCast program has screened thousands of chemicals for biological activity, primarily using high-throughput in vitro bioassays. Adverse outcome pathways (AOPs) offer a means to link pathway-specific biological activities with pote...

Ozone-Induced Pulmonary Injury and Vascular Contractility are Differentially Impacted by Coconut, Fish, and Olive Oil-Rich Diets

EPA Science Inventory

Pulmonary and systemic effects of ozone (O3) are mediated by hypothalamus pituitary adrenal (HPA)-axis activation. Fish oil (FO) and olive oil (OO) dietary supplementation have several cardioprotective benefits, but it is not established if these supplements can protect against t...

Children's Play: The Differential Effects of Intrafamilial Physical and Sexual Abuse.

ERIC Educational Resources Information Center

Harper, Juliet

1991-01-01

This study investigated the play of 40 sexually abused, physically abused, physically and sexually abused, and nonabused children, ages 3-10. Results are analyzed in terms of structural differences (representational or fantasy worlds) and thematic differences (such as domestic life, need for protection, need for nurturance, conflict, chaos, and…

Neurotrophic, Cytoprotective, and Anti-inflammatory Effects of St. John's Wort Extract on Differentiated Mouse Hippocampal HT-22 Neurons

PubMed Central

Bonaterra, Gabriel A.; Schwendler, Anna; Hüther, Julian; Schwarzbach, Hans; Schwarz, Anja; Kolb, Christiane; Abdel-Aziz, Heba; Kinscherf, Ralf

2018-01-01

Introduction: Since ancient times Hypericum perforatum L. named St. John's wort (SJW), has been used in the management of a wide range of applications, including nervous disorders. Development of mood disorders are due to alterations in glutamate metabolism, initiation of inflammatory pathways, and changes of the neuronal plasticity. Previous studies suggest that the glutamatergic system contributes to the pathophysiology of depression. Extracts of SJW have been recommended for the treatment of depression. The aim of the present in vitro study was to evaluate the action of STW3-VI, a special SJW extract in differentiated mouse hippocampal HT-22 neurons. We evaluated the stimulation of neurogenesis, the protective effect against glutamate or N-methyl-D-aspartate receptor induced-excitotoxicity and its anti-inflammatory properties in LPS-activated human macrophages. Results: After 48 h treatment, STW3-VI stimulated the neurite formation by 25% in comparison with the control and showed protective effects against glutamate- or NMDA-induced cytotoxicity by significantly increasing the viability about +25 or +50%. In conjunction with these effects, after pretreatment with STW3-VI, the intracellular reduced glutathione content was significantly 2.3-fold increased compared with the neurons incubated with glutamate alone. Additionally, pre-treatment of human macrophages with STW3-VI showed anti-inflammatory effects after 24 or 48 h concerning inhibition of LPS-induced TNF release by −47.3 and −53.8% (24 h) or −25.0 to −64.8% (48 h). Conclusions: Our data provide new evidence that STW3-VI protects hippocampal cells from NMDA- or glutamate-induced cytotoxicity. Moreover, our results indicate a morphological remodeling by increasing neurite outgrowth and activation of the anti-inflammatory defense by inhibition of the cytokine production in human macrophages after STW3-VI treatment. These protective, neurotrophic and anti-inflammatory properties may be beneficial in the treatment of depressive disorders. PMID:29403374

Effectiveness of skin protection measures in prevention of occupational hand eczema: results of a prospective randomized controlled trial over a follow-up period of 1 year.

PubMed

Kütting, B; Baumeister, T; Weistenhöfer, W; Pfahlberg, A; Uter, W; Drexler, H

2010-02-01

We recently found a very low adherence to a generally recommended skin protection regimen in a sample of 1355 metalworkers. The present study assessed the effectiveness of skin protection as presently recommended, especially the differential contribution of skin care and skin protection, to the prevention of occupational hand eczema. Methods Of 1355 metalworkers screened, 1020 male volunteers, all fit for work, were recruited for a prospective intervention study with four arms (skin care, skin protection, both combined, and control group, i.e. no recommendation). The study was performed from winter 2006/2007 to spring 2008, following each subject for up for 12 months. Both hands were examined using a quantitative skin score, and a standardized personal interview was performed three times. The change of the objective skin score from baseline to 12 months was used as primary outcome measure. After 12 months 800 subjects were included (78.4% of those recruited). The compliance to follow the randomized measure depended on the recommended measure and ranged from 73.7% to 88.7%. While in the control group a significant deterioration was found, the largest and significant improvement was noted in the group following the generally recommended skin protection programme (skin care + skin protection) followed by skin protection alone as second best. The generally recommended skin protection regimen seems to provide effective prevention of occupational skin disease. Therefore, the compliance to follow the skin protection regimen, especially the use of skin protection, should be enhanced.

Screening for the protective effect target of deproteinized extract of calf blood and its mechanisms in mice with CCl4-induced acute liver injury.

PubMed

Xu, Guangyu; Han, Xiao; Yuan, Guangxin; An, Liping; Du, Peige

2017-01-01

Liver injury is a common pathological basis of various liver diseases, and long-term liver injury is often an important initiation factor leading to liver fibrosis and even liver cirrhosis and hepatocellular carcinoma (HCC). It has been reported that deproteinized extract of calf blood (DECB) can inhibit the replication of hepatitis B virus and confers a protective effect on the liver after traumatic liver injury. However, few studies on the regulatory factors and mechanisms of DECB have been reported. In this current study, an acute mouse liver injury model was established with carbon tetrachloride (CCl4). The differentially expressed genes and related cell signal transduction pathways were screened using mRNA expression microarray. STEM software V1.3.6 was used for clustering gene functions, and the DAVID and KEGG databases were applied for the analysis. A total of 1355 differentially expressed genes were selected, among which nine were validated by RT-qPCR. The results showed that the Fas, IL1b, Pik3r1, Pik3r5, Traf2, Traf2, Csf2rb2, Map3k14, Pik3cd and Ppp3cc genes were involved in the regulation of DECB in an acute mouse liver injury model. Targets of the protective effects of DECB and its related mechanisms were found in mice with acute liver injury induced by carbon tetrachloride, which may provide an important theoretical basis for further DECB research.

Review of Nuclear Physics Experiments for Space Radiation

NASA Technical Reports Server (NTRS)

Norbury, John W.; Miller, Jack; Adamczyk, Anne M.; Heilbronn, Lawrence H.; Townsend, Lawrence W.; Blattnig, Steve R.; Norman, Ryan B.; Guetersloh, Stephen B.; Zeitlin, Cary J.

2011-01-01

Human space flight requires protecting astronauts from the harmful effects of space radiation. The availability of measured nuclear cross section data needed for these studies is reviewed in the present paper. The energy range of interest for radiation protection is approximately 100 MeV/n to 10 GeV/n. The majority of data are for projectile fragmentation partial and total cross sections, including both charge changing and isotopic cross sections. The cross section data are organized into categories which include charge changing, elemental, isotopic for total, single and double differential with respect to momentum, energy and angle. Gaps in the data relevant to space radiation protection are discussed and recommendations for future experiments are made.

The natural dual cyclooxygenase and 5-lipoxygenase inhibitor flavocoxid is protective in EAE through effects on Th1/Th17 differentiation and macrophage/microglia activation.

PubMed

Kong, Weimin; Hooper, Kirsten M; Ganea, Doina

2016-03-01

Prostaglandins and leukotrienes, bioactive mediators generated by cyclooxygenases (COX) and 5-lipoxygenase (5-LO) from arachidonic acid, play an essential role in neuroinflammation. High levels of LTB4 and PGE2 and increased expression of COX and 5-LO, as well as high expression of PGE2 receptors were reported in multiple sclerosis (MS) patients and in experimental autoimmune encephalomyelitis (EAE). Prostaglandins and leukotrienes have an interdependent and compensatory role in EAE, which led to the concept of therapy using dual COX/5-LO inhibitors. The plant derived flavocoxid, a dual COX/5-LO inhibitor with anti-inflammatory and antioxidant properties, manufactured as a prescription pharmaconutrient, was reported to be neuroprotective in models of transient ischemic stroke and brain injury. The present study is the first report on prophylactic and therapeutic effects of flavocoxid in EAE. The beneficial effects correlate with reduced expression of proinflammatory cytokines and of COX2 and 5-LO in spinal cords and spleens of EAE mice. The protective mechanisms include: 1. reduction in expression of MHCII/costimulatory molecules and production of proinflammatory cytokines; 2. promotion of the M2 phenotype including IL-10 expression and release by macrophages and microglia; 3. inhibition of Th1 and Th17 differentiation through direct effects on T cells. The direct inhibitory effect on Th1/Th17 differentiation, and promoting the development of M2 macrophages and microglia, represent novel mechanisms for the flavocoxid anti-inflammatory activity. As a dual COX/5-LO inhibitor with antioxidant properties, flavocoxid might be useful as a potential therapeutic medical food agent in MS patients. Copyright © 2015. Published by Elsevier Inc.

Changes in gene expression caused by insect venom immunotherapy responsible for the long-term protection of insect venom-allergic patients.

PubMed

Niedoszytko, Marek; Bruinenberg, Marcel; de Monchy, Jan; Weersma, Rinse K; Wijmenga, Cisca; Jassem, Ewa; Elberink, Joanne N G Oude

2011-06-01

Insect venom immunotherapy (VIT) is the only causative treatment of insect venom allergy (IVA). The immunological mechanism(s) responsible for long-term protection achieved by VIT are largely unknown. A better understanding is relevant for improving the diagnosis, prediction of anaphylaxis, and monitoring and simplifying treatment of IVA. To find genes that are differentially expressed during the maintenance phase of VIT and after stopping, to get clues about the pathways involved in the long-term protective effect of immunotherapy. Whole genome gene expression analysis was performed on RNA samples from 50 patients treated with VIT and 43 healthy controls. Patients were divided into three groups: (1) before the start of VIT; (2) on maintenance phase of VIT for at least 3 years still receiving injections; and (3) after VIT. Of all 48,804 probes present in the array, 48,773 transcripts had sufficient data for further analysis. The list of genes that were differentially expressed (at least log2 FC > 2; P < .05 corrected for multiple testing) during the maintenance phase of VIT as well as after successful VIT contains 89 entities. The function of these genes affects cell signaling, cell differentiation, and ion transport. This study shows that a group of genes is differentially expressed both during and after VIT in comparison with gene expression in patients before VIT. Although the results of this study should be confirmed prospectively, the relevance of these findings is supported by the fact that they are related to putative mechanisms of immunotherapy. Copyright © 2011 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Effects of Mesenchymal Stem Cell Derivatives on Hematopoiesis and Hematopoietic Stem Cells

PubMed Central

Aqmasheh, Sara; Shamsasanjan, karim; Akbarzadehlaleh, Parvin; Pashoutan Sarvar, Davod; Timari, Hamze

2017-01-01

Hematopoiesis is a balance among quiescence, self-renewal, proliferation, and differentiation, which is believed to be firmly adjusted through interactions between hematopoietic stem and progenitor cells (HSPCs) with the microenvironment. This microenvironment is derived from a common progenitor of mesenchymal origin and its signals should be capable of regulating the cellular memory of transcriptional situation and lead to an exchange of stem cell genes expression. Mesenchymal stem cells (MSCs) have self-renewal and differentiation capacity into tissues of mesodermal origin, and these cells can support hematopoiesis through release various molecules that play a crucial role in migration, homing, self-renewal, proliferation, and differentiation of HSPCs. Studies on the effects of MSCs on HSPC differentiation can develop modern solutions in the treatment of patients with hematologic disorders for more effective Bone Marrow (BM) transplantation in the near future. However, considerable challenges remain on realization of how paracrine mechanisms of MSCs act on the target tissues, and how to design a therapeutic regimen with various paracrine factors in order to achieve optimal results for tissue conservation and regeneration. The aim of this review is to characterize and consider the related aspects of the ability of MSCs secretome in protection of hematopoiesis. PMID:28761818

Safety, Protective Immunity, and DIVA Capability of a Rough Mutant Salmonella Pullorum Vaccine Candidate in Broilers.

PubMed

Guo, Rongxian; Jiao, Yang; Li, Zhuoyang; Zhu, Shanshan; Fei, Xiao; Geng, Shizhong; Pan, Zhiming; Chen, Xiang; Li, Qiuchun; Jiao, Xinan

2017-01-01

Salmonella enterica subsp. enterica serovar Gallinarum biovar Pullorum ( Salmonella Pullorum) is highly adapted to chickens causing an acute systemic disease that results in high mortality. Vaccination represents one approach for promoting animal health, food safety and reducing environmental persistence in Salmonella control. An important consideration is that Salmonella vaccination in poultry should not interfere with the salmonellosis monitoring program. This is the basis of the DIVA (Differentiation of Infected and Vaccinated Animals) program. In order to achieve this goal, waaL mutant was developed on a spiC mutant that was developed previously. The safety, efficacy, and DIVA features of this vaccine candidate ( Salmonella Pullorum Δ spiC Δ waaL ) were evaluated in broilers. Our results show that the truncated LPS in the vaccine strain has a differentiating use as both a bacteriological marker (rough phenotype) and also as a serological marker facilitating the differentiation between infected and vaccinated chickens. The rough mutant showed adequate safety being avirulent in the host chicks and showed increased sensitivity to environmental stresses. Single intramuscular immunization of day-old broiler chicks with the mutant confers ideal protection against lethal wild type challenge by significantly stimulating both humoral and cellular immune responses as well as reducing the colonization of the challenge strain. Significantly lower mean pathology scores were observed in the vaccination group compared to the control group. Additionally, the mutant strain generated cross-protection against challenge with the wild type Salmonella Gallinarum thereby improving survival and with the wild type Salmonella Enteritidis thereby reducing colonization. These results suggest that the double-mutant strain may be a safe, effective, and cross-protective vaccine against Salmonella infection in chicks while conforming to the requirements of the DIVA program.

Human Mesenchymal Stem Cells Provide Protection against Radiation-Induced Liver Injury by Antioxidative Process, Vasculature Protection, Hepatocyte Differentiation, and Trophic Effects

PubMed Central

Francois, Sabine; Mouiseddine, Moubarak; Allenet-Lepage, Bénédicte; Voswinkel, Jan; Douay, Luc; Benderitter, Marc; Chapel, Alain

2013-01-01

To evaluate the potential therapeutic effect of the infusion of hMSCs for the correction of liver injuries, we performed total body radiation exposure of NOD/SCID mice. After irradiation, mir-27b level decreases in liver, increasing the directional migration of hMSCs by upregulating SDF1α. A significant increase in plasmatic transaminases levels, apoptosis process in the liver vascular system, and in oxidative stress were observed. hMSC injection induced a decrease in transaminases levels and oxidative stress, a disappearance of apoptotic cells, and an increase in Nrf2, SOD gene expression, which might reduce ROS production in the injured liver. Engrafted hMSCs expressed cytokeratin CK18 and CK19 and AFP genes indicating possible hepatocyte differentiation. The presence of hMSCs expressing VEGF and Ang-1 in the perivascular region, associated with an increased expression of VEGFr1, r2 in the liver, can confer a role of secreting cells to hMSCs in order to maintain the endothelial function. To explain the benefits to the liver of hMSC engraftment, we find that hMSCs secreted NGF, HGF, and anti-inflammatory molecules IL-10, IL1-RA contributing to prevention of apoptosis, increasing cell proliferation in the liver which might correct liver dysfunction. MSCs are potent candidates to repair and protect healthy tissues against radiation damages. PMID:24369528

Estrogens enhance myoblast differentiation in facioscapulohumeral muscular dystrophy by antagonizing DUX4 activity

PubMed Central

Teveroni, Emanuela; Sacconi, Sabrina; Calandra, Patrizia; Cascino, Isabella; Puma, Angela; Garibaldi, Matteo; Morosetti, Roberta; Ricci, Enzo; Trevisan, Carlo Pietro; Galluzzi, Giuliana; Pontecorvi, Alfredo; Deidda, Giancarlo

2017-01-01

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disorder that is characterized by extreme variability in symptoms, with females being less severely affected than males and presenting a higher proportion of asymptomatic carriers. The sex-related factors involved in the disease are not known. Here, we have utilized myoblasts isolated from FSHD patients (FSHD myoblasts) to investigate the effect of estrogens on muscle properties. Our results demonstrated that estrogens counteract the differentiation impairment of FSHD myoblasts without affecting cell proliferation or survival. Estrogen effects are mediated by estrogen receptor β (ERβ), which reduces chromatin occupancy and transcriptional activity of double homeobox 4 (DUX4), a protein whose aberrant expression has been implicated in FSHD pathogenesis. During myoblast differentiation, we observed that the levels and activity of DUX4 increased progressively and were associated with its enhanced recruitment in the nucleus. ERβ interfered with this recruitment by relocalizing DUX4 in the cytoplasm. This work identifies estrogens as a potential disease modifier that underlie sex-related differences in FSHD by protecting against myoblast differentiation impairments in this disease. PMID:28263188

Pathways to serious dieting: significant insights from discontinuity.

PubMed

Huon, G F; Lim, J; Walton, C J; Hayne, A M; Gunewardene, A I

2000-12-01

This paper outlines a strategy for systematically examining the discontinuity in pathways to serious dieting. Eight hundred and twenty-three adolescent females were recruited from six high schools in metropolitan Sydney, Australia. They completed a battery of measures that assessed perceived social influences to diet, predisposition to conformity, protective skills, aspects of positive familial context, and dieting-related attitudes and status. Testing took place over two occasions approximately 10 months apart. Family context, protective skills, and a predisposition to conformity were found to differentiate the vulnerable girls who reported high levels of social influence from those who did not. However, those variables did not differentiate those with high social influence who seriously diet from nondieters. Body mass index, drive for thinness, and body dissatisfaction differentiated all of the comparison groups tested. Age did not consistently differentiate these groups. The findings can tell us what seems to protect girls who appear susceptible to social influences from becoming serious dieters. Copyright 2000 by John Wiley & Sons, Inc.

Beneficial or Deleterious Effects of a Preexisting Hypersensitivity to Bacterial Components on the Course and Outcome of Infection

PubMed Central

Gumenscheimer, Marina; Mitov, Ivan; Galanos, Chris; Freudenberg, Marina A.

2002-01-01

Priming with heat-killed Propionibacterium acnes enhances the sensitivity of mice to lipopolysaccharide (LPS) and other biologically active bacterial components. We show that P. acnes priming has protective and deleterious effects on a subsequent serovar Typhimurium infection. It may result in a complete protection or prolonged survival, or it may accelerate mortality of the infected mice, depending on the number of serovar Typhimurium bacteria administered and on the degree of LPS hypersensitivity at the time of infection. Both effects of P. acnes-induced hypersensitivity are mediated by gamma interferon (IFN-γ) and are based on a differential activation of the innate immune mechanisms which recognize and react against the LPS present in infecting bacteria. In P. acnes-primed mice null for LPS-binding protein (LBP−/− mice), the impaired LPS recognition, due to the absence of LBP, resulted in a higher resistance to serovar Typhimurium infection. A similar P. acnes priming of mice had a protective, but no deleterious effect on a subsequent L. monocytogenes infection. This effect was IFN-γ dependent but independent of LBP. PMID:12228287

Acorus tatarinowii Schott extract protects PC12 cells from amyloid-beta induced neurotoxicity.

PubMed

An, Hong-Mei; Li, Guo-Wen; Lin, Chen; Gu, Chao; Jin, Miao; Sun, Wen-Xian; Qiu, Ming-Feng; Hu, Bing

2014-05-01

Amyloid-beta induced neurotoxicity has been identified as a major cause of Alzheimer's disease. Acorus tatarinowii Schott is one of the most frequently used Chinese herbs for Alzheimer's disease treatment. However, the effects of Acorus tatarinowii Schott on amyloid-beta mediated nerve cell damage remains unknown. In the present study, neuronal differentiated PC12 cells were used as a model to evaluate the effects of A. tatarinowii Schott extract (ATSE) against Abeta25-35 induced neurotoxicity. The results showed pretreatment with ATSE significantly protected PC12 cells from Abeta25-35 induced cell death, lactate dehydrogenase release, DNA damage, mitochondrial dysfunction and cytochrome c release from mitochondria. In addition, pretreatment with ATSE also significantly inhibited Abeta25-35 induced caspase-3 activation and reactive oxygen species generation in PC12 cells. These observations suggested that ATSE protects PC12 cells from amyloid-beta induced neurotoxicity.

End-stage renal disease, dialysis, kidney transplantation and their impact on CD4+ -T-cell differentiation.

PubMed

Schaier, Matthias; Leick, Angele; Uhlmann, Lorenz; Kälble, Florian; Morath, Christian; Eckstein, Volker; Ho, Anthony; Mueller-Tidow, Carsten; Meuer, Stefan; Mahnke, Karsten; Sommerer, Claudia; Zeier, Martin; Steinborn, Andrea

2018-05-02

Premature aging of both CD4 + -regulatory- (Tregs) and CD4 + -responder-T-cells (Tresps) in end-stage renal disease (ESRD) patients is expected to affect the success of later kidney transplantation. Both T-cell populations are released from the thymus as inducible co-stimulatory (ICOS + -) and ICOS - -recent thymic emigrant (RTE)-Tregs/Tresps, which differ primarily in their proliferative capacities. In this study, we analysed the effect of ESRD and subsequent renal replacement therapies on the differentiation of ICOS + - and ICOS - -RTE-Tregs/Tresps into ICOS + - or ICOS - -CD31 - -Memory-Tregs/Tresps and examined whether diverging pathways affected the suppressive activity of ICOS + - and ICOS - -Tregs in co-culture with autologous Tresps. Compared to healthy controls, we found an increased differentiation of ICOS + -RTE-Tregs/Tresps and ICOS - -RTE-Tregs via CD31 + -memory-Tregs/Tresps into CD31 - -memory-Tregs/Tresps in ESRD and dialysis patients. In contrast, ICOS - -RTE-Tresps showed an increased differentiation via ICOS - -mature naïve (MN)-Tresps into CD31 - -memory-Tresps. Thereby, the ratio of ICOS + -Tregs/ICOS + -Tresps was not changed, while that of ICOS - -Tregs/ICOS - -Tresps was significantly increased. This differentiation preserved the suppressive activity of both Treg populations in ESRD and partly in dialysis patients. After transplantation, the increased differentiation of ICOS + - and ICOS - -RTE-Tresps proceeded, while that of ICOS + -RTE-Tregs ceased and that of ICOS - -RTE-Tregs switched to an increased differentiation via ICOS - -MN-Tregs. Consequently, the ratios of ICOS + -Tregs/ICOS + -Tresps and of ICOS - -Tregs/ICOS - -Tresps decreased significantly, reducing the suppressive activity of Tregs markedly. Our data reveal that an increased tolerance-inducing differentiation of ICOS + - and ICOS - -Tregs preserves the functional activity of Tregs in ESRD patients, but this cannot be maintained during long-term renal replacement therapy. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Evaluation of dispersion strengthened nickel-base alloy heat shields for space shuttle application

NASA Technical Reports Server (NTRS)

Johnson, R., Jr.; Killpatrick, D. H.

1976-01-01

The results obtained in a program to evaluate dispersion-strengthened nickel-base alloys for use in a metallic radiative thermal protection system operating at surface temperatures to 1477 K for the space shuttle were presented. Vehicle environments having critical effects on the thermal protection system are defined; TD Ni-20Cr characteristics of material used in the current study are compared with previous results; cyclic load, temperature, and pressure effects on sheet material residual strength are investigated; the effects of braze reinforcement in improving the efficiency of spotwelded joints are evaluated; parametric studies of metallic radiative thermal protection systems are reported; and the design, instrumentation, and testing of full scale subsize heat shield panels in two configurations are described. Initial tests of full scale subsize panels included simulated meteoroid impact tests, simulated entry flight aerodynamic heating, programmed differential pressure loads and temperatures simulating mission conditions, and acoustic tests simulating sound levels experienced during boost flight.

Stem cell factor (SCF) protects osteoblasts from oxidative stress through activating c-Kit-Akt signaling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Lei; Wu, Zhong; Yin, Gang

2014-12-12

Highlights: • SCF receptor c-Kit is functionally expressed in primary and transformed osteoblasts. • SCF protects primary and transformed osteoblasts from H{sub 2}O{sub 2}. • SCF activation of c-Kit in osteoblasts, required for its cyto-protective effects. • c-Kit mediates SCF-induced Akt activation in cultured osteoblasts. • Akt activation is required for SCF-regulated cyto-protective effects in osteoblasts. - Abstract: Osteoblasts regulate bone formation and remodeling, and are main target cells of oxidative stress in the progression of osteonecrosis. The stem cell factor (SCF)-c-Kit pathway plays important roles in the proliferation, differentiation and survival in a range of cell types, but littlemore » is known about its functions in osteoblasts. In this study, we found that c-Kit is functionally expressed in both osteoblastic-like MC3T3-E1 cells and primary murine osteoblasts. Its ligand SCF exerted significant cyto-protective effects against hydrogen peroxide (H{sub 2}O{sub 2}). SCF activated its receptor c-Kit in osteoblasts, which was required for its cyto-protective effects against H{sub 2}O{sub 2}. Pharmacological inhibition (by Imatinib and Dasatinib) or shRNA-mediated knockdown of c-Kit thus inhibited SCF-mediated osteoblast protection. Further investigations showed that protection by SCF against H{sub 2}O{sub 2} was mediated via activation of c-Kit-dependent Akt pathway. Inhibition of Akt activation, through pharmacological or genetic means, suppressed SCF-mediated anti-H{sub 2}O{sub 2} activity in osteoblasts. In summary, we have identified a new SCF-c-Kit-Akt physiologic pathway that protects osteoblasts from H{sub 2}O{sub 2}-induced damages, and might minimize the risk of osteonecrosis caused by oxidative stress.« less

Herd Protection from Drinking Water, Sanitation, and Hygiene Interventions

PubMed Central

Fuller, James A.; Eisenberg, Joseph N. S.

2016-01-01

Herd immunity arises when a communicable disease is less able to propagate because a substantial portion of the population is immune. Nonimmunizing interventions, such as insecticide-treated bednets and deworming drugs, have shown similar herd-protective effects. Less is known about the herd protection from drinking water, sanitation, and hand hygiene (WASH) interventions. We first constructed a transmission model to illustrate mechanisms through which different WASH interventions may provide herd protection. We then conducted an extensive review of the literature to assess the validity of the model results and identify current gaps in research. The model suggests that herd protection accounts for a substantial portion of the total protection provided by WASH interventions. However, both the literature and the model suggest that sanitation interventions in particular are the most likely to provide herd protection, since they reduce environmental contamination. Many studies fail to account for these indirect effects and thus underestimate the total impact an intervention may have. Although cluster-randomized trials of WASH interventions have reported the total or overall efficacy of WASH interventions, they have not quantified the role of herd protection. Just as it does in immunization policy, understanding the role of herd protection from WASH interventions can help inform coverage targets and strategies that indirectly protect those that are unable to be reached by WASH campaigns. Toward this end, studies are needed to confirm the differential role that herd protection plays across the WASH interventions suggested by our transmission model. PMID:27601516

Herd Protection from Drinking Water, Sanitation, and Hygiene Interventions.

PubMed

Fuller, James A; Eisenberg, Joseph N S

2016-11-02

Herd immunity arises when a communicable disease is less able to propagate because a substantial portion of the population is immune. Nonimmunizing interventions, such as insecticide-treated bednets and deworming drugs, have shown similar herd-protective effects. Less is known about the herd protection from drinking water, sanitation, and hand hygiene (WASH) interventions. We first constructed a transmission model to illustrate mechanisms through which different WASH interventions may provide herd protection. We then conducted an extensive review of the literature to assess the validity of the model results and identify current gaps in research. The model suggests that herd protection accounts for a substantial portion of the total protection provided by WASH interventions. However, both the literature and the model suggest that sanitation interventions in particular are the most likely to provide herd protection, since they reduce environmental contamination. Many studies fail to account for these indirect effects and thus underestimate the total impact an intervention may have. Although cluster-randomized trials of WASH interventions have reported the total or overall efficacy of WASH interventions, they have not quantified the role of herd protection. Just as it does in immunization policy, understanding the role of herd protection from WASH interventions can help inform coverage targets and strategies that indirectly protect those that are unable to be reached by WASH campaigns. Toward this end, studies are needed to confirm the differential role that herd protection plays across the WASH interventions suggested by our transmission model. © The American Society of Tropical Medicine and Hygiene.

Physalis angulata induces in vitro differentiation of murine bone marrow cells into macrophages.

PubMed

da Silva, Bruno José Martins; Rodrigues, Ana Paula D; Farias, Luis Henrique S; Hage, Amanda Anastácia P; Do Nascimento, Jose Luiz M; Silva, Edilene O

2014-10-03

The bone marrow is a hematopoietic tissue that, in the presence of cytokines and growth factors, generates all of the circulating blood cells. These cells are important for protecting the organism against pathogens and for establishing an effective immune response. Previous studies have shown immunomodulatory effects of different products isolated from plant extracts. This study aimed to evaluate the immunomodulatory properties of aqueous Physalis angulata (AEPa) extract on the differentiation of bone marrow cells. Increased cellular area, higher spreading ability and several cytoplasmatic projections were observed in the treated cells, using optical microscopy, suggesting cell differentiation. Furthermore, AEPa did not promote the proliferation of lymphocytes and polymorphonuclear leukocytes, however promotes increased the number of macrophages in the culture. The ultrastructural analysis by Transmission Electron Microscopy of treated cells showed spreading ability, high number of cytoplasmatic projections and increase of autophagic vacuoles. Moreover, a high level of LC3b expression by treated cells was detected by flow cytometry, suggesting an autophagic process. Cell surface expression of F4/80 and CD11b also indicated that AEPa may stimulate differentiation of bone marrow cells mainly into macrophages. In addition, AEPa did not differentiate cells into dendritic cells, as assessed by CD11c analysis. Furthermore, no cytotoxic effects were observed in the cells treated with AEPa. Results demonstrate that AEPa promotes the differentiation of bone marrow cells, particularly into macrophages and may hold promise as an immunomodulating agent.

Physalis angulata induces in vitro differentiation of murine bone marrow cells into macrophages

PubMed Central

2014-01-01

Background The bone marrow is a hematopoietic tissue that, in the presence of cytokines and growth factors, generates all of the circulating blood cells. These cells are important for protecting the organism against pathogens and for establishing an effective immune response. Previous studies have shown immunomodulatory effects of different products isolated from plant extracts. This study aimed to evaluate the immunomodulatory properties of aqueous Physalis angulata (AEPa) extract on the differentiation of bone marrow cells. Results Increased cellular area, higher spreading ability and several cytoplasmatic projections were observed in the treated cells, using optical microscopy, suggesting cell differentiation. Furthermore, AEPa did not promote the proliferation of lymphocytes and polymorphonuclear leukocytes, however promotes increased the number of macrophages in the culture. The ultrastructural analysis by Transmission Electron Microscopy of treated cells showed spreading ability, high number of cytoplasmatic projections and increase of autophagic vacuoles. Moreover, a high level of LC3b expression by treated cells was detected by flow cytometry, suggesting an autophagic process. Cell surface expression of F4/80 and CD11b also indicated that AEPa may stimulate differentiation of bone marrow cells mainly into macrophages. In addition, AEPa did not differentiate cells into dendritic cells, as assessed by CD11c analysis. Furthermore, no cytotoxic effects were observed in the cells treated with AEPa. Conclusion Results demonstrate that AEPa promotes the differentiation of bone marrow cells, particularly into macrophages and may hold promise as an immunomodulating agent. PMID:25281406

Differential effect of ethanol and hydrogen peroxide on barrier function and prostaglandin E2 release in differentiated Caco-2 cells: selective prevention by growth factors.

PubMed

Catalioto, Rose-Marie; Festa, Carla; Triolo, Antonio; Altamura, Maria; Maggi, Carlo Alberto; Giuliani, Sandro

2009-02-01

The present study investigates the effects of ethanol and hydrogen peroxide (H(2)O(2)) on the barrier function and prostaglandin E(2) (PGE(2)) release in differentiated Caco-2 cells. Epithelial barrier integrity was estimated by measuring transepithelial electrical resistance (TEER), the transport of reference compounds and lactate dehydrogenase leakage, the PGE(2) release by enzyme immunoassay. Ethanol and H(2)O(2) decreased TEER and increased the transport of lucifer yellow without affecting that of propranolol and phenylalanine. Only the effects of ethanol were accompanied by PGE(2) production and were reversible without causing long-term cytotoxicity. The cyclooxygenase-2 inhibitor, NS-398, prevented the effect of ethanol on both PGE(2) release and TEER, while inhibition of both cyclooxygenase-2 and tyrosine kinase drastically compromised cell viability and TEER recovery. Hepatocyte growth factor, keratinocyte growth factor or insulin prevented the effect of ethanol on cell permeability, but not on PGE(2) release. Their combination prevented the effect of H(2)O(2). In conclusion, ethanol and H(2)O(2) increased paracellular permeability in differentiated Caco-2 cells without affecting transcellular and active transport. Cyclooxygenase-2 stimulated PGE(2) release mediated the reversible effect of ethanol on tight junctions and, meanwhile, contributed to cell survival. Growth factors, normally present in the intestine, exerted a selective protective effect toward paracellular permeability increase induced by irritants.

Selecting compact habitat reserves for species with differential habitat size needs

Treesearch

Vladimir Marianov; Charles ReVelle; Stephanie Snyder

2008-01-01

We propose a model for the design of protected habitat reserves, which maximizes the number of species represented at least once in a limited set of reserved sites or parcels. Most models for reserve design do not differentiate eligible habitat sites by their size. Also, they assume that protection is guaranteed through the selection of one site for any species, not...

Differential Privacy Preserving in Big Data Analytics for Connected Health.

PubMed

Lin, Chi; Song, Zihao; Song, Houbing; Zhou, Yanhong; Wang, Yi; Wu, Guowei

2016-04-01

In Body Area Networks (BANs), big data collected by wearable sensors usually contain sensitive information, which is compulsory to be appropriately protected. Previous methods neglected privacy protection issue, leading to privacy exposure. In this paper, a differential privacy protection scheme for big data in body sensor network is developed. Compared with previous methods, this scheme will provide privacy protection with higher availability and reliability. We introduce the concept of dynamic noise thresholds, which makes our scheme more suitable to process big data. Experimental results demonstrate that, even when the attacker has full background knowledge, the proposed scheme can still provide enough interference to big sensitive data so as to preserve the privacy.

Community violence, protective factors, and adolescent mental health: a profile analysis.

PubMed

Copeland-Linder, Nikeea; Lambert, Sharon F; Ialongo, Nicholas S

2010-01-01

This study examined interrelationships among community violence exposure, protective factors, and mental health in a sample of urban, predominantly African American adolescents (N = 504). Latent Profile Analysis was conducted to identify profiles of adolescents based on a combination of community violence exposure, self-worth, parental monitoring, and parental involvement and to examine whether these profiles differentially predict adolescents' depressive symptoms and aggressive behavior. Three classes were identified-a vulnerable class, a moderate risk/medium protection class, and a moderate risk/high protection class. The classes differentially predicted depressive symptoms but not aggressive behavior for boys and girls. The class with the highest community violence exposure also had the lowest self-worth.

Water extract of the fruits of Alpinia oxyphylla inhibits osteoclast differentiation and bone loss.

PubMed

Ha, Hyunil; Shim, Ki-Shuk; Kim, Taesoo; Lee, Chung-Jo; Park, Ji Hyung; Kim, Han Sung; Ma, Jin Yeul

2014-09-23

Excessive bone resorption by osteoclasts causes pathological bone destruction, seen in various bone diseases. There is accumulating evidence that certain herbal extracts have beneficial effects on bone metabolism. The fruits of Alpinia oxyphylla has been traditionally used for the treatment of diarrhea and enuresis. In this study, we investigated the effects of water extract of the fruits of Alpinia oxyphylla (WEAO) on osteoclast differentiation and osteoclast-mediated bone destruction. For osteoclast differentiation assay, mouse bone marrow-derived macrophages (BMMs) were cultured in the presence of RANKL and M-CSF. RANKL signaling pathways and gene expression of transcription factors regulating osteoclast differentiation were investigated by real-time PCR and Western blotting. A constitutively active form of NFATc1 was retrovirally transduced into BMMs. Bone resorbing activity of mature osteoclast was examined on a plate coated with an inorganic crystalline calcium phosphate. The in vivo effect against bone destruction was assessed in a murine model of RANKL-induced osteoporosis by micro-computed tomography and bone metabolism marker analyses. WEAO dose-dependently inhibited RANKL-induced osteoclast differentiation from BMMs by targeting the early stages of osteoclast differentiation. WEAO inhibited RANKL-induced expression of NFATc1, the master regulator of osteoclast differentiation. Overexpression of a constitutively active form of NFATc1 blunted the inhibitory effect of WEAO on osteoclast differentiation, suggesting that NFATc1 is a critical target of the inhibitory action of WEAO. WEAO inhibited RANKL-induced expression of c-Fos, an upstream activator of NFATc1, by suppressing the classical NF-κB signaling pathway. WEAO also inhibited RANKL-induced down-regulation of Id2 and MafB, negative regulators of NFATc1. WEAO does not directly affect bone resorbing activity of mature osteoclasts. In accordance with the in vitro results, WEAO attenuated RANKL-induced bone destruction in mice by inhibiting osteoclast differentiation. This study demonstrates that WEAO exhibits a protective effect against bone loss by inhibiting RANKL-induced osteoclast differentiation. These findings suggest that WEAO might be useful for the prevention and treatment of bone diseases associated with excessive bone resorption.

Enforced expression of KDR receptor promotes proliferation, survival and megakaryocytic differentiation of TF1 progenitor cell line.

PubMed

Coppola, S; Narciso, L; Feccia, T; Bonci, D; Calabrò, L; Morsilli, O; Gabbianelli, M; De Maria, R; Testa, U; Peschle, C

2006-01-01

Vascular endothelial growth factor (VEGF) receptor-2/kinase insert domain-containing receptor (KDR) is expressed in primitive hematopoietic cells, in megakaryocytes and platelets. In primitive hematopoiesis KDR mediates cell survival via autocrine VEGF, while its effect on cell growth and differentiation has not been elucidated. We induced enforced KDR expression in the granulocyte macrophage-colony-stimulating factor (GM-CSF)-dependent TF1 progenitor cell line (TF1-KDR), treated the cells with VEGF and analyzed their response. In GM-CSF-deprived cells, VEGF induces cell proliferation and protection against apoptosis, followed by enhanced expression of megakaryocytic (MK) markers. Combined with GM-CSF, VEGF induces a mild proliferative stimulus, followed by cell adherence, accumulation in G0/G1, massive MK differentiation and Fas-mediated apoptosis. Accordingly, we observed that MK-differentiating cells, derived from hematopoietic progenitors, produce VEGF, express KDR, inhibition of which reduces MK differentiation, indicating a key role of KDR in megakaryopoiesis. In conclusion, TF1-KDR cells provide a reliable model to investigate the biochemical and molecular mechanisms underlying hematopoietic progenitor proliferation, survival and MK differentiation.

Protection of active aroma compound against moisture and oxygen by encapsulation in biopolymeric emulsion-based edible films.

PubMed

Hambleton, Alicia; Debeaufort, Frédéric; Beney, Laurent; Karbowiak, Thomas; Voilley, Andrée

2008-03-01

Edible films made of iota-carrageenans display interesting advantages: good mechanical properties, stabilization of emulsions, and reduction of oxygen transfers. Moreover, the addition of lipids to iota-carrageenan-based films to form emulsified films decreases the transfer of water vapor and can be considered to encapsulate active molecules as flavors. The aim of this study was to better understand the influence of the composition and the structure of the carrageenan-based film matrices on its barrier properties and thus on its capacity to encapsulate and to protect active substances encapsulated. Granulometry, differential scanning calorimetry, and Fourier transform infrared spectroscopy characterizations of films with or without flavor and/or fat showed that the flavor compound modifies the film structure because of interactions with the iota-carrageenan chains. The study of the water vapor permeability (WVP), realized at 25 and 35 degrees C and for three relative humidity differentials (30-100%, 30-84%, 30-75%), showed that the flavor compound increases significantly the WVP, especially for the weaker gradients, but has no effect on the oxygen permeability. This study brings new understanding of the role of carrageenan as a film matrix and on its capacity to protect encapsulated flavors.

Children Exposed to Intimate Partner Violence: Identifying Differential Effects of Family Environment on Children’s Trauma and Psychopathology Symptoms through Regression Mixture Models

PubMed Central

McDonald, Shelby Elaine; Shin, Sunny; Corona, Rosalie; Maternick, Anna; Graham-Bermann, Sandra A.; Ascione, Frank R.; Williams, James Herbert

2016-01-01

The majority of analytic approaches aimed at understanding the influence of environmental context on children’s socioemotional adjustment assume comparable effects of contextual risk and protective factors for all children. Using self-reported data from 289 maternal caregiver-child dyads, we examined the degree to which there are differential effects of severity of intimate partner violence (IPV) exposure, yearly household income, and number of children in the family on posttraumatic stress symptoms (PTS) and psychopathology symptoms (i.e., internalizing and externalizing problems) among school-age children between the ages of 7 to 12 years. A regression mixture model identified three latent classes that were primarily distinguished by differential effects of IPV exposure severity on PTS and psychopathology symptoms: (1) asymptomatic with low sensitivity to environmental factors (66% of children), (2) maladjusted with moderate sensitivity (24%), and (3) highly maladjusted with high sensitivity (10%). Children with mothers who had higher levels of education were more likely to be in the maladjusted with moderate sensitivity group than the asymptomatic with low sensitivity group. Latino children were less likely to be in both maladjusted groups compared to the asymptomatic group. Overall, the findings suggest differential effects of family environmental factors on PTS and psychopathology symptoms among children exposed to IPV. Implications for research and practice are discussed. PMID:27337691

Children exposed to intimate partner violence: Identifying differential effects of family environment on children's trauma and psychopathology symptoms through regression mixture models.

PubMed

McDonald, Shelby Elaine; Shin, Sunny; Corona, Rosalie; Maternick, Anna; Graham-Bermann, Sandra A; Ascione, Frank R; Herbert Williams, James

2016-08-01

The majority of analytic approaches aimed at understanding the influence of environmental context on children's socioemotional adjustment assume comparable effects of contextual risk and protective factors for all children. Using self-reported data from 289 maternal caregiver-child dyads, we examined the degree to which there are differential effects of severity of intimate partner violence (IPV) exposure, yearly household income, and number of children in the family on posttraumatic stress symptoms (PTS) and psychopathology symptoms (i.e., internalizing and externalizing problems) among school-age children between the ages of 7-12 years. A regression mixture model identified three latent classes that were primarily distinguished by differential effects of IPV exposure severity on PTS and psychopathology symptoms: (1) asymptomatic with low sensitivity to environmental factors (66% of children), (2) maladjusted with moderate sensitivity (24%), and (3) highly maladjusted with high sensitivity (10%). Children with mothers who had higher levels of education were more likely to be in the maladjusted with moderate sensitivity group than the asymptomatic with low sensitivity group. Latino children were less likely to be in both maladjusted groups compared to the asymptomatic group. Overall, the findings suggest differential effects of family environmental factors on PTS and psychopathology symptoms among children exposed to IPV. Implications for research and practice are discussed. Copyright © 2016 Elsevier Ltd. All rights reserved.

Differential effectiveness in patient protection laws: what are the causes? An example from the drive-through delivery laws.

PubMed

Dow, William H; Harris, Dean M; Liu, Zhimei

2006-12-01

In the mid-1990s, many states as well as the federal government began to regulate early postpartum hospital discharge. Length-of-stay patterns changed markedly in response, but effects were much greater in some states than others. In particular, laws directly empowering patients appeared more effective than laws requiring providers to follow practice guidelines. In addition, the effectiveness of regulation could potentially be influenced by state environment, such as managed care penetration as well as exposure to media attention and public pressure on the issue, though these factors alone were insufficient to cause general behavior change. Furthermore, the 1996 federal law had little effect beyond state laws, suggesting that it did not provide substantial benefits to women in self-insured plans exempted from state law regulation by the Employee Retirement Income Security Act. Findings from this study could provide lessons for similar patient protection initiatives.

Osteoporosis and body composition.

PubMed

Crepaldi, G; Romanato, G; Tonin, P; Maggi, S

2007-01-01

The Epidemiologic Study on the Prevalence of Osteoporosis in Italy showed that the prevalence of osteoporosis among women and men aged 60 yr and over is 22.8% and 14.5%, respectively, giving rise to about 80,000 new fractures a yr. Sarcopenia is considered to be one of the main features of the aging process. It is characterized by a reduction in muscle mass and muscle strength, and affects women more than men. It is associated with a increased risk of fractures consequent upon a greater predisposition to falls, but also to the lack of bone remodeling due to reduced muscle mechanical strength. Muscle strength determines quality bone modifications such as density, strength, and microarchitecture. Variations in the ratios of cortical and muscle areas give rise to various types of osteoporosis, with different risks of fracture. Bone mineral density increases with body fat mass, and obesity has a protective effect against osteoporosis. This protective effect is explained by a combination of hormonal (peripheral aromatization of androgens to estrogens in adipose tissue) and mechanical factors (on weight-bearing bone sites), but the hormone leptin also probably mediates fat and bone mass. Serum leptin levels are closely related to body fat mass, and some findings suggest the peripheral effect of leptin, which exerts estrogenic effects, enhancing osteoblastic differentiation and inhibiting late adipocytic differentiation. The overall effect of leptin on bone results from a balance between negative central effects and positive direct peripheral effects, according to serum leptin levels.

Parents as a Resource in Times of Stress: Interactive Contributions of Socialization of Coping and Stress to Youth Psychopathology

PubMed Central

Abaied, Jamie L.; Rudolph, Karen D.

2011-01-01

This study examined the hypothesis that maternal socialization of coping would make a differential contribution to youth depression and externalizing psychopathology depending on youths’ level of exposure to life stress. A sample of 155 youth (M age = 12.41, SD = 1.21) and their maternal caregivers completed semi-structured interviews and questionnaires in a two-wave longitudinal study over a one-year period. Results provided evidence for two types of socialization x stress interactions—an amplification-effects model and a differential-effects model. In the context of interpersonal stress, findings supported an amplification-effects model wherein the risk and protective effects of engagement and disengagement socialization of coping emerged in youth exposed to high but not mild levels of stress. In the context of noninterpersonal stress, findings supported a differential-effects model wherein disengagement socialization of coping contributed to heightened risk among youth exposed to high stress but dampened risk among youth exposed to mild stress. This research identifies maternal socialization of coping as a noteworthy contributor to risk for youth psychopathology, and highlights the need to consider parenting x environment interactions when investigating parenting processes related to youth psychopathology. PMID:19908139

Bone-derived mesenchymal stromal cells from HIV transgenic mice exhibit altered proliferation, differentiation capacity and paracrine functions along with impaired therapeutic potential in kidney injury

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cheng, Kang; Rai, Partab; Lan, Xiqian

Mesenchymal stem cells (MSCs) secrete paracrine factors that could be cytoprotective and serve roles in immunoregulation during tissue injury. Although MSCs express HIV receptors, and co-receptors, and are susceptible to HIV infection, whether HIV-1 may affect biological properties of MSCs needs more study. We evaluated cellular proliferation, differentiation and paracrine functions of MSCs isolated from compact bones of healthy control mice and Tg26 HIV-1 transgenic mice. The ability of MSCs to protect against cisplatin toxicity was studied in cultured renal tubular cells as well as in intact mice. We successfully isolated MSCs from healthy mice and Tg26 HIV-1 transgenic micemore » and found the latter expressed viral Nef, Vpu, NL4-3 and Vif genes. The proliferation and differentiation of Tg26 HIV-1 MSCs was inferior to MSCs from healthy mice. Moreover, transplantation of Tg26 HIV-1 MSCs less effectively improved outcomes compared with healthy MSCs in mice with acute kidney injury. Also, Tg26 HIV-1 MSCs secreted multiple cytokines, but at significantly lower levels than healthy MSCs, which resulted in failure of conditioned medium from these MSCs to protect cultured renal tubular cells from cisplatin toxicity. Therefore, HIV-1 had adverse biological effects on MSCs extending to their proliferation, differentiation, function, and therapeutic potential. These findings will help in advancing mechanistical insight in renal injury and repair in the setting of HIV-1 infection. -- Highlights: •MSCs isolated from HIV mice displayed HIV genes. •MSCs isolated from HIV mice exhibited attenuated growth and paracrine functions. •AKI mice with transplanted HIV-MSC displayed poor outcome. •HIV-1 MSC secreted multiple cytokines but at a lower level.« less

Dietary selenium protects adiponectin knockout mice against chronic inflammation induced colon cancer.

PubMed

Saxena, Arpit; Fayad, Raja; Kaur, Kamaljeet; Truman, Samantha; Greer, Julian; Carson, James A; Chanda, Anindya

2017-04-03

Selenium (Se) is an essential dietary micronutrient that has been examined for protection against different types of cancers including colon cancer. Despite an established inverse association between Se and chronic inflammation induced colon cancer (CICC), the mechanistic understanding of Se's protective effects requires additional in-vivo studies using preclinical animal models of CICC. Adiponectin (APN) is an adipocytokine that is protective against CICC as well. However, its role in the anti-mutagenic effects of the Se-diet remains unknown. To address this knowledge gap, here we examine the ability of dietary Se in reducing CICC in APN knockout mice (KO) and its wild-type C57BL/6. CICC was induced with the colon cancer agent 1,2 dimethyl hydrazine (DMH) along with dextran sodium sulfate (DSS). Se-enhanced diet increased selenoproteins, Gpx-1 and Gpx-2, in the colon tissues, thereby reducing oxidative stress. Se-mediated reduction of CICC was evident from the histopathological studies in both mouse models. In both mice, reduction in inflammation and tumorigenesis associated well with reduced p65 phosphorylation and elevated 53 phosphorylation. Finally, we show that in both models Se-administration promotes goblet cell differentiation with a concomitant increase in the levels of associated proteins, Muc-2 and Math-1. Our findings suggest that Se's protection against CICC involves both colonic epithelial protection and anti-tumor effects that are independent of APN.

Neuroprotective effects of metabotropic glutamate receptor group II and III activators against MPP(+)-induced cell death in human neuroblastoma SH-SY5Y cells: the impact of cell differentiation state.

PubMed

Jantas, D; Greda, A; Golda, S; Korostynski, M; Grygier, B; Roman, A; Pilc, A; Lason, W

2014-08-01

Recent studies have documented that metabotropic glutamate receptors from group II and III (mGluR II/III) are a potential target in the symptomatic treatment of Parkinson's disease (PD), however, the neuroprotective effects of particular mGluR II/III subtypes in relation to PD pathology are recognized only partially. In the present study, we investigated the effect of various mGluR II/III activators in the in vitro model of PD using human neuroblastoma SH-SY5Y cell line and mitochondrial neurotoxin MPP(+). We demonstrated that all tested mGluR ligands: mGluR II agonist - LY354740, mGluR III agonist - ACPT-I, mGluR4 PAM - VU0361737, mGluR8 agonist - (S)-3,4-DCPG, mGluR8 PAM - AZ12216052 and mGluR7 allosteric agonist - AMN082 were protective against MPP(+)-evoked cell damage in undifferentiated (UN-) SH-SY5Y cells with the highest neuroprotection mediated by mGluR8-specific agents. However, in retinoic acid- differentiated (RA-) SH-SY5Y cells we found protection mediated only by mGluR8 activators. We also demonstrated the cell proliferation stimulating effect for mGluR4 and mGluR8 PAMs. Next, we showed that the protection mediated by mGluR II/III activators in UN-SH-SY5Y was not accompanied by the modulation of caspase-3 activity, however, a decrease in the number of apoptotic nuclei was found. Finally, we showed that the inhibitor of necroptosis, necrostatin-1 blocked the mGluR III-mediated protection. Altogether our comparative in vitro data add a further proof to neuroprotective effects of mGluR agonists or PAMs and point to mGluR8 as a promising target for neuroprotective interventions in PD. The results also suggest the participation of necroptosis-related molecular pathways in neuroprotective effects of mGluR III activation. Copyright © 2014 Elsevier Ltd. All rights reserved.

Metabolic fate of saturated and monounsaturated dietary fats: the Mediterranean diet revisited from epidemiological evidence to cellular mechanisms.

PubMed

Bergouignan, Audrey; Momken, Iman; Schoeller, Dale A; Simon, Chantal; Blanc, Stéphane

2009-01-01

Increasing evidence indicates favourable effects of the Mediterranean diet, partly associated to its monounsaturated fatty acids (MUFA) content on both obesity and diabetes. However, neither the underlying mechanisms by which the Mediterranean diet exerts its protective effect, nor the interplay with other environmental factors (i.e. physical activity), are fully characterised. In this review, we examined recent data on how the metabolic fate of MUFA and saturated fatty acids (SFA) differs. Because of differential packaging into lipoproteins, hydrolysis of triacylglycerol-rich lipoproteins by lipoprotein lipase and transport into oxidative tissues, MUFA are oxidised more than SFA. This high MUFA oxidation favour lipid oxidation and according to the oxidative balance concept reduces the risk of obesity. It also improves the intra-muscular triacylglycerol turnover, which mitigates the SFA-induced accumulation of diacylglycerol and ceramides, and thus protects the insulin sensitivity and cell viability. Finally, physical activity through its action on the energy turnover differentially regulates the metabolism of SFA and MUFA. The putative combined role of AMP-activated kinase and mitochondrial glycerol-3-phosphate transferase on the intra-muscular partitioning of MUFA and SFA provides new areas of research to better understand the beneficial effects of the Mediterranean diet and physical activity on obesity and diabetes.

Cardioprotective Effects of Quercetin in Cardiomyocyte under Ischemia/Reperfusion Injury

PubMed Central

Chen, Yi-Wen; Chou, Hsiu-Chuan; Lin, Szu-Ting; Chen, You-Hsuan; Chang, Yu-Jung; Chen, Linyi; Chan, Hong-Lin

2013-01-01

Quercetin, a polyphenolic compound existing in many vegetables, fruits, has antiinflammatory, antiproliferation, and antioxidant effect on mammalian cells. Quercetin was evaluated for protecting cardiomyocytes from ischemia/reperfusion injury, but its protective mechanism remains unclear in the current study. The cardioprotective effects of quercetin are achieved by reducing the activity of Src kinase, signal transducer and activator of transcription 3 (STAT3), caspase 9, Bax, intracellular reactive oxygen species production, and inflammatory factor and inducible MnSOD expression. Fluorescence two-dimensional differential gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) can reveal the differentially expressed proteins of H9C2 cells treated with H2O2 or quercetin. Although 17 identified proteins were altered in H2O2-induced cells, these proteins such as alpha-soluble NSF attachment protein (α-SNAP), Ena/VASP-like protein (Evl), and isopentenyl-diphosphate delta-isomerase 1 (Idi-1) were reverted by pretreatment with quercetin, which correlates with kinase activation, DNA repair, lipid, and protein metabolism. Quercetin dephosphorylates Src kinase in H2O2-induced H9C2 cells and likely blocks the H2O2-induced inflammatory response through STAT3 kinase modulation. This probably contributes to prevent ischemia/reperfusion injury in cardiomyocytes. PMID:23573126

Dietary fat overcomes the protective activity of thrombospondin-1 signaling in the Apc(Min/+) model of colon cancer.

PubMed

Soto-Pantoja, D R; Sipes, J M; Martin-Manso, G; Westwood, B; Morris, N L; Ghosh, A; Emenaker, N J; Roberts, D D

2016-05-30

Thrombospondin 1 is a glycoprotein that regulates cellular phenotype through interactions with its cellular receptors and extracellular matrix-binding partners. Thrombospondin 1 locally regulates angiogenesis and inflammatory responses that contribute to colorectal carcinogenesis in Apc(Min/+) mice. The ability of thrombospondin 1 to regulate responses of cells and tissues to a variety of stresses suggested that loss of thrombospondin 1 may also have broader systemic effects on metabolism to modulate carcinogenesis. Apc(Min/+):Thbs1(-/-) mice exhibited decreased survival and higher tumor multiplicities in the small and large intestine relative to Apc(Min/+) mice when fed a low (5%) fat western diet. However, the protective effect of endogenous thrombospondin 1 was lost when the mice were fed a western diet containing 21% fat. Biochemical profiles of liver tissue identified systemic metabolic changes accompanying the effects of thrombospondin 1 and dietary lipid intake on tumorigenesis. A high-fat western diet differentially regulated elements of amino acid, energy and lipid metabolism in Apc(Min/+):Thbs1(-/-) mice relative to Apc(Min/+):Thbs1(+/+)mice. Metabolic changes in ketone body and tricarboxylic acid cycle intermediates indicate functional interactions between Apc and thrombospondin 1 signaling that control mitochondrial function. The cumulative diet-dependent differential changes observed in Apc(Min/+):Thbs1(-/-) versus Apc(Min/+) mice include altered amino acid and lipid metabolism, mitochondrial dysfunction, eicosanoids and ketone body formation. This metabolic profile suggests that the protective role of thrombospondin 1 to decrease adenoma formation in Apc(Min/+) mice results in part from improved mitochondrial function.

Are Limits of Concern a useful concept to improve the environmental risk assessment of GM plants?

PubMed

Dolezel, Marion; Miklau, Marianne; Heissenberger, Andreas; Reichenbecher, Wolfram

2017-01-01

The European Food Safety Authority (EFSA) has introduced a concept for the environmental risk assessment of genetically modified (GM) plants which foresees the definition of ecological threshold values defining acceptable adverse effects of the GM plant on the environment (Limits of Concern, LoC). We analysed the LoC concept by scrutinising its feasibility with regard to important aspects of the environmental risk assessment. We then considered its relationship with protection goals, the comparative safety assessment and the stepwise testing approach. We finally discussed its usefulness for assessing long-term effects, effects on non-target organisms and species of conservation concern. The LoC concept is a possible approach to introduce ecological thresholds into environmental risk assessment in order to evaluate environmental harm. However, the concept leaves many important aspects open. Thresholds for environmental harm for protection goals need spatial and temporal differentiation from LoCs used for ERA indicators. Regionalisation of LoCs must be provided for as biodiversity levels and protection goals vary across the EU. Further guidance is needed with respect to the consequences, in case LoCs are exceeded and a link needs to be established between environmentally relevant results from the comparative safety assessment and the LoC concept. LoCs for long-term effects have to be evaluated by long-term monitoring. LoCs for non-target organisms need to be discriminated according to the species and parameters assessed. The overall LoC concept is considered useful if LoCs are further specified and differentiated. Although LoCs will finally be determined by political decisions, they should be based on scientific grounds in order to increase confidence in the conclusions on the safety of GM plants.

Differential lung ventilation via tracheostomy using two endotracheal tubes in an infant: a case report.

PubMed

Demirkol, Demet; Ataman, Yasemin; Gündoğdu, Gökhan

2017-09-08

This case report presents differential lung ventilation in an infant. The aim is to define an alternative technique for performing differential lung ventilation in children. To the best of our knowledge, this is the first report of this kind. A 4.2-kg, 2.5-month-old Asian boy was referred to our facility with refractory hypoxemia and hypercarbia due to asymmetric lung disease with atelectasis of the left lung and hyperinflation of the right lung. He was unresponsive to conventional ventilator strategies; different ventilator settings were required. To perform differential lung ventilation, two separate single-lumen endotracheal tubes were inserted into the main bronchus of each lung by tracheotomy; the tracheal tubes were attached to discrete ventilators. The left lung was ventilated with a lung salvage strategy using high-frequency oscillatory ventilation, and the right lung was ventilated with a lung-protective strategy using pressure-regulated volume control mode. Differential lung ventilation was performed successfully with this technique without complications. Differential lung ventilation may be a lifesaving procedure in select patients who have asymmetric lung disease. Inserting two single-lumen endotracheal tubes via tracheotomy for differential lung ventilation can be an effective and safe alternative method.

Knockdown of SALL4 Protein Enhances All-trans Retinoic Acid-induced Cellular Differentiation in Acute Myeloid Leukemia Cells*

PubMed Central

Liu, Li; Liu, Liang; Leung, Lai-Han; Cooney, Austin J.; Chen, Changyi; Rosengart, Todd K.; Ma, Yupo; Yang, Jianchang

2015-01-01

All-trans retinoic acid (ATRA) is a differentiation agent that revolutionized the treatment of acute promyelocytic leukemia. However, it has not been useful for other types of acute myeloid leukemia (AML). Here we explored the effect of SALL4, a stem cell factor, on ATRA-induced AML differentiation in both ATRA-sensitive and ATRA-resistant AML cells. Aberrant SALL4 expression has been found in nearly all human AML cases, whereas, in normal bone marrow and peripheral blood cells, its expression is only restricted to hematopoietic stem/progenitor cells. We reason that, in AMLs, SALL4 activation may prevent cell differentiation and/or protect self-renewal that is seen in normal hematopoietic stem/progenitor cells. Indeed, our studies show that ATRA-mediated myeloid differentiation can be largely blocked by exogenous expression of SALL4, whereas ATRA plus SALL4 knockdown causes significantly increased AML differentiation and cell death. Mechanistic studies indicate that SALL4 directly associates with retinoic acid receptor α and modulates ATRA target gene expression. SALL4 is shown to recruit lysine-specific histone demethylase 1 (LSD1) to target genes and alter the histone methylation status. Furthermore, coinhibition of LSD1 and SALL4 plus ATRA treatment exhibited the strongest anti-AML effect. These findings suggest that SALL4 plays an unfavorable role in ATRA-based regimes, highlighting an important aspect of leukemia therapy. PMID:25737450

Female mice lacking active nadph-oxidase enzymes are protected against “western diet”--induced obesity and metabolic syndrome

USDA-ARS?s Scientific Manuscript database

NADPH oxidase (Nox) enzymes have been implicated in regulation of adipocyte differentiation and inflammation in a variety of tissues. We examined the effects of feeding AIN-93G or a “Western diet” (WD) (45% fat, 0.5% cholesterol) on development of obesity and “metabolic syndrome” in wild type (WT) m...

Studies of the Use of Electrochemical Impedance Spectroscopy to Characterize and Assess the Performance of Lacquers Used to Protect Aluminum Sheet and Can Ends

NASA Astrophysics Data System (ADS)

Ali, Mohammad

This study involved investigating the feasibility of using Electrochemical Impedance Spectroscopy to assess the performance of coatings used to protect aluminum in beverage containers, and developing an accelerated testing procedure. In the preliminary investigation, tests were performed to ensure that the EIS systems at hand are capable, functional and consistent. This was followed by EIS testing of kitchen-aluminum foil and high-impedance epoxy polymer as a baseline for chemically-active and chemically-inert systems. The ability of EIS to differentiate between intact and flawed coatings was tested by investigating deliberately damaged coatings. The effects of varying the pH and oxygen content on the performance of the coated aluminum samples were also tested. From this investigation, it has been concluded that EIS can be used to differentiate between intact and flawed coatings and detect corrosion before it is visually observable. Signatures of corrosion have been recorded and a preliminary testing procedure has been drawn.

miR-133a enhances the protective capacity of cardiac progenitors cells after myocardial infarction.

PubMed

Izarra, Alberto; Moscoso, Isabel; Levent, Elif; Cañón, Susana; Cerrada, Inmaculada; Díez-Juan, Antonio; Blanca, Vanessa; Núñez-Gil, Iván-J; Valiente, Iñigo; Ruíz-Sauri, Amparo; Sepúlveda, Pilar; Tiburcy, Malte; Zimmermann, Wolfram-H; Bernad, Antonio

2014-12-09

miR-133a and miR-1 are known as muscle-specific microRNAs that are involved in cardiac development and pathophysiology. We have shown that both miR-1 and miR-133a are early and progressively upregulated during in vitro cardiac differentiation of adult cardiac progenitor cells (CPCs), but only miR-133a expression was enhanced under in vitro oxidative stress. miR-1 was demonstrated to favor differentiation of CPCs, whereas miR-133a overexpression protected CPCs against cell death, targeting, among others, the proapoptotic genes Bim and Bmf. miR-133a-CPCs clearly improved cardiac function in a rat myocardial infarction model by reducing fibrosis and hypertrophy and increasing vascularization and cardiomyocyte proliferation. The beneficial effects of miR-133a-CPCs seem to correlate with the upregulated expression of several relevant paracrine factors and the plausible cooperative secretion of miR-133a via exosomal transport. Finally, an in vitro heart muscle model confirmed the antiapoptotic effects of miR-133a-CPCs, favoring the structuration and contractile functionality of the artificial tissue. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

miR-133a Enhances the Protective Capacity of Cardiac Progenitors Cells after Myocardial Infarction

PubMed Central

Izarra, Alberto; Moscoso, Isabel; Levent, Elif; Cañón, Susana; Cerrada, Inmaculada; Díez-Juan, Antonio; Blanca, Vanessa; Núñez-Gil, Iván-J.; Valiente, Iñigo; Ruíz-Sauri, Amparo; Sepúlveda, Pilar; Tiburcy, Malte; Zimmermann, Wolfram-H.; Bernad, Antonio

2014-01-01

Summary miR-133a and miR-1 are known as muscle-specific microRNAs that are involved in cardiac development and pathophysiology. We have shown that both miR-1 and miR-133a are early and progressively upregulated during in vitro cardiac differentiation of adult cardiac progenitor cells (CPCs), but only miR-133a expression was enhanced under in vitro oxidative stress. miR-1 was demonstrated to favor differentiation of CPCs, whereas miR-133a overexpression protected CPCs against cell death, targeting, among others, the proapoptotic genes Bim and Bmf. miR-133a-CPCs clearly improved cardiac function in a rat myocardial infarction model by reducing fibrosis and hypertrophy and increasing vascularization and cardiomyocyte proliferation. The beneficial effects of miR-133a-CPCs seem to correlate with the upregulated expression of several relevant paracrine factors and the plausible cooperative secretion of miR-133a via exosomal transport. Finally, an in vitro heart muscle model confirmed the antiapoptotic effects of miR-133a-CPCs, favoring the structuration and contractile functionality of the artificial tissue. PMID:25465869

Effects of Tithonia diversifolia (Hemsl.) A. Gray Extract on Adipocyte Differentiation of Human Mesenchymal Stem Cells

PubMed Central

Di Giacomo, Claudia; Vanella, Luca; Sorrenti, Valeria; Santangelo, Rosa; Barbagallo, Ignazio; Calabrese, Giovanna; Genovese, Carlo; Mastrojeni, Silvana; Ragusa, Salvatore; Acquaviva, Rosaria

2015-01-01

Tithonia diversifolia (Hemsl.) A. Gray (Asteraceae) is widely used in traditional medicine. There is increasing interest on the in vivo protective effects of natural compounds contained in plants against oxidative damage caused from reactive oxygen species. In the present study the total phenolic and flavonoid contents of aqueous, methanol and dichloromethane extracts of leaves of Tithonia diversifolia (Hemsl.) A. Gray were determined; furthermore, free radical scavenging capacity of each extract and the ability of these extracts to inhibit in vitro plasma lipid peroxidation were also evaluated. Since oxidative stress may be involved in trasformation of pre-adipocytes into adipocytes, to test the hypothesis that Tithonia extract may also affect adipocyte differentiation, human mesenchymal stem cell cultures were treated with Tithonia diversifolia aqueous extract and cell viability, free radical levels, Oil-Red O staining and western bolt analysis for heme oxygenase and 5'-adenosine monophoshate-activated protein kinase were carried out. Results obtained in the present study provide evidence that Tithonia diversifolia (Hemsl.) A. Gray exhibits interesting health promoting properties, resulting both from its free radical scavenger capacity and also by induction of protective cellular systems involved in cellular stress defenses and in adipogenesis of mesenchymal cells. PMID:25848759

Protection by [6]-shogaol against lipopolysaccharide-induced toxicity in murine astrocytes is related to production of brain-derived neurotrophic factor.

PubMed

Shim, Sehwan; Kim, Sokho; Kwon, Young-Bae; Kwon, Jungkee

2012-03-01

[6]-Shogaol has beneficial effects in spinal neuronal regeneration, but associated molecules and mechanisms are not identified. Neurotrophic factors, including brain-derived neurotrophic factor (BDNF), are associated with proliferation and differentiation of neuronal cells and exert a neuroprotective effect in neurodegenerative models. We investigated whether treatment with [6]-shogaol increases BDNF expression in lipopolysaccharide (LPS)-treated astrocytes, and examined the effect of [6]-shogaol on neuronal protection. [6]-Shogaol significantly attenuated the cell death induced by LPS. Western blotting showed that [6]-shogaol treatment reduced Bax expression and increased B-cell lymphoma (Bcl)-2 and BclxL expression in LPS-treated cells, consistent with the effects of BDNF treatment. Furthermore, K252a, a blocker of neurotrophic factors, attenuated the cellular protective effects of [6]-shogaol and BDNF. This study provides the first evidence that [6]-shogaol increases the expression of BDNF in LPS-treated astrocytes. Furthermore, these experimental results indicate that production of BDNF in astrocytes might be related to altered cell viability following [6]-shogaol treatment. Thus, the neuroprotective effects of [6]-shogaol is mediated by up-regulation of BDNF. Copyright © 2011 Elsevier Ltd. All rights reserved.

Massive Boson Production at Small qT in Soft-Collinear Effective Theory

NASA Astrophysics Data System (ADS)

Becher, Thomas; Neubert, Matthias; Wilhelm, Daniel

2013-01-01

We study the differential cross sections for electroweak gauge-boson and Higgs production at small and very small transverse-momentum qT. Large logarithms are resummed using soft-collinear effective theory. The collinear anomaly generates a non-perturbative scale q*, which protects the processes from receiving large long-distance hadronic contributions. A numerical comparison of our predictions with data on the transverse-momentum distribution in Z-boson production at the Tevatron and LHC is given.

Differential concentration-specific effects of caffeine on cell viability, oxidative stress, and cell cycle in pulmonary oxygen toxicity in vitro

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tiwari, Kirti Kumar; Chu, Chun; Couroucli, Xanthi

Highlights: • Caffeine at 0.05 mM decreases oxidative stress in hyperoxia. • Caffeine at 1 mM decreases cell viability, increases oxidative stress in hyperoxia. • Caffeine at 1 but not 0.05 mM, abrogates hyperoxia-induced G2/M arrest. - Abstract: Caffeine is used to prevent bronchopulmonary dysplasia (BPD) in premature neonates. Hyperoxia contributes to the development of BPD, inhibits cell proliferation and decreases cell survival. The mechanisms responsible for the protective effect of caffeine in pulmonary oxygen toxicity remain largely unknown. A549 and MLE 12 pulmonary epithelial cells were exposed to hyperoxia or maintained in room air, in the presence of differentmore » concentrations (0, 0.05, 0.1 and 1 mM) of caffeine. Caffeine had a differential concentration-specific effect on cell cycle progression, oxidative stress and viability, with 1 mM concentration being deleterious and 0.05 mM being protective. Reactive oxygen species (ROS) generation during hyperoxia was modulated by caffeine in a similar concentration-specific manner. Caffeine at 1 mM, but not at the 0.05 mM concentration decreased the G2 arrest in these cells. Taken together this study shows the novel funding that caffeine has a concentration-specific effect on cell cycle regulation, ROS generation, and cell survival in hyperoxic conditions.« less

Opposing Effects of Fasting Metabolism on Tissue Tolerance in Bacterial and Viral Inflammation

PubMed Central

Wang, Andrew; Huen, Sarah C.; Luan, Harding H.; Yu, Shuang; Zhang, Cuiling; Gallezot, Jean-Dominique; Booth, Carmen J.; Medzhitov, Ruslan

2017-01-01

Summary Acute infections are associated with a set of stereotypic behavioral responses, including anorexia, lethargy, and social withdrawal. Although these so called sickness behaviors are the most common and familiar symptoms of infections, their roles in host defense are largely unknown. Here we investigated the role of anorexia in models of bacterial and viral infections. We found that anorexia was protective while nutritional supplementation was detrimental in bacterial sepsis. Furthermore, glucose was necessary and sufficient for these effects. In contrast, nutritional supplementation protected against mortality from influenza infection and viral sepsis, while blocking glucose utilization was lethal. In both bacterial and viral models, these effects were largely independent of pathogen load and magnitude of inflammation. Instead, we identify opposing metabolic requirements tied to cellular stress adaptations critical for tolerance of differential inflammatory states. PMID:27610573

Effects of nucleotides on the denaturation of F actin: a differential scanning calorimetry and FTIR spectroscopy study.

PubMed

Bombardier, H; Wong, P; Gicquaud, C

1997-07-30

We have utilized DSC and high pressure FTIR spectroscopy to study the specificity and mechanism by which ATP protects actin against heat and pressure denaturation. Analysis of the thermograms shows that ATP raises the transition temperature Tm for actin from 69.6 to 75.8 degrees C, and the calorimetric enthalpy, deltaH, from 680 to 990 kJ/mole. Moreover, the peak becomes sharper indicating a more cooperative process. Among the other nucleotide triphosphates, only UTP increases the Tm by 2.5 degrees C, whereas GTP and CTP have negligable effects; ADP and AMP are less active, increasing the Tm by 2.1 and 1.6 degrees C, respectively. Therefore, gamma phosphate plays a key role in this protection, but its hydrolysis is not implicated since the nonhydrolysable analogue of ATP, ATP-PNP have the same activity as ATP. FTIR spectroscopy demonstrates that ATP also protects actin against high pressure denaturation. Analysis of the amide I band during the increase in pressure clearly illustrates that ATP protects particularly a region rich in beta-sheets of the actin molecule.

Protection of Primary Dopaminergic Midbrain Neurons by GPR139 Agonists Supports Different Mechanisms of MPP+ and Rotenone Toxicity

PubMed Central

Bayer Andersen, Kirsten; Leander Johansen, Jens; Hentzer, Morten; Smith, Garrick Paul; Dietz, Gunnar P. H.

2016-01-01

The G-protein coupled receptor 139 (GPR139) is expressed specifically in the brain in areas of relevance for motor control. GPR139 function and signal transduction pathways are elusive, and results in the literature are even contradictory. Here, we examined the potential neuroprotective effect of GPR139 agonism in primary culture models of dopaminergic (DA) neuronal degeneration. We find that in vitro GPR139 agonists protected primary mesencephalic DA neurons against 1-methyl-4-phenylpyridinium (MPP+)-mediated degeneration. Protection was concentration-dependent and could be blocked by a GPR139 antagonist. However, the protection of DA neurons was not found against rotenone or 6-hydroxydopamine (6-OHDA) mediated degeneration. Our results support differential mechanisms of toxicity for those substances commonly used in Parkinson’s disease (PD) models and potential for GPR139 agonists in neuroprotection. PMID:27445691

mSieve: Differential Behavioral Privacy in Time Series of Mobile Sensor Data.

PubMed

Saleheen, Nazir; Chakraborty, Supriyo; Ali, Nasir; Mahbubur Rahman, Md; Hossain, Syed Monowar; Bari, Rummana; Buder, Eugene; Srivastava, Mani; Kumar, Santosh

2016-09-01

Differential privacy concepts have been successfully used to protect anonymity of individuals in population-scale analysis. Sharing of mobile sensor data, especially physiological data, raise different privacy challenges, that of protecting private behaviors that can be revealed from time series of sensor data. Existing privacy mechanisms rely on noise addition and data perturbation. But the accuracy requirement on inferences drawn from physiological data, together with well-established limits within which these data values occur, render traditional privacy mechanisms inapplicable. In this work, we define a new behavioral privacy metric based on differential privacy and propose a novel data substitution mechanism to protect behavioral privacy. We evaluate the efficacy of our scheme using 660 hours of ECG, respiration, and activity data collected from 43 participants and demonstrate that it is possible to retain meaningful utility, in terms of inference accuracy (90%), while simultaneously preserving the privacy of sensitive behaviors.

mSieve: Differential Behavioral Privacy in Time Series of Mobile Sensor Data

PubMed Central

Saleheen, Nazir; Chakraborty, Supriyo; Ali, Nasir; Mahbubur Rahman, Md; Hossain, Syed Monowar; Bari, Rummana; Buder, Eugene; Srivastava, Mani; Kumar, Santosh

2016-01-01

Differential privacy concepts have been successfully used to protect anonymity of individuals in population-scale analysis. Sharing of mobile sensor data, especially physiological data, raise different privacy challenges, that of protecting private behaviors that can be revealed from time series of sensor data. Existing privacy mechanisms rely on noise addition and data perturbation. But the accuracy requirement on inferences drawn from physiological data, together with well-established limits within which these data values occur, render traditional privacy mechanisms inapplicable. In this work, we define a new behavioral privacy metric based on differential privacy and propose a novel data substitution mechanism to protect behavioral privacy. We evaluate the efficacy of our scheme using 660 hours of ECG, respiration, and activity data collected from 43 participants and demonstrate that it is possible to retain meaningful utility, in terms of inference accuracy (90%), while simultaneously preserving the privacy of sensitive behaviors. PMID:28058408

Live Attenuated Leishmania donovani Centrin Gene-Deleted Parasites Induce IL-23-Dependent IL-17-Protective Immune Response against Visceral Leishmaniasis in a Murine Model.

PubMed

Banerjee, Antara; Bhattacharya, Parna; Dagur, Pradeep K; Karmakar, Subir; Ismail, Nevien; Joshi, Amritanshu B; Akue, Adovi D; KuKuruga, Mark; McCoy, John Philip; Dey, Ranadhir; Nakhasi, Hira L

2018-01-01

No vaccine exists against visceral leishmaniasis. To develop effective vaccines, we have previously reported protective role of live attenuated centrin gene-deleted Leishmania donovani ( LdCen -/- ) parasites through induction of Th1 type immune response in mice, hamsters, and dogs. In this study, we specifically explored the role of Th17 cells in LdCen -/- -induced host protection in mice. Our results showed that compared with wild-type L. donovani infection, LdCen -/- parasites induce significantly higher expression of Th17 differentiation cytokines in splenic dendritic cells. There was also induction of IL-17 and its promoting cytokines in total splenocytes and in both CD4 and CD8 T cells following immunization with LdCen -/- Upon challenge with wild-type parasites, IL-17 and its differentiating cytokines were significantly higher in LdCen -/- -immunized mice compared with nonimmunized mice that resulted in parasite control. Alongside IL-17 induction, we observed induction of IFN-γ-producing Th1 cells as reported earlier. However, Th17 cells are generated before Th1 cells. Neutralization of either IL-17 or IFN-γ abrogated LdCen -/- -induced host protection further confirming the essential role of Th17 along with Th1 cytokines in host protection. Treatment with recombinant IL-23, which is required for stabilization and maintenance of IL-17, heightened Th17, and Tc17 responses in immunized mice splenocytes. In contrast, Th17 response was absent in immunized IL-23R -/- mice that failed to induce protection upon virulent Leishmania challenge suggesting that IL-23 plays an essential role in IL-17-mediated protection by LdCen -/- parasites. This study unveiled the role of IL-23-dependent IL-17 induction in LdCen -/- parasite-induced immunity and subsequent protection against visceral leishmaniasis.

Osteoblasts Protect AML Cells from SDF-1-Induced Apoptosis

PubMed Central

Kremer, Kimberly N.; Dudakovic, Amel; McGee-Lawrence, Meghan E.; Philips, Rachael L.; Hess, Allan D.; Smith, B. Douglas; van Wijnen, Andre J.; Karp, Judith E.; Kaufmann, Scott H.; Westendorf, Jennifer J.; Hedin, Karen E.

2014-01-01

The bone marrow provides a protective environment for acute myeloid leukemia (AML) cells that often allows leukemic stem cells to survive standard chemotherapeutic regimens. Targeting these leukemic stem cells within the bone marrow is critical for preventing relapse. We recently demonstrated that SDF-1, a chemokine abundant in the bone marrow, induces apoptosis in AML cell lines and in patient samples expressing high levels of its receptor, CXCR4. Here we show that a subset of osteoblast lineage cells within the bone marrow can protect AML cells from undergoing apoptosis in response to the SDF-1 naturally present in that location. In co-culture systems, osteoblasts at various stages of differentiation protected AML cell lines and patient isolates from SDF-1-induced apoptosis. The differentiation of the osteoblast cell lines, MC3T3 and W-20-17, mediated this protection via a cell contact-independent mechanism. In contrast, bone marrow-derived mesenchymal cells, the precursors of osteoblasts, induced apoptosis in AML cells via a CXCR4-dependent mechanism and failed to protect AML cells from exogenously added SDF-1. These results indicate that osteoblasts in the process of differentiation potently inhibit the SDF-1-driven apoptotic pathway of CXCR4-expressing AML cells residing in the bone marrow. Drugs targeting this protective mechanism could potentially provide a new approach to treating AML by enhancing the SDF-1-induced apoptosis of AML cells residing within the bone marrow microenvironment. PMID:24851270

Resveratrol Increases Osteoblast Differentiation In Vitro Independently of Inflammation.

PubMed

Ornstrup, Marie Juul; Harsløf, Torben; Sørensen, Lotte; Stenkjær, Liselotte; Langdahl, Bente Lomholt; Pedersen, Steen Bønløkke

2016-08-01

Low-grade inflammation negatively affects bone. Resveratrol is a natural compound proven to possess both anti-inflammatory and bone protective properties. However, it is uncertain if the bone effects are mediated though anti-inflammatory effects. Firstly, we investigated if resveratrol affects proliferation and differentiation of human bone marrow-derived mesenchymal stem cells. Secondly, we investigated if inflammation negatively affects proliferation and differentiation, and if resveratrol counteracts this through anti-inflammatory effects. Mesenchymal stem cells were obtained from bone marrow aspiration in 13 healthy individuals and cultured towards the osteoblast cell lineage. The cells were stimulated with resveratrol, lipopolysaccharide (LPS), LPS + resveratrol, or vehicle (control) for 21 days. Compared to control, resveratrol decreased cell number by 35 % (p < 0.05) and induced differentiation (a 3-fold increase in alkaline phosphatase (p < 0.002), while P1NP and OPG showed similar trends). LPS induced inflammation with a 44-fold increase in interleukin-6 (p < 0.05) and an extremely prominent increase in interleukin-8 production (p < 0.05) relative to control. In addition, LPS increased cell count (p < 0.05) and decreased differentiation (a reduction in P1NP production (p < 0.02)). Co-stimulation with LPS + resveratrol did not reduce interleukin-6 or interleukin-8, but nonetheless, cell count was reduced (p < 0.05) and alkaline phosphatase, P1NP, and OPG increased (p < 0.05 for all). Thus, resveratrol stimulates osteoblast differentiation independently of inflammation.

On the use of dexamethasone-loaded liposomes to induce the osteogenic differentiation of human mesenchymal stem cells.

PubMed

Monteiro, Nelson; Martins, Albino; Ribeiro, Diana; Faria, Susana; Fonseca, Nuno A; Moreira, João N; Reis, Rui L; Neves, Nuno M

2015-09-01

Stem cells have received considerable attention by the scientific community because of their potential for tissue engineering and regenerative medicine. The most frequently used method to promote their differentiation is supplementation of the in vitro culture medium with growth/differentiation factors (GDFs). The limitations of that strategy caused by the short half-life of GDFs limit its efficacy in vivo and consequently its clinical use. Thus, the development of new concepts that enable the bioactivity and bioavailability of GDFs to be protected, both in vitro and in vivo, is very relevant. Nanoparticle-based drug delivery systems can be injected, protect the GDFs and enable spatiotemporal release kinetics to be controlled. Liposomes are well-established nanodelivery devices presenting significant advantages, viz. a high load-carrying capacity, relative safety and easy production, and a versatile nature in terms of possible formulations and surface functionalization. The main objective of the present study was to optimize the formulation of liposomes to encapsulate dexamethasone (Dex). Our results showed that the optimized Dex-loaded liposomes do not have any cytotoxic effect on human bone marrow-derived mesenchymal stem cells (hBMSCs). More importantly, they were able to promote an earlier induction of differentiation of hBMSCs into the osteogenic lineage, as demonstrated by the expression of osteoblastic markers, both phenotypically and genotypically. We concluded that Dex-loaded liposomes represent a viable nanoparticle strategy with enhanced safety and efficacy for tissue engineering and regenerative medicine. Copyright © 2013 John Wiley & Sons, Ltd.

Interleukin-33/ST2 system attenuates aldosterone-induced adipogenesis and inflammation.

PubMed

Martínez-Martínez, Ernesto; Cachofeiro, Victoria; Rousseau, Elodie; Álvarez, Virginia; Calvier, Laurent; Fernández-Celis, Amaya; Leroy, Céline; Miana, María; Jurado-López, Raquel; Briones, Ana M; Jaisser, Frederic; Zannad, Faiez; Rossignol, Patrick; López-Andrés, Natalia

2015-08-15

Interleukin-33 (IL-33) but not soluble ST2 (sST2) exerts anti-inflammatory and protective effects in several tissues. Aldosterone, a proinflammatory mediator which promotes adipogenesis, is elevated in obese patients. The aim of this study was to investigate the interactions between IL-33/ST2 system and Aldosterone in adipose tissue. Rats fed a high fat diet presented increased sST2 expression, diminished IL-33/sST2 ratio and enhanced levels of differentiation and inflammation in adipose tissue as compared to controls. A similar pattern was observed in adipose tissue from C57BL/6 Aldosterone-treated mice. In both animal models, Aldosterone was correlated with sST2. Treatment of 3T3-L1 adipocytes with IL-33 delayed adipocyte differentiation diminished lipid accumulation and decreased inflammation. Aldosterone decreased IL-33 and increased sST2 expressions in differentiated adipocytes. Aldosterone-induced adipocyte differentiation and inflammation were blocked by IL-33 treatment, but sST2 did not exert any effects. The crosstalk between IL-33/ST2 and Aldosterone could be relevant in the metabolic consequences of obesity. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

The Effect of Chronic Kidney Disease on T Cell Alloimmunity

PubMed Central

Winterberg, Pamela D.; Ford, Mandy L.

2017-01-01

Purpose of review Altered differentiation and activation of T cell subsets occur in patients with CKD, but the impact on graft rejection and protective immunity during transplantation are not fully understood. Recent findings Patients with CKD have decreased frequency of naïve T cells, accumulation of activated, terminally differentiated memory cells, and skewed regulatory versus T helper 17 ratio. Naïve and memory T cell subsets do not appear to improve following kidney transplantation. Retained thymic output is associated with acute rejection, while naïve lymphopenia and accumulation of CD8+TEMRA cells correlate with long-term graft dysfunction. CD28null memory cells accumulate during CKD and appear to confer protection against acute rejection under standard immunosuppression and possibly co-stimulation blockade. T cells bearing CD57 are also increased in patients with CKD and may underlie rejection during co-stimulation blockade. Summary The mechanisms by which CKD alters the differentiation and activation status of T cell subsets is poorly understood. Further research is also needed to understand which cell populations mediate rejection under various immunosuppressive regimens. To date, there is little use of animal models of organ failure in transplant immunology research. CKD mouse models may help identify novel pathways and targets to better control alloimmunity in post-transplant. PMID:27926546

Differential expression of IGFBPs in Laron syndrome-derived lymphoblastoid cell lines: Potential correlation with reduced cancer incidence.

PubMed

Somri, Lina; Sarfstein, Rive; Lapkina-Gendler, Lena; Nagaraj, Karthik; Laron, Zvi; Bach, Leon A; Werner, Haim

2018-04-01

Laron syndrome (LS), or primary growth hormone (GH) insensitivity, is a growth disorder that results from mutation of the GH-receptor (GHR) gene leading to congenital insulin-like growth factor-1 (IGF-1) deficiency. Recent epidemiological studies have shown that LS patients are protected from cancer development. Genome-wide profiling identified genes and signaling pathways that are differentially represented in LS patients, and that may contribute to cancer protection. The present study was aimed at evaluating the hypothesis that IGF binding proteins (IGFBPs) are differentially expressed in LS, most probably as a result of low circulating levels of IGF-1. Furthermore, we postulated that IGFBPs might be differentially regulated by oxidative stress in this condition and, therefore, may contribute to cancer evasion. Our results show that IGFBP-3, which is predominantly protective, was highly expressed in LS-derived lymphoblastoid cells in comparison to control cells from the same ethnic group. On the other hand, levels of IGFBP-2, -4, -5, and -6 were diminished in LS patients, as demonstrated by RQ-PCR, Western immunoblots and confocal immunofluorescence. In addition, our data provide evidence for a pattern of IGFBP response to H 2 O 2 treatment that might be associated with distinct expression of apoptosis markers (BCL2, pro-caspase-9, pro-caspase-3) in LS. In summary, differential expression of specific IGFBPs in LS might be correlated with cellular mechanisms underlying cancer protection and, probably, additional phenotypes due to congenital IGF-1 deficiency. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cartilage Protective and Chondrogenic Capacity of WIN-34B, a New Herbal Agent, in the Collagenase-Induced Osteoarthritis Rabbit Model and in Progenitor Cells from Subchondral Bone

PubMed Central

Huh, Jeong-Eun; Park, Yeon-Cheol; Seo, Byung-Kwan; Lee, Jae-Dong; Baek, Yong-Hyeon; Choi, Do-Young; Park, Dong-Suk

2013-01-01

We sought to determine the cartilage repair capacity of WIN-34B in the collagenase-induced osteoarthritis rabbit model and in progenitor cells from subchondral bone. The cartilage protective effect of WIN-34B was measured by clinical and histological scores, cartilage area, and proteoglycan and collagen contents in the collagenase-induced osteoarthritis rabbit model. The efficacy of chondrogenic differentiation of WIN-34B was assessed by expression of CD105, CD73, type II collagen, and aggrecan in vivo and was analyzed by the surface markers of progenitor cells, the mRNA levels of chondrogenic marker genes, and the level of proteoglycan, GAG, and type II collagen in vitro. Oral administration of WIN-34B significantly increased cartilage area, and this was associated with the recovery of proteoglycan and collagen content. Moreover, WIN-34B at 200 mg/kg significantly increased the expression of CD105, CD73, type II collagen, and aggrecan compared to the vehicle group. WIN-34B markedly enhanced the chondrogenic differentiation of CD105 and type II collagen in the progenitor cells from subchondral bone. Also, we confirmed that treatment with WIN-34B strongly increased the number of SH-2(CD105) cells and expression type II collagen in subchondral progenitor cells. Moreover, WIN-34B significantly increased proteoglycan, as measured by alcian blue staining; the mRNA level of type II α1 collagen, cartilage link protein, and aggrecan; and the inhibition of cartilage matrix molecules, such as GAG and type II collagen, in IL-1β-treated progenitor cells. These findings suggest that WIN-34B could be a potential candidate for effective anti-osteoarthritic therapy with cartilage repair as well as cartilage protection via enhancement of chondrogenic differentiation in the collagenase-induced osteoarthritis rabbit model and progenitor cells from subchondral bone. PMID:23983790

Effect of restriction vegan diet's on muscle mass, oxidative status, and myocytes differentiation: A pilot study.

PubMed

Vanacore, Daniela; Messina, Giovanni; Lama, Stefania; Bitti, Giuseppe; Ambrosio, Pasqualina; Tenore, Giancarlo; Messina, Antonietta; Monda, Vincenzo; Zappavigna, Silvia; Boccellino, Mariarosaria; Novellino, Ettore; Monda, Marcellino; Stiuso, Paola

2018-01-10

This study was conceived to evaluate the effects of three different diets on body composition, metabolic parameters, and serum oxidative status. We enrolled three groups of healthy men (omnivores, vegetarians, and vegans) with similar age, weight and BMI, and we observed a significant decrease in muscle mass index and lean body mass in vegan compared to vegetarian and omnivore groups, and higher serum homocysteine levels in vegetarians and vegans compared to omnivores. We studied whether serum from omnivore, vegetarian, and vegan subjects affected oxidative stress, growth and differentiation of both cardiomyoblast cell line H9c2 and H-H9c2 (H9c2 treated with H 2 O 2 to induce oxidative damage). We demonstrated that vegan sera treatment of both H9c2 and H-H9c2 cells induced an increase of TBARS values and cell death and a decrease of free NO 2- compared to vegetarian and omnivorous sera. Afterwards, we investigated the protective effects of vegan, vegetarian, and omnivore sera on the morphological changes induced by H 2 O 2 in H9c2 cell line. We showed that the omnivorous sera had major antioxidant and differentiation properties compared to vegetarian and vegan sera. Finally, we evaluated the influence of the three different groups of sera on MAPKs pathway and our data suggested that ERK expression increased in H-H9c2 cells treated with vegetarian and vegan sera and could promote cell death. The results obtained in this study demonstrated that restrictive vegan diet could not prevent the onset of metabolic and cardiovascular diseases nor protect by oxidative damage. © 2018 Wiley Periodicals, Inc.

Oxidative Stress, Redox Regulation and Diseases of Cellular Differentiation

PubMed Central

Ye, Zhi-Wei; Zhang, Jie; Townsend, Danyelle M.; Tew, Kenneth D.

2015-01-01

Background Within cells, there is a narrow concentration threshold that governs whether reactive oxygen species (ROS) induce toxicity or act as second messengers. Scope of review We discuss current understanding of how ROS arise, facilitate cell signaling, cause toxicities and disease related to abnormal cell differentiation and those (primarily) sulfur based pathways that provide nucleophilicity to offset these effects. Primary conclusions Cellular redox homeostasis mediates a plethora of cellular pathways that determine life and death events. For example, ROS intersect with GSH based enzyme pathways to influence cell differentiation, a process integral to normal hematopoiesis, but also affecting a number of diverse cell differentiation related human diseases. Recent attempts to manage such pathologies have focused on intervening in some of these pathways, with the consequence that differentiation therapy targeting redox homeostasis has provided a platform for drug discovery and development. General Significance The balance between electrophilic oxidative stress and protective biomolecular nucleophiles predisposes the evolution of modern life forms. Imbalances of the two can produce aberrant redox homeostasis with resultant pathologies. Understanding the pathways involved provides opportunities to consider interventional strategies. PMID:25445706

Protection against renal ischemia-reperfusion injury through hormesis? Dietary intervention versus cold exposure.

PubMed

Shushimita, Shushimita; Grefhorst, Aldo; Steenbergen, Jacobie; de Bruin, Ron W F; Ijzermans, Jan N M; Themmen, Axel P N; Dor, Frank J M F

2016-01-01

Dietary restriction (DR) and fasting (FA) induce robust protection against the detrimental effects of renal ischemia-reperfusion injury (I/RI). Several mechanisms of protection have been proposed, such as hormesis. Hormesis is defined as a life-supporting beneficial effect resulting from the cellular responses to single or multiple rounds of (mild) stress. The cold exposure (CE) model is a stress model similar to DR, and has been shown to have hormetic effects and has proved to increase longevity. CE is considered to be the most robust method to increase metabolism through activation of brown adipocytes. BAT has been considered important in etiology of obesity and its metabolic consequences. Since DR, FA, and CE models are proposed to work through hormesis, we investigated physiology of adipose tissue and effect on BAT in these models and compared them to ad libitum (AL) fed mice. We also studied the differential effect of these stress models on immunological changes, and effect of CE on renal I/RI. We show similar physiological changes in adiposity in male C57Bl/6 mice due to DR, FA and CE, but the CE mice were not protected against renal I/RI. The immunophenotypic changes observed in the CE mice were similar to the AL animals, in contrast to FA mice, that showed major immunophenotypic changes in the B and T cell development stages in primary and secondary lymphoid organs. Our findings thus demonstrate that DR, FA and CE are hormetic stress models. DR and FA protect against renal I/IR, whereas CE could not. Copyright © 2015 Elsevier Inc. All rights reserved.

46 CFR 282.24 - Protection and indemnity insurance.

Code of Federal Regulations, 2011 CFR

2011-10-01

... differential. The adjustment of the wage percentage differential shall not be used for Japan, where operators incur minimal costs for deductible absorptions, rather than no costs. For Japan, the insurance related...

Caveolin and Proteasome in Tocotrienol Mediated Myocardial Protection

PubMed Central

Das, Manika; Das, Samarjit; Wang, Ping; Powell, Saul R.; Das, Dipak K.

2008-01-01

The effect of different isomers of tocotrienol was tested on myocardial ischemia reperfusion injury. Although all of the tocotrienol isomers offered some degree of cardioprotection, gamma-tocotrienol was the most protective as evident from the result of myocardial apoptosis. To study the mechanism of tocotrienol mediated cardioprotection, we examined the interaction and/or translocation of different signaling components to caveolins and activity of proteasome. The results suggest that differential interaction of MAP kinases with caveolin 1/3 in conjuncture with proteasome stabilization play a unique role in tocotrienol mediated cardioprotection possibly by altering the availability of pro-survival and anti-survival proteins. PMID:18769056

Cancer Risk-Assessment of Radiation Damage in Ataxia Telangiectasia Heterozygous Human Breast Epithelial Cell Cultures

NASA Technical Reports Server (NTRS)

Applewhite, Lisa C.

2002-01-01

This paper describes the study of the markers of cellular changes that are found during the onset of carcinogenesis. Several of the biological factors are markers of stress response, oncoprotein expression, and differentiation factors. Oxidative stress response agents such as heat shock proteins (HSPs) protect cells from oxidative stresses such as ionizing radiation. The onocoprotein HER-2/neu, a specific breast cancer marker, indicates early onset of cancer. Additional structural and morphogenetic markers of differentiation were considered in order to determine initial cellular changes at the initial onset of cancer. As an additional consideration, all-trans retinoic acid (RA), a differentiation agent, was considered because of its known role in regulating normal differentiation and inhibiting tumor proliferation via specific nuclear receptors. This paper discusses study and results of the preliminary analyses of gamma irradiation of AT heterozygous human breast epithelial cells (WH). Comparisons are also made of the effects various RA concentrations post-irradiation.

Early Adolescent Outcomes of Institutionally-Deprived and Non-Deprived Adoptees. II: Language as a Protective Factor and a Vulnerable Outcome

ERIC Educational Resources Information Center

Croft, Carla; Beckett, Celia; Rutter, Michael; Castle, Jenny; Colvert, Emma; Groothues, Christine; Hawkins, Amanda; Kreppner, Jana; Stevens, Suzanne E.; Sonuga-Barke, Edmund J. S.

2007-01-01

Background: There is uncertainty about the extent to which language skills are part of general intelligence and even more uncertainty on whether deprivation has differential effects on language and non-language skills. Methods: Language and cognitive outcomes at 6 and 11 years of age were compared between a sample of 132 institution-reared…

Bean α-amylase inhibitor 1 in transgenic peas (Pisum sativum) provides complete protection from pea weevil (Bruchus pisorum) under field conditions

PubMed Central

Morton, Roger L.; Schroeder, Hart E.; Bateman, Kaye S.; Chrispeels, Maarten J.; Armstrong, Eric; Higgins, Thomas J. V.

2000-01-01

Two α-amylase inhibitors, called αAI-1 and αAI-2, that share 78% amino acid sequence identity and have a differential specificity toward mammalian and insect α-amylases are present in different accessions of the common bean (Phaseolus vulgaris). Using greenhouse-grown transgenic peas (Pisum sativum), we have shown previously that expression of αAI-1 in pea seeds can provide complete protection against the pea weevil (Bruchus pisorum). Here, we report that αAI-1 also protects peas from the weevil under field conditions. The high degree of protection is explained by our finding that αAI-1 inhibits pea bruchid α-amylase by 80% over a broad pH range (pH 4.5–6.5). αAI-2, on the other hand, is a much less effective inhibitor of pea bruchid α-amylase, inhibiting the enzyme by only 40%, and only in the pH 4.0–4.5 range. Nevertheless, this inhibitor was still partially effective in protecting field-grown transgenic peas against pea weevils. The primary effect of αAI-2 appeared to be a delay in the maturation of the larvae. This contrasts with the effect of αAI-1, which results in larval mortality at the first or second instar. These results are discussed in relationship to the use of amylase inhibitors with different specificities to bring about protection of crops from their insect pests or to decrease insect pest populations below the economic injury level. PMID:10759552

TLR4 ligands lipopolysaccharide and monophosphoryl lipid a differentially regulate effector and memory CD8+ T Cell differentiation.

PubMed

Cui, Weiguo; Joshi, Nikhil S; Liu, Ying; Meng, Hailong; Kleinstein, Steven H; Kaech, Susan M

2014-05-01

Vaccines formulated with nonreplicating pathogens require adjuvants to help bolster immunogenicity. The role of adjuvants in Ab production has been well studied, but how they influence memory CD8(+) T cell differentiation remains poorly defined. In this study we implemented dendritic cell-mediated immunization to study the effects of commonly used adjuvants, TLR ligands, on effector and memory CD8(+) T cell differentiation in mice. Intriguingly, we found that the TLR4 ligand LPS was far more superior to other TLR ligands in generating memory CD8(+) T cells upon immunization. LPS boosted clonal expansion similar to the other adjuvants, but fewer of the activated CD8(+) T cells died during contraction, generating a larger pool of memory cells. Surprisingly, monophosphoryl lipid A (MPLA), another TLR4 ligand, enhanced clonal expansion of effector CD8(+) T cells, but it also promoted their terminal differentiation and contraction; thus, fewer memory CD8(+) T cells formed, and MPLA-primed animals were less protected against secondary infection compared with those primed with LPS. Furthermore, gene expression profiling revealed that LPS-primed effector cells displayed a stronger pro-memory gene expression signature, whereas the gene expression profile of MPLA-primed effector cells aligned closer with terminal effector CD8(+) T cells. Lastly, we demonstrated that the LPS-TLR4-derived "pro-memory" signals were MyD88, but not Toll/IL-1R domain-containing adapter inducing IFN-β, dependent. This study reveals the influential power of adjuvants on the quantity and quality of CD8(+) T cell memory, and that attention to adjuvant selection is crucial because boosting effector cell expansion may not always equate with more memory T cells or greater protection.

TLR4 ligands LPS and MPLA differentially regulate effector and memory CD8+ T cell differentiation

PubMed Central

Cui, Weiguo; Joshi, Nikhil S.; Liu, Ying; Meng, Hailong; Kleinstein, Steven H; Kaech, Susan M.

2014-01-01

Vaccines formulated with non-replicating pathogens require adjuvants to help bolster immunogenicity. The role of adjuvants in antibody production has been well studied, but how they influence memory CD8+ T cell differentiation remains poorly defined. Here we implemented dendritic cell (DC)-mediated immunization to study the effects of commonly used adjuvants, TLR ligands, on effector and memory CD8+ T cell differentiation in mice. Intriguingly, we found that the TLR4 ligand LPS was far more superior to other TLR ligands in generating memory CD8+ T cells upon immunization. LPS boosted clonal expansion similar to the other adjuvants, but fewer of the activated CD8+ T cells died during contraction, generating a larger pool of memory cells. Surprisingly, monophosphoryl lipid A (MPLA), another TLR4 ligand, enhanced clonal expansion of effector CD8+ T cells, but also promoted their terminal differentiation and contraction; thus, fewer memory CD8+ T cells formed and MPLA-primed animals were less protected against secondary infection compared to those primed with LPS. Furthermore, gene expression profiling revealed that LPS-primed effector cells displayed a stronger pro-memory gene expression signature, whereas the gene expression profile of MPLA-primed effector cells aligned closer with terminal effector CD8+ T cells. Lastly, we demonstrated that the LPS-TLR4-derived “pro-memory” signals were MyD88, but not Trif, dependent. This study reveals the influential power of adjuvants on the quantity and quality of CD8+ T cell memory, and that attention to adjuvant selection is crucial because boosting effector cell expansion may not always equate with more memory T cells or greater protection. PMID:24659688

Solvent effect on redox properties of hexanethiolate monolayer-protected gold nanoclusters.

PubMed

Su, Bin; Zhang, Meiqin; Shao, Yuanhua; Girault, Hubert H

2006-11-02

The capacitance of monolayer-protected gold nanoclusters (MPCs), C(MPC), in solution has been theoretically reconsidered from an electrostatic viewpoint, in which an MPC is considered as an isolated charged sphere within two dielectric layers, the intrinsic coating monolayer, and the bulk solvent. The model predicts that the bulk solvent provides an important contribution to C(MPC) and influences the redox properties of MPCs. This theoretical prediction is then examined experimentally by comparing the redox properties of MPCs in four organic solvents: 1,2-dichloroethane (DCE), dichloromethane (DCM), chlorobenzene (CB), and toluene (TOL), in all of which MPCs have excellent solubility. Furthermore, this set of organic solvents features a dielectric constant in a range from 10.37 (DCE) to 2.38 (TOL), which is wide enough to probe the solvent effect. In these organic solvents, tetrahexylammonium bis(trifluoromethylsulfonyl)imide (THATf2N) is used as the supporting electrolyte. Cyclic and differential pulse voltammetric results provide concrete evidence that, despite the monolayer protection, the solvent plays a significant effect on the properties of MPCs in solution.

Hormonal Contraceptives Differentially Suppress TFV and TAF Inhibition of HIV Infection and TFV-DP in Blood and Genital Tract CD4+ T cells.

PubMed

Shen, Zheng; Rodriguez-Garcia, Marta; Patel, Mickey V; Bodwell, Jack; Kashuba, Angela D M; Wira, Charles R

2017-12-18

HIV prevention research is focused on combining antiretrovirals (ARV) and progestin contraceptives to prevent HIV infection and pregnancy. The possibility that progestins compromise ARV anti-HIV activity prompted us to evaluate the effects of progestins on tenofovir (TFV) and TFV-alafenamide (TAF) on HIV infection and intracellular TFV-diphosphate (TFV-DP) concentrations in blood and genital CD4+ T cells. Following incubation of blood CD4+ T cells with TFV or TAF, Medroxyprogesterone acetate (MPA), but not Levonorgestrel, Norethisterone or progesterone, suppressed the anti-HIV effect of TFV by reducing intracellular TFV-DP, but had no effect on TAF inhibition of infection or TFV-DP. In contrast, with genital CD4+ T cells, MPA suppressed TAF inhibition of HIV infection and lowered of TFV-DP concentrations without affecting TFV protection. These findings demonstrate that MPA selectively compromises TFV and TAF protection in blood and genital CD4+ T cells and suggests that MPA may decrease ARV protection in individuals who use ARV intermittently for prevention.

Hesperetin Alleviates the Inhibitory Effects of High Glucose on the Osteoblastic Differentiation of Periodontal Ligament Stem Cells

PubMed Central

Kim, So Yeon; Lee, Jin-Yong; Park, Yong-Duk; Kang, Kyung Lhi; Lee, Jeong-Chae; Heo, Jung Sun

2013-01-01

Hesperetin (3′,5,7-trihydroxy-4-methoxyflavanone) is a metabolite of hesperidin (hesperetin-7-O-rutinoside), which belongs to the flavanone subgroup and is found mainly in citrus fruits. Hesperetin has been reported to be an effective osteoinductive compound in various in vivo and in vitro models. However, how hesperetin effects osteogenic differentiation is not fully understood. In this study, we investigated the capacity of hesperetin to stimulate the osteogenic differentiation of periodontal ligament stem cells (PDLSCs) and to relieve the anti-osteogenic effect of high glucose. Osteogenesis of PDLSCs was assessed by measurement of alkaline phosphatase (ALP) activity, and evaluation of the mRNA expression of ALP, runt-related gene 2 (Runx2), osterix (OSX), and FRA1 as osteogenic transcription factors, as well as assessment of protein expression of osteopontin (OPN) and collagen type IA (COLIA). When PDLSCs were exposed to a high concentration (30 mM) of glucose, osteogenic activity decreased compared to control cells. Hesperetin significantly increased ALP activity at doses of 1, 10, and 100 µM. Pretreatment of cells with hesperetin alleviated the high-glucose-induced suppression of the osteogenic activity of PDLSCs. Hesperetin scavenged intracellular reactive oxygen species (ROS) produced under high glucose condition. Furthermore, hesperetin increased the activity of the PI3K/Akt and β-catenin pathways. Consistent with this, blockage of Akt or β-catenin diminished the protective effect of hesperetin against high glucose-inhibited osteogenic differentiation. Collectively, our results suggest that hesperetin alleviates the high glucose-mediated suppression of osteogenic differentiation in PDLSCs by regulating ROS levels and the PI3K/Akt and β-catenin signaling pathways. PMID:23840726

TRANSCRIPTIONAL PROFILES FOR GLUTAMATE TRANSPORTERS REVEAL DIFFERENCES BETWEEN ORGANOPHOSPHATES BUT SIMILARITIES WITH UNRELATED NEUROTOXICANTS

PubMed Central

Slotkin, Theodore A.; Lobner, Doug; Seidler, Frederic J.

2010-01-01

The developmental neurotoxicity of organophosphates involves mechanisms other than their shared property as cholinesterase inhibitors, among which are excitotoxicity and oxidative stress. We used PC12 cells as a neurodevelopmental model to compare the effects of chlorpyrifos and diazinon on the expression of genes encoding glutamate transporters. Chlorpyrifos had a greater effect in cells undergoing nerve growth factor-induced neurodifferentiation as compared to undifferentiated PC12 cells, with peak sensitivity at the initiation of differentiation, reflecting a global upregulation of all the glutamate transporter genes expressed in this cell line. In differentiating cells, chlorpyrifos had a significantly greater effect than did diazinon and concordance analysis indicated no resemblance in their expression patterns. At the same time, the smaller effects of diazinon were highly concordant with those of an organochlorine pesticide (dieldrin) and a metal (divalent nickel). We also performed similar evaluations for the cystine/glutamate exchanger, which provides protection against oxidative stress by moving cystine into the cell; again, chlorpyrifos had the greatest effect, in this case reducing expression in undifferentiated and differentiating cells. Our results point to excitotoxicity and oxidative stress as major contributors to the noncholinesterase mechanisms that distinguish the neurodevelopmental outcomes betweem different organophosphates while providing a means whereby apparently unrelated neurotoxicants may produce similar outcomes. PMID:20600679

Physical basis of radiation protection in space travel

NASA Astrophysics Data System (ADS)

Durante, Marco; Cucinotta, Francis A.

2011-10-01

The health risks of space radiation are arguably the most serious challenge to space exploration, possibly preventing these missions due to safety concerns or increasing their costs to amounts beyond what would be acceptable. Radiation in space is substantially different from Earth: high-energy (E) and charge (Z) particles (HZE) provide the main contribution to the equivalent dose in deep space, whereas γ rays and low-energy α particles are major contributors on Earth. This difference causes a high uncertainty on the estimated radiation health risk (including cancer and noncancer effects), and makes protection extremely difficult. In fact, shielding is very difficult in space: the very high energy of the cosmic rays and the severe mass constraints in spaceflight represent a serious hindrance to effective shielding. Here the physical basis of space radiation protection is described, including the most recent achievements in space radiation transport codes and shielding approaches. Although deterministic and Monte Carlo transport codes can now describe well the interaction of cosmic rays with matter, more accurate double-differential nuclear cross sections are needed to improve the codes. Energy deposition in biological molecules and related effects should also be developed to achieve accurate risk models for long-term exploratory missions. Passive shielding can be effective for solar particle events; however, it is limited for galactic cosmic rays (GCR). Active shielding would have to overcome challenging technical hurdles to protect against GCR. Thus, improved risk assessment and genetic and biomedical approaches are a more likely solution to GCR radiation protection issues.

Assessment of the potential activity of major dietary compounds as selective estrogen receptor modulators in two distinct cell models for proliferation and differentiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lecomte, Sylvain; Lelong, Marie; Bourgine, Gaëlle

Estrogen receptors (ERs) α and β are distributed in most tissues of women and men. ERs are bound by estradiol (E2), a natural hormone, and mediate the pleiotropic and tissue-specific effects of E2, such as proliferation of breast epithelial cells or protection and differentiation of neuronal cells. Numerous environmental molecules, called endocrine disrupting compounds, also interact with ERs. Phytoestrogens belong to this large family and are considered potent therapeutic molecules that act through their selective estrogen receptor modulator (SERM) activity. Using breast cancer cell lines as a model of estrogen-dependent proliferation and a stably ER-expressing PC12 cell line as amore » model of neuronal differentiating cells, we studied the SERM activity of major dietary compounds, such as apigenin, liquiritigenin, daidzein, genistein, coumestrol, resveratrol and zearalenone. The ability of these compounds to induce ER-transactivation and breast cancer cell proliferation and enhance Nerve Growth Factor (NGF) -induced neuritogenesis was assessed. Surprisingly, although all compounds were able to activate the ER through an estrogen responsive element reporter gene, they showed differential activity toward proliferation or differentiation. Apigenin and resveratrol showed a partial or no proliferative effect on breast cancer cells but fully contributed to the neuritogenesis effect of NGF. However, daidzein and zearalenone showed full effects on cellular proliferation but did not induce cellular differentiation. In summary, our results suggest that the therapeutic potential of phytoestrogens can diverge depending on the molecule and the phenotype considered. Hence, apigenin and resveratrol might be used in the development of therapeutics for breast cancer and brain diseases. - Highlights: • SERM activity of dietary compounds on proliferation and differentiation is studied. • All the dietary compounds tested transactivate estrogen receptors. • Apigenin and resveratrol could be good candidates for future therapeutics. • Daidzein and zearalenone are to be avoided to maintain human health.« less

SNJ-1945, a calpain inhibitor, protects SH-SY5Y cells against MPP(+) and rotenone.

PubMed

Knaryan, Varduhi H; Samantaray, Supriti; Park, Sookyoung; Azuma, Mitsuyoshi; Inoue, Jun; Banik, Naren L

2014-07-01

Complex pathophysiology of Parkinson's disease involves multiple CNS cell types. Degeneration in spinal cord neurons alongside brain has been shown to be involved in Parkinson's disease and evidenced in experimental parkinsonism. However, the mechanisms of these degenerative pathways are not well understood. To unravel these mechanisms SH-SY5Y neuroblastoma cells were differentiated into dopaminergic and cholinergic phenotypes, respectively, and used as cell culture model following exposure to two parkinsonian neurotoxicants MPP(+) and rotenone. SNJ-1945, a cell-permeable calpain inhibitor was tested for its neuroprotective efficacy. MPP(+) and rotenone dose-dependently elevated the levels of intracellular free Ca(2+) and induced a concomitant rise in the levels of active calpain. SNJ-1945 pre-treatment significantly protected cell viability and preserved cellular morphology following MPP(+) and rotenone exposure. The neurotoxicants elevated the levels of reactive oxygen species more profoundly in SH-SY5Y cells differentiated into dopaminergic phenotype, and this effect could be attenuated with SNJ-1945 pre-treatment. In contrast, significant levels of inflammatory mediators cyclooxygenase-2 (Cox-2 and cleaved p10 fragment of caspase-1) were up-regulated in the cholinergic phenotype, which could be dose-dependently attenuated by the calpain inhibitor. Overall, SNJ-1945 was efficacious against MPP(+) or rotenone-induced reactive oxygen species generation, inflammatory mediators, and proteolysis. A post-treatment regimen of SNJ-1945 was also examined in cells and partial protection was attained with calpain inhibitor administration 1-3 h after exposure to MPP(+) or rotenone. Taken together, these results indicate that calpain inhibition is a valid target for protection against parkinsonian neurotoxicants, and SNJ-1945 is an efficacious calpain inhibitor in this context. SH-SY5Y cells, differentiated as dopaminergic (TH positive) and cholinergic (ChAT positive), were used as in vitro models for Parkinson's disease. MPP+ and rotenone induced up-regulation of calpain, expression, and activity as a common mechanism of neurodegeneration. SNJ-1945, a novel calpain inhibitor, protected both the cell phenotypes against MPP+ and rotenone. © 2013 International Society for Neurochemistry.

Nicotinamide N-methyltransferase expression in SH-SY5Y neuroblastoma and N27 mesencephalic neurones induces changes in cell morphology via ephrin-B2 and Akt signalling

PubMed Central

Thomas, M G; Saldanha, M; Mistry, R J; Dexter, D T; Ramsden, D B; Parsons, R B

2013-01-01

Nicotinamide N-methyltransferase (NNMT, E.C. 2.1.1.1) N-methylates nicotinamide to produce 1-methylnicotinamide (MeN). We have previously shown that NNMT expression protected against neurotoxin-mediated cell death by increasing Complex I (CxI) activity, resulting in increased ATP synthesis. This was mediated via protection of the NDUFS3 subunit of CxI from degradation by increased MeN production. In the present study, we have investigated the effects of NNMT expression on neurone morphology and differentiation. Expression of NNMT in SH-SY5Y human neuroblastoma and N27 rat mesencephalic dopaminergic neurones increased neurite branching, synaptophysin expression and dopamine accumulation and release. siRNA gene silencing of ephrin B2 (EFNB2), and inhibition of Akt phosphorylation using LY294002, demonstrated that their sequential activation was responsible for the increases observed. Incubation of SH-SY5Y with increasing concentrations of MeN also increased neurite branching, suggesting that the effects of NNMT may be mediated by MeN. NNMT had no significant effect on the expression of phenotypic and post-mitotic markers, suggesting that NNMT is not involved in determining phenotypic fate or differentiation status. These results demonstrate that NNMT expression regulates neurone morphology in vitro via the sequential activation of the EFNB2 and Akt cellular signalling pathways. PMID:23764850

Nicotinamide N-methyltransferase expression in SH-SY5Y neuroblastoma and N27 mesencephalic neurones induces changes in cell morphology via ephrin-B2 and Akt signalling.

PubMed

Thomas, M G; Saldanha, M; Mistry, R J; Dexter, D T; Ramsden, D B; Parsons, R B

2013-06-13

Nicotinamide N-methyltransferase (NNMT, E.C. 2.1.1.1) N-methylates nicotinamide to produce 1-methylnicotinamide (MeN). We have previously shown that NNMT expression protected against neurotoxin-mediated cell death by increasing Complex I (CxI) activity, resulting in increased ATP synthesis. This was mediated via protection of the NDUFS3 subunit of CxI from degradation by increased MeN production. In the present study, we have investigated the effects of NNMT expression on neurone morphology and differentiation. Expression of NNMT in SH-SY5Y human neuroblastoma and N27 rat mesencephalic dopaminergic neurones increased neurite branching, synaptophysin expression and dopamine accumulation and release. siRNA gene silencing of ephrin B2 (EFNB2), and inhibition of Akt phosphorylation using LY294002, demonstrated that their sequential activation was responsible for the increases observed. Incubation of SH-SY5Y with increasing concentrations of MeN also increased neurite branching, suggesting that the effects of NNMT may be mediated by MeN. NNMT had no significant effect on the expression of phenotypic and post-mitotic markers, suggesting that NNMT is not involved in determining phenotypic fate or differentiation status. These results demonstrate that NNMT expression regulates neurone morphology in vitro via the sequential activation of the EFNB2 and Akt cellular signalling pathways.

Protecting Mammalian Hair Cells from Aminoglycoside-Toxicity: Assessing Phenoxybenzamine's Potential.

PubMed

Majumder, Paromita; Moore, Paulette A; Richardson, Guy P; Gale, Jonathan E

2017-01-01

Aminoglycosides (AGs) are widely used antibiotics because of their low cost and high efficacy against gram-negative bacterial infection. However, AGs are ototoxic, causing the death of sensory hair cells in the inner ear. Strategies aimed at developing or discovering agents that protect against aminoglycoside ototoxicity have focused on inhibiting apoptosis or more recently, on preventing antibiotic uptake by the hair cells. Recent screens for ototoprotective compounds using the larval zebrafish lateral line identified phenoxybenzamine as a potential protectant for aminoglycoside-induced hair cell death. Here we used live imaging of FM1-43 uptake as a proxy for aminoglycoside entry, combined with hair-cell death assays to evaluate whether phenoxybenzamine can protect mammalian cochlear hair cells from the deleterious effects of the aminoglycoside antibiotic neomycin. We show that phenoxybenzamine can block FM1-43 entry into mammalian hair cells in a reversible and dose-dependent manner, but pre-incubation is required for maximal inhibition of entry. We observed differential effects of phenoxybenzamine on FM1-43 uptake in the two different types of cochlear hair cell in mammals, the outer hair cells (OHCs) and inner hair cells (IHCs). The requirement for pre-incubation and reversibility suggests an intracellular rather than an extracellular site of action for phenoxybenzamine. We also tested the efficacy of phenoxybenzamine as an otoprotective agent. In mouse cochlear explants the hair cell death resulting from 24 h exposure to neomycin was steeply dose-dependent, with 50% cell death occurring at ~230 μM for both IHC and OHC. We used 250 μM neomycin in subsequent hair-cell death assays. At 100 μM with 1 h pre-incubation, phenoxybenzamine conferred significant protection to both IHCs and OHCs, however at higher concentrations phenoxybenzamine itself showed clear signs of ototoxicity and an additive toxic effect when combined with neomycin. These data do not support the use of phenoxybenzamine as a therapeutic agent in mammalian inner ear. Our findings do share parallels with the observations from the zebrafish lateral line model but they also highlight the necessity for validation in the mammalian system and the potential for differential effects on sensory hair cells from different species, in different systems and even between cells in the same organ.

Elucidating the Role of CD84 and AHR in Modulation of LPS-Induced Cytokines Production by Cruciferous Vegetable-Derived Compounds Indole-3-Carbinol and 3,3′-Diindolylmethane

PubMed Central

Wang, Thomas T. Y.; Pham, Quynhchi; Kim, Young S.

2018-01-01

Modulation of the immune system by cancer protective food bioactives has preventive and therapeutic importance in prostate cancer, but the mechanisms remain largely unclear. The current study tests the hypothesis that the diet-derived cancer protective compounds, indole-3-carbinol (I3C) and 3,3′-diindolylmethane (DIM), affect the tumor microenvironment by regulation of inflammatory responses in monocytes and macrophages. We also ask whether I3C and DIM act through the aryl hydrocarbon (AHR)-dependent pathway or the signaling lymphocyte activation molecule (SLAM) family protein CD84-mediated pathway. The effect of I3C and DIM was examined using the human THP-1 monocytic cell in its un-differentiated (monocyte) and differentiated (macrophage) state. We observed that I3C and DIM inhibited lipopolysaccharide (LPS) induction of IL-1β mRNA and protein in the monocyte form but not the macrophage form of THP-1. Interestingly, CD84 mRNA but not protein was inhibited by I3C and DIM. AHR siRNA knockdown experiments confirmed that the inhibitory effects of I3C and DIM on IL-1β as well as CD84 mRNA are regulated through AHR-mediated pathways. Additionally, the AHR ligand appeared to differentially regulate other LPS-induced cytokines expression. Hence, cross-talk between AHR and inflammation-mediated pathways, but not CD84-mediated pathways, in monocytes but not macrophages may contribute to the modulation of tumor environments by I3C and DIM in prostate cancer. PMID:29364159

Role of Th17 Cell in Tubercle Bacillus Infection

NASA Astrophysics Data System (ADS)

Zhang, Dandan

2018-01-01

Tuberculosis is mainly a kind of lung disease. Normal immune cell expression can inhibit proliferation of tubercle bacillus in the lungs, but this may also lead to chronic inflammation and pathological lesion. Th17 cell is a newly discovered CD4 + effector T cell subsets, whose differentiation and roles are influenced by various cytokines in the surrounding environment. Th17 cell plays an important role in resisting tubercle bacillus infection, but also it may cause pathological damage through the inflammatory response. Therefore, to balance two kinds of roles of Th17 cells in tubercle bacillus infection can effectively protect the body. This paper intends to do a summary on differentiation, regulation, and biological functions of Th17 cell.

Implications of heterogeneous impacts of protected areas on deforestation and poverty

PubMed Central

Hanauer, Merlin M.; Canavire-Bacarreza, Gustavo

2015-01-01

Protected areas are a popular policy instrument in the global fight against loss of biodiversity and ecosystem services. However, the effectiveness of protected areas in preventing deforestation, and their impacts on poverty, are not well understood. Recent studies have found that Bolivia's protected-area system, on average, reduced deforestation and poverty. We implement several non-parametric and semi-parametric econometric estimators to characterize the heterogeneity in Bolivia's protected-area impacts on joint deforestation and poverty outcomes across a number of socioeconomic and biophysical moderators. Like previous studies from Costa Rica and Thailand, we find that Bolivia's protected areas are not associated with poverty traps. Our results also indicate that protection did not have a differential impact on indigenous populations. However, results from new multidimensional non-parametric estimators provide evidence that the biophysical characteristics associated with the greatest avoided deforestation are the characteristics associated with the potential for poverty exacerbation from protection. We demonstrate that these results would not be identified using the methods implemented in previous studies. Thus, this study provides valuable practical information on the impacts of Bolivia's protected areas for conservation practitioners and demonstrates methods that are likely to be valuable to researchers interested in better understanding the heterogeneity in conservation impacts. PMID:26460125

Implications of heterogeneous impacts of protected areas on deforestation and poverty.

PubMed

Hanauer, Merlin M; Canavire-Bacarreza, Gustavo

2015-11-05

Protected areas are a popular policy instrument in the global fight against loss of biodiversity and ecosystem services. However, the effectiveness of protected areas in preventing deforestation, and their impacts on poverty, are not well understood. Recent studies have found that Bolivia's protected-area system, on average, reduced deforestation and poverty. We implement several non-parametric and semi-parametric econometric estimators to characterize the heterogeneity in Bolivia's protected-area impacts on joint deforestation and poverty outcomes across a number of socioeconomic and biophysical moderators. Like previous studies from Costa Rica and Thailand, we find that Bolivia's protected areas are not associated with poverty traps. Our results also indicate that protection did not have a differential impact on indigenous populations. However, results from new multidimensional non-parametric estimators provide evidence that the biophysical characteristics associated with the greatest avoided deforestation are the characteristics associated with the potential for poverty exacerbation from protection. We demonstrate that these results would not be identified using the methods implemented in previous studies. Thus, this study provides valuable practical information on the impacts of Bolivia's protected areas for conservation practitioners and demonstrates methods that are likely to be valuable to researchers interested in better understanding the heterogeneity in conservation impacts. © 2015 The Author(s).

Organization of food protection behavior is differentially influenced by 192 IgG-saporin lesions of either the medial septum or the nucleus basalis magnocellularis

PubMed Central

Martin, Megan M.; Winter, Shawn S.; Cheatwood, Joseph L.; Carter, Lynniece A.; Jones, Jeana L.; Weathered, Scott L.; Wagner, Steven J.; Wallace, Douglas G.

2008-01-01

Converging lines of evidence have supported a role for the nucleus basalis magnocellularis (NB) in attentional mechanisms; however, debate continues regarding the role of the medial septum in behavior (MS). Recent studies have supported a role for the septohippocampal system in the online processing of internally generated cues. The current study was designed to investigate a possible double dissociation in rat food protection behavior, a natural behavior that has been shown to depend on external and internal sources of information. The study examined the effects of intraparenchymal injections of 192 IgG-saporin into either the MS or NB on the organization of food protection behavior. NB cholinergic lesions reduced the number of successful food protection behaviors while sparing the temporal organization of food protection behavior. In contrast, MS cholinergic lesions disrupted the temporal organization of food protection behavior while sparing the ability to successfully protect food items. These observations are consistent with a double dissociation of NB and MS cholinergic systems' contributions to processing external and internal sources of information and provide further evidence for the septohippocampal system's involvement in processing internally generated cues. PMID:18823954

Rebamipide alleviates radiation-induced colitis through improvement of goblet cell differentiation in mice.

PubMed

Jang, Hyosun; Park, Sunhoo; Lee, Janet; Myung, Jae Kyung; Jang, Won-Suk; Lee, Sun-Joo; Myung, Hyunwook; Lee, Changsun; Kim, Hyewon; Lee, Seung-Sook; Jin, Young-Woo; Shim, Sehwan

2018-04-01

Radiation-induced colitis is a common clinical problem associated with radiotherapy and accidental exposure to ionizing radiation. Goblet cells play a pivotal role in the intestinal barrier against pathogenic bacteria. Rebamipide, an anti-gastric ulcer drug, has the effects to promote goblet cell proliferation. The aim of this study was to investigate whether radiation-induced colonic injury could be alleviated by rebamipide. This study orally administered rebamipide for 6 days to mice, which were subjected to 13 Gy abdominal irradiation, to evaluate the therapeutic effects of rebamipide against radiation-induced colitis. To confirm the effects of rebamipide on irradiated colonic epithelial cells, this study used the HT29 cell line. Rebamipide clearly alleviated the acute radiation-induced colitis, as reflected by the histopathological data, and significantly increased the number of goblet cells. The drug also inhibited intestinal inflammation and protected from bacterial translocation during acute radiation-induced colitis. Furthermore, rebamipide significantly increased mucin 2 expression in both the irradiated mouse colon and human colonic epithelial cells. Additionally, rebamipide accelerated not only the recovery of defective tight junctions but also the differentiation of impaired goblet cells in an irradiated colonic epithelium, which indicates that rebamipide has beneficial effects on the colon. Rebamipide is a therapeutic candidate for radiation-induced colitis, owing to its ability to inhibit inflammation and protect the colonic epithelial barrier. © 2017 The Authors Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Phenotypic and Functional Characterization of Herpes Simplex Virus Glycoprotein B Epitope-Specific Effector and Memory CD8+ T Cells from Symptomatic and Asymptomatic Individuals with Ocular Herpes

PubMed Central

Khan, Arif A.; Srivastava, Ruchi; Spencer, Doran; Garg, Sumit; Fremgen, Daniel; Vahed, Hawa; Lopes, Patricia P.; Pham, Thanh T.; Hewett, Charlie; Kuang, Jasmine; Ong, Nicolas; Huang, Lei; Scarfone, Vanessa M.; Nesburn, Anthony B.

2015-01-01

ABSTRACT Herpes simplex virus 1 (HSV-1) glycoprotein B (gB)-specific CD8+ T cells protect mice from herpes infection and disease. However, whether and which HSV-1 gB-specific CD8+ T cells play a key role in the “natural” protection seen in HSV-1-seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical herpes disease) remain to be determined. In this study, we have dissected the phenotypes and the functions of HSV-1 gB-specific CD8+ T cells from HLA-A*02:01 positive, HSV-1 seropositive ASYMP and symptomatic (SYMP) individuals (with a history of numerous episodes of recurrent ocular herpes disease). We found the following. (i) Healthy ASYMP individuals maintained a significantly higher proportion of differentiated HSV-1 gB-specific effector memory CD8+ T cells (TEM cells) (CD45RAlow CCR7low CD44high CD62Llow). In contrast, SYMP patients had frequent less-differentiated central memory CD8+ T cells (TCM cells) (CD45RAlow CCR7high CD44low CD62Lhigh). (ii) ASYMP individuals had significantly higher proportions of multifunctional effector CD8+ T cells which responded mainly to gB342–350 and gB561–569 “ASYMP” epitopes, and simultaneously produced IFN-γ, CD107a/b, granzyme B, and perforin. In contrast, effector CD8+ T cells from SYMP individuals were mostly monofunctional and were directed mainly against nonoverlapping gB17–25 and gB183–191 “SYMP” epitopes. (iii) Immunization of an HLA-A*02:01 transgenic mouse model of ocular herpes with “ASYMP” CD8+ TEM cell epitopes, but not with “SYMP” CD8+ TCM cell epitopes, induced a strong CD8+ T cell-dependent protective immunity against ocular herpes infection and disease. Our findings provide insights into the role of HSV-specific CD8+ TEM cells in protection against herpes and should be considered in the development of an effective vaccine. IMPORTANCE A significantly higher proportion of differentiated and multifunctional HSV-1 gB-specific effector memory CD8+ T cells (TEM cells) (CD45RAlow CCR7low CD44high CD62Llow) were found in healthy ASYMP individuals who are seropositive for HSV-1 but never had any recurrent herpetic disease, while there were frequent less-differentiated and monofunctional central memory CD8+ T cells (TCM cells) (CD45RAlow CCR7high CD44low CD62Lhigh) in SYMP patients. Immunization with “ASYMP” CD8+ TEM cell epitopes, but not with “SYMP” CD8+ TCM cell epitopes, induced a strong protective HSV-specific CD8+ T cell response in HLA-A*02:01 transgenic mice. These findings are important for the development of a safe and effective T cell-based herpes vaccine. PMID:25609800

Differential TCR signals for T helper cell programming.

PubMed

Morel, Penelope A

2018-05-02

Upon encounter with their cognate antigen naïve CD4 T cells become activated and are induced to differentiate into several possible T helper (Th) cell subsets. This differentiation depends on a number of factors including antigen presenting cells, cytokines and costimulatory molecules. The strength of the T cell receptor (TCR) signal, related to the affinity of TCR for antigen and antigen dose, has emerged as a dominant factor in determining Th cell fate. Recent studies have revealed that TCR signals of high or low strength do not simply induce quantitatively different signals in the T cells, but rather qualitatively distinct pathways can be induced based on TCR signal strength. This review examines the recent literature in this area and highlights important new developments in our understanding of Th cell differentiation and TCR signal strength. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Genetic and environmental overlap between borderline personality disorder traits and psychopathy: evidence for promotive effects of factor 2 and protective effects of factor 1.

PubMed

Hunt, E; Bornovalova, M A; Patrick, C J

2015-05-01

Previous studies have reported strong genetic and environmental overlap between antisocial-externalizing (factor 2; F2) features of psychopathy and borderline personality disorder (BPD) tendencies. However, this line of research has yet to examine etiological associations of affective-interpersonal (factor 1, F1) features of psychopathy with BPD tendencies. The current study investigated differential phenotypic and genetic overlap of psychopathy factors 1 and 2 with BPD tendencies in a sample of over 250 male and female community-recruited adult twin pairs. Consistent with previous research, biometric analyses revealed strong genetic and non-shared environmental correlations of F2 with BPD tendencies, suggesting that common genetic and non-shared environmental factors contribute to both phenotypes. In contrast, negative genetic and non-shared environmental correlations were observed between F1 and BPD tendencies, indicating that the genetic factors underlying F1 serve as protective factors against BPD. No gender differences emerged in the analyses. These findings provide further insight into associations of psychopathic features - F1 as well as F2 - and BPD tendencies. Implications for treatment and intervention are discussed, along with how psychopathic traits may differentially influence the manifestation of BPD tendencies.

Differential Response: What to Make of the Existing Research? A Response to Hughes et al.

ERIC Educational Resources Information Center

Drake, Brett

2013-01-01

This article is a response to "Issues in Differential Response", a review of the current evidence pertaining to differential response (DR) programs in child protective services (CPS). In my view, the Hughes, Rycus, Saunders-Adams, Hughes, and Hughes article suffers from several weaknesses. First, DR programs are critiqued as if they were…

Hydrogen gas treatment prolongs replicative lifespan of bone marrow multipotential stromal cells in vitro while preserving differentiation and paracrine potentials.

PubMed

Kawasaki, Haruhisa; Guan, Jianjun; Tamama, Kenichi

2010-07-02

Cell therapy with bone marrow multipotential stromal cells/mesenchymal stem cells (MSCs) represents a promising approach in the field of regenerative medicine. Low frequency of MSCs in adult bone marrow necessitates ex vivo expansion of MSCs after harvest; however, such a manipulation causes cellular senescence with loss of differentiation, proliferative, and therapeutic potentials of MSCs. Hydrogen molecules have been shown to exert organ protective effects through selective reduction of hydroxyl radicals. As oxidative stress is one of the key insults promoting cell senescence in vivo as well as in vitro, we hypothesized that hydrogen molecules prevent senescent process during MSC expansion. Addition of 3% hydrogen gas enhanced preservation of colony forming early progenitor cells within MSC preparation and prolonged the in vitro replicative lifespan of MSCs without losing differentiation potentials and paracrine capabilities. Interestingly, 3% hydrogen gas treatment did not decrease hydroxyl radical, protein carbonyl, and 8-hydroxydeoxyguanosine, suggesting that scavenging hydroxyl radical might not be responsible for these effects of hydrogen gas in this study. Copyright 2010 Elsevier Inc. All rights reserved.

Hydrogen gas treatment prolongs replicative lifespan of bone marrow multipotential stromal cells in vitro while preserving differentiation and paracrine potentials

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kawasaki, Haruhisa; Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210; Guan, Jianjun

2010-07-02

Cell therapy with bone marrow multipotential stromal cells/mesenchymal stem cells (MSCs) represents a promising approach in the field of regenerative medicine. Low frequency of MSCs in adult bone marrow necessitates ex vivo expansion of MSCs after harvest; however, such a manipulation causes cellular senescence with loss of differentiation, proliferative, and therapeutic potentials of MSCs. Hydrogen molecules have been shown to exert organ protective effects through selective reduction of hydroxyl radicals. As oxidative stress is one of the key insults promoting cell senescence in vivo as well as in vitro, we hypothesized that hydrogen molecules prevent senescent process during MSC expansion.more » Addition of 3% hydrogen gas enhanced preservation of colony forming early progenitor cells within MSC preparation and prolonged the in vitro replicative lifespan of MSCs without losing differentiation potentials and paracrine capabilities. Interestingly, 3% hydrogen gas treatment did not decrease hydroxyl radical, protein carbonyl, and 8-hydroxydeoxyguanosine, suggesting that scavenging hydroxyl radical might not be responsible for these effects of hydrogen gas in this study.« less

An Aminopropyl Carbazole Derivative Induces Neurogenesis by Increasing Final Cell Division in Neural Stem Cells.

PubMed

Shin, Jae-Yeon; Kong, Sun-Young; Yoon, Hye Jin; Ann, Jihyae; Lee, Jeewoo; Kim, Hyun-Jung

2015-07-01

P7C3 and its derivatives, 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(p-tolylamino)propan-2-ol (1) and N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-N-(3-methoxyphenyl)-4-methylbenzenesulfonamide (2), were previously reported to increase neurogenesis in rat neural stem cells (NSCs). Although P7C3 is known to increase neurogenesis by protecting newborn neurons, it is not known whether its derivatives also have protective effects to increase neurogenesis. In the current study, we examined how 1 induces neurogenesis. The treatment of 1 in NSCs increased numbers of cells in the absence of epidermal growth factor (EGF) and fibroblast growth factor 2 (FGF2), while not affecting those in the presence of growth factors. Compound 1 did not induce astrocytogenesis during NSC differentiation. 5-Bromo-2'-deoxyuridine (BrdU) pulsing experiments showed that 1 significantly enhanced BrdU-positive neurons. Taken together, our data suggest that 1 promotes neurogenesis by the induction of final cell division during NSC differentiation.

CD8 T cell memory: it takes all kinds

PubMed Central

Hamilton, Sara E.; Jameson, Stephen C.

2012-01-01

Understanding the mechanisms that regulate the differentiation and maintenance of CD8+ memory T cells is fundamental to the development of effective T cell-based vaccines. Memory cell differentiation is influenced by the cytokines that accompany T cell priming, the history of previous antigen encounters, and the tissue sites into which memory cells migrate. These cues combine to influence the developing CD8+ memory pool, and recent work has revealed the importance of multiple transcription factors, metabolic molecules, and surface receptors in revealing the type of memory cell that is generated. Paired with increasingly meticulous subsetting and sorting of memory populations, we now know the CD8+ memory pool to be phenotypically and functionally heterogeneous in nature. This includes both recirculating and tissue-resident memory populations, and cells with varying degrees of inherent longevity and protective function. These data point to the importance of tailored vaccine design. Here we discuss how the diversity of the memory CD8+ T cell pool challenges the notion that “one size fits all” for pathogen control, and how distinct memory subsets may be suited for distinct aspects of protective immunity. PMID:23230436

Religiousness as a factor of hesitation against doping behavior in college-age athletes.

PubMed

Zenic, Natasa; Stipic, Marija; Sekulic, Damir

2013-06-01

Religiousness is rarely studied as protective factor against substance use and misuse in sport. Further, we have found no investigation where college-age athletes were sampled and studied accordingly. The aim of the present study was to identify gender-specific protective effects of the religiousness (measured by Santa Clara Questionnaire) and other social, educational, and sport variables as a potential factors of hesitation against doping behaviors in sport-science-students from Mostar, Bosnia, and Herzegovina (51 women and 111 men; age range, 18-26). The gender differences for the non-parametric variables were established by Kruskall-Wallis test, while for the parametric variables the t-test for independent samples was used. Multiple regression calculations revealed religiousness as the most significant predictor of the social, health, sport and legal factors of hesitation against doping behaviors in both genders. However, the differential influence of the social, educational, sport and religious factors in relation to negative consequences of the doping behaviors is found for men and women. Such differential influence must be emphasized in tailoring the anti-doping policy and interventions.

A General Theory of Sexual Differentiation

PubMed Central

Arnold, Arthur P.

2016-01-01

A general theory of mammalian sexual differentiation is proposed. All biological sex differences are the result of the inequality in effects of the sex chromosomes, which are the only factors that differ in XX vs. XY zygotes. This inequality leads to male-specific effects of the Y chromosome, including expression of the testis-determining gene Sry that causes differentiation of testes. Thus, Sry sets up lifelong sex differences in effects of gonadal hormones. Y genes also act outside of the gonads to cause male-specific effects. Differences in the number of X chromosomes between XX and XY cells causes sex differences in expression (1) of Xist, (2) of X genes that escape inactivation, and (2) of parentally imprinted X genes. Sex differences in phenotype are ultimately the result of multiple, independent sex-biasing factors, hormonal and sex chromosomal. These factors act in parallel and in combination to induce sex differences. They can also can offset each other to reduce sex differences. Other mechanisms, operating at the level of populations, cause groups of males to differ on average from groups of females. The theory has advantages for directing attention to inherent sex-biasing factors that operate in many tissues to cause sex differences, to cause sex-biased protection from disease, and to frame questions for further study. PMID:27870435

A general theory of sexual differentiation.

PubMed

Arnold, Arthur P

2017-01-02

A general theory of mammalian sexual differentiation is proposed. All biological sex differences are the result of the inequality in effects of the sex chromosomes, which are the only factors that differ in XX vs. XY zygotes. This inequality leads to male-specific effects of the Y chromosome, including expression of the testis-determining gene Sry that causes differentiation of testes. Thus, Sry sets up lifelong sex differences in effects of gonadal hormones. Y genes also act outside of the gonads to cause male-specific effects. Differences in the number of X chromosomes between XX and XY cells cause sex differences in expression (1) of Xist, (2) of X genes that escape inactivation, and (3) of parentally imprinted X genes. Sex differences in phenotype are ultimately the result of multiple, independent sex-biasing factors, hormonal and sex chromosomal. These factors act in parallel and in combination to induce sex differences. They also can offset each other to reduce sex differences. Other mechanisms, operating at the level of populations, cause groups of males to differ on average from groups of females. The theory frames questions for further study, and directs attention to inherent sex-biasing factors that operate in many tissues to cause sex differences, and to cause sex-biased protection from disease. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Effects of Lactobacillus rhamnosus GG on the maturation and differentiation of dendritic cells in rotavirus-infected mice.

PubMed

Jiang, Y; Ye, L; Cui, Y; Yang, G; Yang, W; Wang, J; Hu, J; Gu, W; Shi, C; Huang, H; Wang, C

2017-08-24

Rotavirus-related diarrhoea is considered one of the most important diseases in field animal production. In addition to the classic vaccine strategy, a number of studies have utilised probiotics, such as Lactobacillus rhamnosus GG (LGG), to prevent rotavirus-induced diarrhoea. Although it has been partially revealed that Toll-like receptors (TLRs) are involved in the LGG-mediated protection against rotavirus infection, the details of the underlying immunologic mechanisms remain largely unknown. In this study, three-to-four-week-old female BALB/c mice were divided into three groups and orally administered phosphate buffered saline (PBS), PBS plus rotavirus or LGG plus rotavirus, respectively. The differentiation and maturation of dendritic cells (DCs) were then determined by FACS, the expression levels of TLR-3 and nuclear factor kappa beta (NF-κB) were evaluated using real time PCR, and the production of inflammatory cytokines in mesenteric lymph nodes (MLNs) were determined by ELISA. The results demonstrated that rotavirus infection significantly increased the percentage of CD11c + CD11b + CD8a - DCs and decreased the percentage of CD11c + CD11b - CD8a + DCs in MLNs. By contrast, the presence of LGG significantly decreased the percentage of CD11c + CD11b + CD8a - DCs and increased the percentage of CD11c + CD11b - CD8a + DCs, which indicates that the differentiation of DCs is involved in the protective effects of LGG. Rotavirus infection also resulted in the increased expression of surface markers such as CD40, CD80 and MHC-II in DCs, and the administration of LGG significantly increased the expression level further. The mRNA levels of TLR-3 and NF-κB in the intestine and MLNs were also significantly increased in the presence of rotavirus, which was further increased in the presence of LGG. The production of inflammatory cytokines was also determined, and the results showed that rotavirus caused the increased production of interleukin (IL)-12 and tumour necrosis factor alpha; this effect was further enhanced by LGG. Meanwhile, although rotavirus infection led to the increased production of IL-6 and IL-10, the presence of LGG significantly decreased the mRNA levels of these cytokines. By contrast, rotavirus infection resulted in the decreased production of interferon gamma (IFN-γ), and the administration of LGG significantly increased the levels of IFN-γ. Taken together, the protective effects of LGG were partially due to the modulation of the differentiation and maturation of DCs, the increased production of TLR-3 and NF-κB, and the modulation of inflammatory cytokines.

Intestinal epithelial cell secretion of RELM-beta protects against gastrointestinal worm infection

USDA-ARS?s Scientific Manuscript database

IL-4 and IL-13 protect against parasitic helminths, but little is known about the mechanism of host protection. We show that IL-4/IL-13 confer immunity against worms by inducing intestinal epithelial cells (IEC) to differentiate into goblet cells that secrete resistin-like molecule beta (RELMB). R...

Effects of tea and coffee on cardiovascular disease risk.

PubMed

Bøhn, Siv K; Ward, Natalie C; Hodgson, Jonathan M; Croft, Kevin D

2012-06-01

Tea and coffee have been associated with risk of cardiovascular disease (CVD), both positively and negatively. Epidemiological data suggest that black and green tea may reduce the risk of both coronary heart disease and stroke by between 10 and 20%. Experimental and clinical trial data generally indicate either neutral or beneficial effects on risk factors and pathways linked to the development of CVD. Controversy still exists regarding the effects of coffee, where there have been concerns regarding associations with hypercholesterolaemia, hypertension and myocardial infarction. However, long term moderate intake of coffee is not associated with detrimental effects in healthy individuals and may even protect against the risk of developing type 2 diabetes. The detrimental effects of coffee may be associated with the acute pressor effects, most likely due to caffeine at high daily intakes, and lipids from boiled coffee can contribute to raised serum cholesterol. Genetic polymorphisms in enzymes involved in uptake, metabolism and excretion of tea and coffee compounds are also associated with differential biological effects. Potential mechanisms by which tea and coffee phytochemicals can exert effects for CVD protection include the regulation of vascular tone through effects on endothelial function, improved glucose metabolism, increased reverse cholesterol transport and inhibition of foam cell formation, inhibition of oxidative stress, immunomodulation and effects on platelet function (adhesion and activation, aggregation and clotting). The phytochemical compounds in tea and coffee and their metabolites are suggested to influence protective endogenous pathways by modulation of gene-expression. It is not known exactly which compounds are responsible for the suggestive protective effects of tea and coffee. Although many biologically active compounds have been identified with known biological effects, tea and coffee contain many unidentified compounds with potential bioactivity.

The functions of social support as protective factors for suicidal ideation in a sample of air force personnel.

PubMed

Bryan, Craig J; Hernandez, Ann Marie

2013-10-01

This study examined various functions of social support (i.e., tangible, esteem, belonging, and appraisal) were examined as protective factors for suicidal ideation in a sample of 273 active duty Air Force Security Forces personnel. Generalized linear regression analyses were conducted to determine if various social support functions were differentially associated with the presence and severity of suicidal ideation, both as main effects and as moderators of emotional distress. None of the four social support functions differentiated suicidal from nonsuicidal Airmen, but esteem support (i.e., feeling respected, encouraged, and valued by others) was associated with significantly less severe suicidal ideation (B = -.074, SE = .025, p = .003). A significant interaction of tangible support (i.e., access to material resources) with emotional distress indicated that emotional distress was associated with more severe suicidal ideation only among Airmen reporting low levels of tangible support (B = .006, SE = .003, p = .018). When considered concurrently, both tangible and self-esteem functions of social support are differentially associated with decreased suicidal ideation among Airmen, but belonging (i.e., having someone to do things with) and appraisal (i.e., having someone to talk to about problems) functions were not. Findings suggest that different aspects of social support affect suicidal ideation in different ways. © 2013 The American Association of Suicidology.

Aflatoxicosis chemoprevention by probiotic Lactobacillius and lack of effect on the major histocompatibility complex.

PubMed

Rawal, Sumit; Bauer, Miranda M; Mendoza, Kristelle M; El-Nezami, Hani; Hall, Jeffery R; Kim, Ji Eun; Stevens, John R; Reed, Kent M; Coulombe, Roger A

2014-10-01

Turkeys are extremely sensitive to aflatoxin B1 (AFB1) which causes decreased growth, immunosuppression and liver necrosis. The purpose of this study was to determine whether probiotic Lactobacillus, shown to be protective in animal and clinical studies, would likewise confer protection in turkeys, which were treated for 11 days with either AFB1 (AFB; 1 ppm in diet), probiotic (PB; 1 × 10(11) CFU/ml; oral, daily), probiotic + AFB1 (PBAFB), or PBS control (CNTL). The AFB1 induced drop in body and liver weights were restored to normal in CNTL and PBAFB groups. Hepatotoxicity markers were not significantly reduced by probiotic treatment. Major histocompatibility complex (MHC) genes BG1 and BG4, which are differentially expressed in liver and spleens, were not significantly affected by treatments. These data indicate modest protection, but the relatively high dietary AFB1 treatment, and the extreme sensitivity of this species may reveal limits of probiotic-based protection strategies. Copyright © 2014 Elsevier Ltd. All rights reserved.

Balancing Immune Protection and Immune Pathology by CD8+ T-Cell Responses to Influenza Infection

PubMed Central

Duan, Susu; Thomas, Paul G.

2016-01-01

Influenza A virus (IAV) is a significant human pathogen causing annual epidemics and periodic pandemics. CD8+ cytotoxic T lymphocyte (CTL)-mediated immunity contributes to the clearance of virus-infected cells, and CTL immunity targeting the conserved internal proteins of IAVs is a key protection mechanism when neutralizing antibodies are absent during heterosubtypic IAV infection. However, CTL infiltration into the airways, its cytotoxicity, and the effects of produced proinflammatory cytokines can cause severe lung tissue injury, thereby contributing to immunopathology. Studies have discovered complicated and exquisite stimulatory and inhibitory mechanisms that regulate CTL magnitude and effector activities during IAV infection. Here, we review the state of knowledge on the roles of IAV-specific CTLs in immune protection and immunopathology during IAV infection in animal models, highlighting the key findings of various requirements and constraints regulating the balance of immune protection and pathology involved in CTL immunity. We also discuss the evidence of cross-reactive CTL immunity as a positive correlate of cross-subtype protection during secondary IAV infection in both animal and human studies. We argue that the effects of CTL immunity on protection and immunopathology depend on multiple layers of host and viral factors, including complex host mechanisms to regulate CTL magnitude and effector activity, the pathogenic nature of the IAV, the innate response milieu, and the host historical immune context of influenza infection. Future efforts are needed to further understand these key host and viral factors, especially to differentiate those that constrain optimally effective CTL antiviral immunity from those necessary to restrain CTL-mediated non-specific immunopathology in the various contexts of IAV infection, in order to develop better vaccination and therapeutic strategies for modifying protective CTL immunity. PMID:26904022

Osthole promotes neuronal differentiation and inhibits apoptosis via Wnt/β-catenin signaling in an Alzheimer's disease model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yao, Yingjia; Gao, Zhong; Liang, Wenbo

Neurogenesis is the process by which neural stem cells (NSCs) proliferate and differentiate into neurons. This is diminished in several neurodegenerative disorders such as Alzheimer's disease (AD), which is characterized by the deposition of amyloid (A)β peptides and neuronal loss. Stimulating NSCs to replace lost neurons is therefore a promising approach for AD treatment. Our previous study demonstrated that osthole modulates NSC proliferation and differentiation, and may reduce Aβ protein expression in nerve cells. Here we investigated the mechanism underlying the effects of osthole on NSCs. We found that osthole enhances NSC proliferation and neuronal differentiation while suppressing apoptosis, effectsmore » that were exerted via activation of Wnt/β-catenin signaling. These results provide evidence that osthole can potentially be used as a therapeutic agent in the treatment of AD and other neurodegenerative disorders. - Highlights: • An Alzheimer's disease model was successfully established by transfecting APP gene into neural stem cells in vitro. • Roles of osthole in experimental AD cells were studied. • Osthole promotes proliferation and differentiation into neurons and inhibits accumulation of Aβ{sub 1–42} peptide and apoptosis. • Osthole exerts protection via Wnt/β-catenin signaling pathway.« less

A Polysaccharide Isolated from Mycelia of the Lion's Mane Medicinal Mushroom Hericium erinaceus (Agaricomycetes) Induced Apoptosis in Precancerous Human Gastric Cells.

PubMed

Wang, Mingxing; Zhang, Yanqiu; Xiao, Xulang; Xu, Duoduo; Gao, Yang; Gao, Qipin

2017-01-01

Hericium erinaceus is typically used in traditional Chinese medicine for mucosal protection, healing of gastric ulcers, and treatment of gastritis. We purified from the cultured mycelia of H. erinaceus a polysaccharide with anti-gastric ulcer and antigastritis activity, but its effects on gastric malignancy have not been elucidated. We examined the differential effects of this purified polysaccharide, named EP-1, on the human gastric (GES-1) cell line and a precancerous cell line (MC) that was transformed from GES-1 using N-methyl-N'-nitro-N-nitrosoguanidine. We observed that the polysaccharide potently induced cell apoptosis and cell cycle arrest at the G0/G1 phase in the MC cell line but did not have any effect on the GES-1 cell line at the same doses. Further mechanistic studies revealed that the polysaccharide exerted its activity through an apoptosis-associated pathway by modulating the expression of Bax, Bcl-2, and caspase-3. Differential effects of the polysaccharide on the GES-1 and MC cell lines indicate that the polysaccharide was effective in preventing gastric cancer progression.

Fibronectin is a survival factor for differentiated osteoblasts

NASA Technical Reports Server (NTRS)

Globus, R. K.; Doty, S. B.; Lull, J. C.; Holmuhamedov, E.; Humphries, M. J.; Damsky, C. H.

1998-01-01

The skeletal extracellular matrix produced by osteoblasts contains the glycoprotein fibronectin, which regulates the adhesion, differentiation and function of various adherent cells. Interactions with fibronectin are required for osteoblast differentiation in vitro, since fibronectin antagonists added to cultures of immature fetal calvarial osteoblasts inhibit their progressive differentiation. To determine if fibronectin plays a unique role in fully differentiated osteoblasts, cultures that had already formed mineralized nodules in vitro were treated with fibronectin antagonists. Fibronectin antibodies caused >95% of the cells in the mature cultures to display characteristic features of apoptosis (nuclear condensation, apoptotic body formation, DNA laddering) within 24 hours. Cells appeared to acquire sensitivity to fibronectin antibody-induced apoptosis as a consequence of differentiation, since antibodies failed to kill immature cells and the first cells killed were those associated with mature nodules. Intact plasma fibronectin, as well as fragments corresponding to the amino-terminal, cell-binding, and carboxy-terminal domains of fibronectin, independently induced apoptosis of mature (day-13), but not immature (day-4), osteoblasts. Finally, transforming growth factor-beta1 partially protected cells from the apoptotic effects of fibronectin antagonists. Thus, in the course of maturation cultured osteoblasts switch from depending on fibronectin for differentiation to depending on fibronectin for survival. These data suggest that fibronectin, together with transforming growth factor-beta1, may affect bone formation, in part by regulating the survival of osteoblasts.

Differential protective effects of immune lymphoid cells against transplanted line Ib leukemia and immune polioencephalomyelitis. [X radiation, mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Duffey, P.S.; Lukasewycz, O.A.; Olson, D.S.

1978-12-01

The capacity of immune cells obtained from the major lymphoid compartments to protect C58 mice from transplanted line Ib leukemia, and from an age-dependent autoimmune CNS disease (immune polioencephalomyelitis = IPE) elicited by immunizing old C58 mice with inactivated Ib cells was quantified. Cells used for comparative adoptive protection tests were harvested from the major lymphoid compartments 14 to 15 days after young C58 mice were immunized with inactivated Ib cell preparations. Regression curves were plotted from survival data and the log/sub 10/PD/sub 50/ values were determined. Immune spleen (ISC) and peritoneal cells (IPEC) were significantly more protective against transplantedmore » Ib cells than immune lymph node (ILNC), thymic (ITC), and marrow cells (IMC). In contrast, IPEC and IMC were not protective against IPE and ITC were only marginally protective. ILNC afforded significant protection to transplantable leukemia but were only marginally protective to IPE. When ISC were treated with anti-thy 1.2 serum and complement, protection against transplanted leukemia and IPE was reduced > 99%. When donors of immune lymphoid cells were treated with 12.5 mg of cortisone acetate daily for 2 days before lymphoid cells were harvested, protection against transplanted Ib cells by ISC was reduced by approximately 90% whereas protection against IPE was totally eliminated. Considered together, these results indicate that the protective mechanisms to transplantable leukemia and IPE differ significantly in the same indicator mouse strain.« less

Characterization of Nα-Fmoc-protected dipeptide isomers by electrospray ionization tandem mass spectrometry (ESI-MS(n)): effect of protecting group on fragmentation of dipeptides.

PubMed

Ramesh, M; Raju, B; Srinivas, R; Sureshbabu, V V; Vishwanatha, T M; Hemantha, H P

2011-07-30

A series of positional isomeric pairs of Fmoc-protected dipeptides, Fmoc-Gly-Xxx-OY/Fmoc-Xxx-Gly-OY (Xxx=Ala, Val, Leu, Phe) and Fmoc-Ala-Xxx-OY/Fmoc-Xxx-Ala-OY (Xxx=Leu, Phe) (Fmoc=[(9-fluorenylmethyl)oxy]carbonyl) and Y=CH(3)/H), have been characterized and differentiated by both positive and negative ion electrospray ionization ion-trap tandem mass spectrometry (ESI-IT-MS(n)). In contrast to the behavior of reported unprotected dipeptide isomers which mainly produce y(1)(+) and/or a(1)(+) ions, the protonated Fmoc-Xxx-Gly-OY, Fmoc-Ala-Xxx-OY and Fmoc-Xxx-Ala-OY yield significant b(1)(+) ions. These ions are formed, presumably with stable protonated aziridinone structures. However, the peptides with Gly- at the N-terminus do not form b(1)(+) ions. The [M+H](+) ions of all the peptides undergo a McLafferty-type rearrangement followed by loss of CO(2) to form [M+H-Fmoc+H](+). The MS(3) collision-induced dissociation (CID) of these ions helps distinguish the pairs of isomeric dipeptides studied in this work. Further, negative ion MS(3) CID has also been found to be useful for differentiating these isomeric peptide acids. The MS(3) of [M-H-Fmoc+H](-) of isomeric peptide acids produce c(1)(-), z(1)(-) and y(1)(-) ions. Thus the present study of Fmoc-protected peptides provides additional information on mass spectral characterization of the dipeptides and distinguishes the positional isomers. Copyright © 2011 John Wiley & Sons, Ltd.

High-Throughput Phenotypic Screening of Human Astrocytes to Identify Compounds That Protect Against Oxidative Stress.

PubMed

Thorne, Natasha; Malik, Nasir; Shah, Sonia; Zhao, Jean; Class, Bradley; Aguisanda, Francis; Southall, Noel; Xia, Menghang; McKew, John C; Rao, Mahendra; Zheng, Wei

2016-05-01

Astrocytes are the predominant cell type in the nervous system and play a significant role in maintaining neuronal health and homeostasis. Recently, astrocyte dysfunction has been implicated in the pathogenesis of many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Astrocytes are thus an attractive new target for drug discovery for neurological disorders. Using astrocytes differentiated from human embryonic stem cells, we have developed an assay to identify compounds that protect against oxidative stress, a condition associated with many neurodegenerative diseases. This phenotypic oxidative stress assay has been optimized for high-throughput screening in a 1,536-well plate format. From a screen of approximately 4,100 bioactive tool compounds and approved drugs, we identified a set of 22 that acutely protect human astrocytes from the consequences of hydrogen peroxide-induced oxidative stress. Nine of these compounds were also found to be protective of induced pluripotent stem cell-differentiated astrocytes in a related assay. These compounds are thought to confer protection through hormesis, activating stress-response pathways and preconditioning astrocytes to handle subsequent exposure to hydrogen peroxide. In fact, four of these compounds were found to activate the antioxidant response element/nuclear factor-E2-related factor 2 pathway, a protective pathway induced by toxic insults. Our results demonstrate the relevancy and utility of using astrocytes differentiated from human stem cells as a disease model for drug discovery and development. Astrocytes play a key role in neurological diseases. Drug discovery efforts that target astrocytes can identify novel therapeutics. Human astrocytes are difficult to obtain and thus are challenging to use for high-throughput screening, which requires large numbers of cells. Using human embryonic stem cell-derived astrocytes and an optimized astrocyte differentiation protocol, it was possible to screen approximately 4,100 compounds in titration to identify 22 that are cytoprotective of astrocytes. This study is the largest-scale high-throughput screen conducted using human astrocytes, with a total of 17,536 data points collected in the primary screen. The results demonstrate the relevancy and utility of using astrocytes differentiated from human stem cells as a disease model for drug discovery and development. ©AlphaMed Press.

The protective effect of astaxanthin on fetal alcohol spectrum disorder in mice.

PubMed

Zheng, Dong; Li, Yi; He, Lei; Tang, Yamei; Li, Xiangpen; Shen, Qingyu; Yin, Deling; Peng, Ying

2014-09-01

Astaxanthin is a strong antioxidant with the ability of reducing the markers of inflammation. To explore the protective effect of astaxanthin on maternal ethanol induced embryonic deficiency, and to investigate the underlying mechanisms, we detected the morphology, expression of neural marker genes, oxidative stress indexes, and inflammatory factors in mice model of fetal alcohol spectrum disorder with or without astaxanthin pretreatment. Our results showed that astaxanthin blocked maternal ethanol induced retardation of embryonic growth, and the down-regulation of neural marker genes, Otx1 and Sox2. Moreover, astaxanthin also reversed the increases of malondialdehyde (MDA), hydrogen peroxide (H2O2), and the decrease of glutathione peroxidase (GPx) in fetal alcohol spectrum disorder. In addition, maternal ethanol induced up-regulation of toll-like receptor 4 (TLR4), and the down-streaming myeloid differentiation factor 88 (MyD88), NF-κB, TNF-α, and IL-1β in embryos, and this was inhibited by astaxanthin pretreatment. These results demonstrated a protective effect of astaxanthin on fetal alcohol spectrum disorder, and suggested that oxidative stress and TLR4 signaling associated inflammatory reaction are involved in this process. Copyright © 2014 Elsevier Ltd. All rights reserved.

Involvement of the histamine H{sub 4} receptor in clozapine-induced hematopoietic toxicity: Vulnerability under granulocytic differentiation of HL-60 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goto, Aya; Mouri, Akihiro; Nagai, Tomoko

Clozapine is an effective antipsychotic for treatment-resistant schizophrenia, but can cause fatal hematopoietic toxicity as agranulocytosis. To elucidate the mechanism of hematopoietic toxicity induced by clozapine, we developed an in vitro assay system using HL-60 cells, and investigated the effect on hematopoiesis. HL-60 cells were differentiated by all-trans retinoic acid (ATRA) into three states according to the following hematopoietic process: undifferentiated HL-60 cells, those undergoing granulocytic ATRA-differentiation, and ATRA-differentiated granulocytic cells. Hematopoietic toxicity was evaluated by analyzing cell survival, cell proliferation, granulocytic differentiation, apoptosis, and necrosis. In undifferentiated HL-60 cells and ATRA-differentiated granulocytic cells, both clozapine (50 and 100 μM)more » and doxorubicin (0.2 µM) decreased the cell survival rate, but olanzapine (1–100 µM) did not. Under granulocytic differentiation for 5 days, clozapine, even at a concentration of 25 μM, decreased survival without affecting granulocytic differentiation, increased caspase activity, and caused apoptosis rather than necrosis. Histamine H{sub 4} receptor mRNA was expressed in HL-60 cells, whereas the expression decreased under granulocytic ATRA-differentiation little by little. Both thioperamide, a histamine H{sub 4} receptor antagonist, and DEVD-FMK, a caspase-3 inhibitor, exerted protection against clozapine-induced survival rate reduction, but not of live cell counts. 4-Methylhistamine, a histamine H{sub 4} receptor agonist, decreased the survival rate and live cell counts, as did clozapine. HL-60 cells under granulocytic differentiation are vulnerable under in vitro assay conditions to hematopoietic toxicity induced by clozapine. Histamine H{sub 4} receptor is involved in the development of clozapine-induced hematopoietic toxicity through apoptosis, and may be a potential target for preventing its occurrence through granulocytic differentiation. - Highlights: • HL-60 cells under granulocytic differentiation were vulnerable for clozapine. • HL-60 cells would be in vitro assay systems for hematopoietic toxicity by clozapine. • Histamine H{sub 4} receptor was involved in hematopoietic toxicity with apoptosis. • Histamine H{sub 4} receptor may be therapeutic target to prevent hematopoietic toxicity.« less

Motivating women and men to take protective action against rape: examining direct and indirect persuasive fear appeals.

PubMed

Morrison, Kelly

2005-01-01

This article examines the effectiveness of persuasive fear appeals in motivating women to enroll in self-defense classes to take protective action against rape. Witte's extended parallel process model is used as a framework to examine the relations between perceived invulnerability, perceived fear, and fear control processes. Because women may perceive invulnerability to rape, persuasive fear appeals targeted toward them may be ineffective in achieving attitude, intention, and behavioral change toward protecting themselves. One possible solution is to persuade men to talk with women about whom they care. Results indicated that women did not perceive invulnerability to rape, and although there was no differential impact between high- and low-threat messages, women did report positive intention and behaviors in response to direct fear appeals. Moreover, men reported positive intention and behaviors in response to indirect fear appeals.

Protection by an oral disubstituted hydroxylamine derivative against loss of retinal ganglion cell differentiation following optic nerve crush.

PubMed

Lindsey, James D; Duong-Polk, Karen X; Dai, Yi; Nguyen, Duy H; Leung, Christopher K; Weinreb, Robert N

2013-01-01

Thy-1 is a cell surface protein that is expressed during the differentiation of retinal ganglion cells (RGCs). Optic nerve injury induces progressive loss in the number of RGCs expressing Thy-1. The rate of this loss is fastest during the first week after optic nerve injury and slower in subsequent weeks. This study was undertaken to determine whether oral treatment with a water-soluble N-hydroxy-2,2,6,6-tetramethylpiperidine derivative (OT-440) protects against loss of Thy-1 promoter activation following optic nerve crush and whether this effect targets the earlier quick phase or the later slow phase. The retina of mice expressing cyan fluorescent protein under control of the Thy-1 promoter (Thy1-CFP mice) was imaged using a blue-light confocal scanning laser ophthalmoscope (bCSLO). These mice then received oral OT-440 prepared in cream cheese or dissolved in water, or plain vehicle, for two weeks and were imaged again prior to unilateral optic nerve crush. Treatments and weekly imaging continued for four more weeks. Fluorescent neurons were counted in the same defined retinal areas imaged at each time point in a masked fashion. When the counts at each time point were directly compared, the numbers of fluorescent cells at each time point were greater in the animals that received OT-440 in cream cheese by 8%, 27%, 52% and 60% than in corresponding control animals at 1, 2, 3 and 4 weeks after optic nerve crush. Similar results were obtained when the vehicle was water. Rate analysis indicated the protective effect of OT-440 was greatest during the first two weeks and was maintained in the second two weeks after crush for both the cream cheese vehicle study and water vehicle study. Because most of the fluorescent cells detected by bCSLO are RGCs, these findings suggest that oral OT-440 can either protect against or delay early degenerative responses occurring in RGCs following optic nerve injury.

The Impact of Mitochondrial Complex Inhibition on mESC Differentiation

EPA Science Inventory

The Impact of Mitochondrial Complex Inhibition on mESC Differentiation JE Royland, SH Warren, S Jeffay, MR Hoopes, HP Nichols, ES Hunter U.S. Environmental Protection Agency, Integrated Systems Toxicology Division, Research Triangle Park, NC The importance of mitochondrial funct...

Issues in Differential Response

ERIC Educational Resources Information Center

Hughes, Ronald C.; Rycus, Judith S.; Saunders-Adams, Stacey M.; Hughes, Laura K.; Hughes, Kelli N.

2013-01-01

Differential response (DR), also referred to as alternative response (AR), family assessment response (FAR), or multiple track response, was developed to incorporate family-centered, strengths-based practices into child protective services (CPS), primarily by diverting lower risk families into an assessment track rather than requiring the…

Differential effects of omega-3 fatty acid docosahexaenoic acid and palmitate on the circadian transcriptional profile of clock genes in immortalized hypothalamic neurons.

PubMed

Greco, James A; Oosterman, Johanneke E; Belsham, Denise D

2014-10-15

Diets high in saturated fatty acids (SFAs) are associated with the development of circadian dysregulation, obesity, and Type 2 diabetes mellitus. Conversely, polyunsaturated fatty acids (PUFAs) have recently been identified to improve insulin sensitivity, reduce weight gain, and relieve obesity-induced inflammation. While saturated fatty acids, such as the prevalent dietary fatty acid palmitate, have been implicated in circadian disruption, there is a paucity of studies regarding the effects of PUFAs on circadian parameters. Therefore, the immortalized murine neuronal model, mHypoE-37, was utilized to examine the effects of the SFA palmitate and omega-3 PUFA docosahexaenoic acid (DHA) on circadian rhythms. The mHypoE-37 neurons express the core clock genes, Bmal1, Per2, and Rev-erbα, in a circadian manner. 25 μM of palmitate significantly increased the transcriptional expression of Bmal1, without altering the expression of inflammatory markers TLR4, IκBα, and IL-6, nor the orexigenic neuropeptide AgRP, suggesting that the observed disruption of the molecular clock is the result of a mechanism distinct from that of hypothalamic cellular inflammation. Furthermore, treatment with the PUFA DHA resulted in alterations in the circadian expression profile of Bmal1, although differentially from the effects of palmitate. In the presence of DHA, the disruptive effects of palmitate on Bmal1 were less pronounced, suggesting a protective effect of DHA. These studies are the first to identify the potential for omega-3 PUFAs to protect against palmitate-mediated dysregulation of circadian parameters and will ultimately improve the understanding of circadian control mechanisms. Copyright © 2014 the American Physiological Society.

Maternal care and paternal protection influence response to psychotherapy treatment for adult depression.

PubMed

Johnstone, Jeanette M; Carter, Janet D; Luty, Suzanne E; Mulder, Roger T; Frampton, Christopher M; Joyce, Peter R

2013-07-01

Adverse childhood experiences of neglect, overprotection and abuse, well-recognized risk factors for the development of adult psychopathology, were examined as predictors of response to psychotherapy treatment for adults with depression. Outpatients in a randomized clinical trial of interpersonal psychotherapy (IPT) or cognitive-behavioral therapy (CBT) completed the parental bonding instrument (PBI) at baseline to establish levels of care and protection. Childhood abuse was asked about using clinical interviews. The PBI variables were examined in tertiles while the abuse variables were categorized as "none," "some," and "severe." Associations between these childhood adversities and treatment response were examined in those who completed the trial. Of 177 outpatients with depression who were randomized, 159 completed an adequate trial of therapy. Within these 159 patients, 57% were categorized as responders to treatment. The mean percentage improvement on the MADRS was 57.7% (±31.4). Across both treatments, patients reporting intermediate levels of maternal care had the best response to treatment. Also across both treatments, the interaction effects of maternal care and paternal protection by treatment were statistically significant. Examining the two therapies independently, maternal care and paternal protection were associated with a differential response to IPT but not CBT. Reports of abuse, whether physical, emotional or sexual, did not impact treatment response. This study examined patients who completed treatment, which may have attenuated the findings. Two categories of childhood adversity were measured although a range of other adverse childhood experiences exist. The results were from exploratory analyses and require replication. Maternal care, demonstrating a robust main effect across treatments, appears to be the childhood variable most strongly associated with response to psychotherapy in this sample. In addition, maternal care and paternal protection were associated with a differential response to treatment. These results suggest that the quality of on-going intra-familial relationships has a greater impact on treatment response than experiences of abuse. The findings may aid clinicians in selecting which psychotherapy to use, depending on a patient's childhood history. Copyright © 2013 Elsevier B.V. All rights reserved.

Manganese Superoxide Dismutase Gene-Modified Mesenchymal Stem Cells Attenuate Acute Radiation-Induced Lung Injury.

PubMed

Chen, Hai-Xu; Xiang, Hang; Xu, Wen-Huan; Li, Ming; Yuan, Jie; Liu, Juan; Sun, Wan-Jun; Zhang, Rong; Li, Jun; Ren, Zhao-Qi; Zhang, Xiao-Mei; Du, Bin; Wan, Jun; Wu, Ben-Yan; Zeng, Qiang; He, Kun-Lun; Yang, Chao

2017-06-01

Radiation-induced lung injury (RILI) is a major clinical complication for radiotherapy in thoracic tumors. An immediate effect of lung irradiation is the generation of reactive oxygen that can produce oxidative damage to DNA, lipids, and proteins resulting in lung cell injury or death. Currently, the medical management of RILI remains supportive. Therefore, there is an urgent need for the development of countermeasures. The present study aimed to evaluate the protective effect of manganese superoxide dismutase (MnSOD) gene-modified mesenchymal stem cells (MSCs) to facilitate the improved recovery of RILI. Here, nonobese diabetic/severe combined immunodeficiency mice received a 13 Gy dose of whole-thorax irradiation, and were then transfused intravenously with MnSOD-MSCs and monitored for 30 days. Lung histopathologic analysis, plasma levels of inflammatory cytokines (interleukin [IL]-1, IL-6, IL-10, and tumor necrosis factor-α), profibrotic factor transforming growth factor-β1, and the oxidative stress factor (hydroxyproline) were evaluated after MnSOD-MSC transplant. Apoptotic rates were evaluated by terminal deoxynucleotidyl transferase-mediated nick-end labeling immunohistochemical method. Colonization and differentiation of MnSOD-MSCs in the irradiated lung were analyzed by immunofluorescence staining. Consequently, systemic administration of MnSOD-MSCs significantly attenuated lung inflammation, ameliorated lung damage, and protected the lung cells from apoptosis. MnSOD-MSCs could differentiate into epithelial-like cells in vivo. MnSOD-MSCs were effective in modulating RILI in mice and had great potential for accelerating from bench to bedside.

MASM, a Matrine Derivative, Offers Radioprotection by Modulating Lethal Total-Body Irradiation-Induced Multiple Signaling Pathways in Wistar Rats.

PubMed

Li, Jianzhong; Xu, Jing; Lu, Yiming; Qiu, Lei; Xu, Weiheng; Lu, Bin; Hu, Zhenlin; Chu, Zhiyong; Chai, Yifeng; Zhang, Junping

2016-05-17

Matrine is an alkaloid extracted from Sophora flavescens Ait and has many biological activities, such as anti-inflammatory, antitumor, anti-fibrosis, and immunosuppressive properties. In our previous studies, the matrine derivative MASM was synthesized and exhibited potent inhibitory activity against liver fibrosis. In this study, we mainly investigated its protection against lethal total-body irradiation (TBI) in rats. Administration of MASM reduced the radiation sickness characteristics and increased the 30-day survival of rats before or after lethal TBI. Ultrastructural observation illustrated that pretreatment of rats with MASM significantly attenuated the TBI-induced morphological changes in the different organs of irradiated rats. Gene expression profiles revealed that pretreatment with MASM had a dramatic effect on gene expression changes caused by TBI. Pretreatment with MASM prevented differential expression of 53% (765 genes) of 1445 differentially expressed genes induced by TBI. Pathway enrichment analysis indicated that these genes were mainly involved in a total of 21 pathways, such as metabolic pathways, pathways in cancer, and mitogen-activated protein kinase (MAPK) pathways. Our data indicated that pretreatment of rats with MASM modulated these pathways induced by TBI, suggesting that the pretreatment with MASM might provide the protective effects on lethal TBI mainly or partially through the modulation of these pathways, such as multiple MAPK pathways. Therefore, MASM has the potential to be used as an effective therapeutic or radioprotective agent to minimize irradiation damages and in combination with radiotherapy to improve the efficacy of cancer therapy.

Filaggrin-dependent secretion of sphingomyelinase protects against staphylococcal α-toxin-induced keratinocyte death.

PubMed

Brauweiler, Anne M; Bin, Lianghua; Kim, Byung Eui; Oyoshi, Michiko K; Geha, Raif S; Goleva, Elena; Leung, Donald Y M

2013-02-01

The skin of patients with atopic dermatitis (AD) has defects in keratinocyte differentiation, particularly in expression of the epidermal barrier protein filaggrin. AD skin lesions are often exacerbated by Staphylococcus aureus-mediated secretion of the virulence factor α-toxin. It is unknown whether lack of keratinocyte differentiation predisposes to enhanced lethality from staphylococcal toxins. We investigated whether keratinocyte differentiation and filaggrin expression protect against cell death induced by staphylococcal α-toxin. Filaggrin-deficient primary keratinocytes were generated through small interfering RNA gene knockdown. RNA expression was determined by using real-time PCR. Cell death was determined by using the lactate dehydrogenase assay. Keratinocyte cell survival in filaggrin-deficient (ft/ft) mouse skin biopsies was determined based on Keratin 5 staining. α-Toxin heptamer formation and acid sphingomyelinase expression were determined by means of immunoblotting. We found that filaggrin expression, occurring as the result of keratinocyte differentiation, significantly inhibits staphylococcal α-toxin-mediated pathogenicity. Furthermore, filaggrin plays a crucial role in protecting cells by mediating the secretion of sphingomyelinase, an enzyme that reduces the number of α-toxin binding sites on the keratinocyte surface. Finally, we determined that sphingomyelinase enzymatic activity directly prevents α-toxin binding and protects keratinocytes against α-toxin-induced cytotoxicity. The current study introduces the novel concept that S aureus α-toxin preferentially targets and destroys filaggrin-deficient keratinocytes. It also provides a mechanism to explain the increased propensity for S aureus-mediated exacerbation of AD skin disease. Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Effect of Drying Methods on Protein and DNA Conformation Changes in Lactobacillus rhamnosus GG Cells by Fourier Transform Infrared Spectroscopy.

PubMed

Hlaing, Mya M; Wood, Bayden R; McNaughton, Don; Ying, DanYang; Dumsday, Geoff; Augustin, Mary Ann

2017-03-01

Microencapsulation protects cells against environmental stress encountered during the production of probiotics, which are used as live microbial food ingredients. Freeze-drying and spray-drying are used in the preparation of powdered microencapsulated probiotics. This study examines the ability of Fourier transform infrared (FTIR) spectroscopy to detect differences in cells exposed to freeze-drying and spray-drying of encapsulated Lactobacillus rhamnosus GG cells. The FTIR analysis clearly demonstrated there were more significant molecular changes in lipid, fatty acid content, protein, and DNA conformation of nonencapsulated compared to encapsulated bacterial cells. The technique was also able to differentiate between spray-dried and freeze-dried cells. The results also revealed the extent of protection from a protein-carbohydrate-based encapsulant matrix on the cells depending on the type drying process. The extent of this protection to the dehydration stress was shown to be less in spray-dried cells than in freeze-dried cells. This suggests that FTIR could be used as a rapid, noninvasive, and real-time measurement technique to detect detrimental drying effects on cells.

Notoginsenoside R1 attenuates glucose-induced podocyte injury via the inhibition of apoptosis and the activation of autophagy through the PI3K/Akt/mTOR signaling pathway

PubMed Central

Huang, Guodong; Zou, Bingyu; Lv, Jianzhen; Li, Tongyu; Huai, Guoli; Xiang, Shaowei; Lu, Shilong; Luo, Huan; Zhang, Yaping; Jin, Yi; Wang, Yi

2017-01-01

Injury to terminally differentiated podocytes contributes ignificantly to proteinuria and glomerulosclerosis. The aim of this study was to examine the protective effects of notoginsenoside R1 (NR1) on the maintenance of podocyte number and foot process architecture via the inhibition of apoptosis, the induction of autophagy and the maintenance pf podocyte biology in target cells. The effects of NR1 on conditionally immortalized human podocytes under high glucose conditions were evaluated by determining the percentage apoptosis, the percentage autophagy and the expression levels of slit diaphragm proteins. Our results revealed that NR1 protected the podocytes against high glucose-induced injury by decreasing apoptosis, increasing autophagy and by promoting cytoskeletal recovery. The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway was further investigated in order to elucidate the mechanisms responsible for the protective effects of NR1 on podocytes. Our data indicated that treatment with NR increased the phosphorylation levels of PI3K, Akt and mTOR, leading to the activation of the PI3K/Akt/mTOR signaling pathway in podocytes. To the best of our knowledge, this is the first in vitro study to demonstrate that NR1 protects podocytes by activating the PI3K/Akt/mTOR pathway. PMID:28112381

Quercetin Exerts Differential Neuroprotective Effects Against H2O2 and Aβ Aggregates in Hippocampal Neurons: the Role of Mitochondria.

PubMed

Godoy, Juan A; Lindsay, Carolina B; Quintanilla, Rodrigo A; Carvajal, Francisco J; Cerpa, Waldo; Inestrosa, Nibaldo C

2017-11-01

Amyloid-β peptide (Aβ) is one of the major players in the pathogenesis of Alzheimer's disease (AD). Despite numerous studies, the mechanisms by which Aβ induces neurodegeneration are not completely understood. Oxidative stress is considered a major contributor to the pathogenesis of AD, and accumulating evidence indicates that high levels of reactive oxygen species (ROS) are involved in Aβ-induced neurodegeneration. Moreover, Aβ can induce the deregulation of calcium homeostasis, which also affects mitochondrial function and triggers neuronal cell death. In the present study, we analyzed the effects of quercetin, a plant flavonoid with antioxidant properties, on oxidative stress- and Aβ-induced degeneration. Our results indicate that quercetin efficiently protected against H 2 O 2 -induced neuronal toxicity; however, this protection was only partial in rat hippocampal neurons that were treated with Aβ. Treatment with quercetin decreased ROS levels, recovered the normal morphology of mitochondria, and prevented mitochondrial dysfunction in neurons that were treated with H 2 O 2 . By contrast, quercetin treatment partially rescued hippocampal neurons from Aβ-induced mitochondrial injury. Most importantly, quercetin treatment prevented the toxic effects that are induced by H 2 O 2 in hippocampal neurons and, to a lesser extent, the Aβ-induced toxicity that is associated with the superoxide anion, which is a precursor of ROS production in mitochondria. Collectively, these results indicate that quercetin exerts differential effects on the prevention of H 2 O 2 - and Aβ-induced neurotoxicity in hippocampal neurons and may be a powerful tool for dissecting the molecular mechanisms underlying Aβ neurotoxicity.

Does the type of CIA policy significantly affect bar and restaurant employment in Minnesota cities?

PubMed Central

Klein, Elizabeth G.; Forster, Jean L.; Erickson, Darin J.; Lytle, Leslie A.; Schillo, Barbara

2009-01-01

Background Clean indoor air (CIA) policies that include free-standing bars and restaurants have been adopted by communities to protect employees in all workplaces from exposure to environmental tobacco smoke, most notably employees working in restaurants and free-standing bars. However, due to the perception of negative economic effects on alcohol-licensed hospitality businesses, partial CIA policies (those that provide an exemption for free-standing bars) have been proposed as a means to reduce the risk of economic effects of comprehensive CIA policies applied to all worksites. Objective To determine if partial CIA produce differential economic effects compared to comprehensive CIA policies using bar and restaurant employment per capita. Design, setting, and subjects Ten cities in the state of Minnesota were studied from 2003 to 2006. Economic data were drawn from monthly employment in bars and restaurants, and a pooled time-series was completed to evaluate three types of local CIA policies: Comprehensive, partial, or none beyond the state law. Results Communities with a comprehensive CIA policy had a decrease of 9 employees per 10,000 residents compared with communities with a partial CIA policies (p=0.10). Communities with any type of CIA policy (partial or comprehensive) had an increase of 3 employees per 10,000 residents compared to communities without any CIA policies (p=0.36). Conclusion There were no significant differential economic effects by CIA policy type in Minnesota cities. These findings support the adoption of comprehensive CIA policies to provide all employees protection from environmental tobacco smoke exposure. PMID:19184432

F-spondin inhibits migration and differentiation of osteoclastic precursors.

PubMed

Oka, Hiroko; Mori, Maya; Kihara, Hisae

2011-12-01

Clinically, severe cemental resorption is a rare consequence of periodontitis, although alveolar bone resorption by osteoclasts is one of the main pathologic changes. F-spondin is a secreted neuronal glycoprotein that localizes to the cementum. F-spondin is among the cementum-specific factors in periodontal tissue that have been reported. However, the effects of F-spondin on osteoclastogenesis have not yet been established. We examined the effects of F-spondin on stages of osteoclastogenesis, migration, and differentiation in a mouse osteoclastic precursor model, RAW 264 cells. RAW 264 cells were treated with recombinant F-spondin. Macrophage colony stimulating factor (M-CSF)-induced cell migration was examined by migration assay performed with cell culture inserts. Osteoclastic differentiation was measured by counting tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells. In a transmigration assay, F-spondin significantly downregulated M-CSF-induced cell migration. Further, F-spondin significantly reduced the number of receptor activator of nuclear factor-kappa B ligand-induced TRAP-positive multinucleated cells. The receptor-associated protein, an antagonist of the low-density lipoprotein (LDL) receptor family, blocked the effects of F-spondin on M-CSF-induced migration. The suppressive effect of F-spondin on M-CSF-induced cell migration was blocked by knockdown of LDL receptor-related protein 8 (LRP8), a member of the LDL receptor family. Our findings suggest that F-spondin downregulates recruitment to the root side of periodontal tissue via LRP8 and inhibits differentiation of osteoclastic precursors. It is suggested that F-spondin is essential to protect the root surface from resorption.

Evaluation of the photoprotective effect of β-cyclodextrin on the emission of volatile degradation products of ranitidine.

PubMed

Jamrógiewicz, Marzena; Wielgomas, Bartosz; Strankowski, Michał

2014-09-01

The process of the photo-excitation of ranitidine hydrochloride (RAN) in a solid state makes visible changes to its colour and generates an unpleasant odour. The purpose of the present study was to observe the protective effects of β-cyclodextrin (CD) complexation as well as the effect of the mixture of two stoichiometries 1:1 and 1:2 (RAN:CD, IC) on the photostability of samples in a solid state. Samples of inclusion complexes (IC) and physical mixtures (PM) were prepared and irradiated for 48h in a Suntest CPS+ chamber. Irradiated samples were analyzed using nuclear magnetic resonance ((1)H NMR), infrared spectroscopy (FT-IR), the differential scanning calorimetry method (DSC) and thermogravimetry analysis (TGA). Volatiles were monitored with the use of headspace-solid phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS). The protective effect of CD was noticed with respect to IC, and also PM. Achieved photostabilization of complexed RAN against photodegradation could be explained due to either the inclusion of the furan part of RAN into the CD cavity as shown by the (1)H NMR ROESY (rotation frame nuclear Overhauser effect spectroscopy) spectrum or the screening effect of CD. FT-IR spectra, DSC curves and microscope images of irradiated samples of protected RAN did not indicate any physical changes, such as phase transfer. Copyright © 2014 Elsevier B.V. All rights reserved.

Lithium attenuates lead induced toxicity on mouse non-adherent bone marrow cells.

PubMed

Banijamali, Mahsan; Rabbani-Chadegani, Azra; Shahhoseini, Maryam

2016-07-01

Lead is a poisonous heavy metal that occurs in all parts of environment and causes serious health problems in humans. The aim of the present study was to investigate the possible protective effect of lithium against lead nitrate induced toxicity in non-adherent bone marrow stem cells. Trypan blue and MTT assays represented that exposure of the cells to different concentrations of lead nitrate decreased viability in a dose dependent manner, whereas, pretreatment of the cells with lithium protected the cells against lead toxicity. Lead reduced the number and differentiation status of bone marrow-derived precursors when cultured in the presence of colony stimulating factor (CSF), while the effect was attenuated by lithium. The cells treated with lead nitrate exhibited cell shrinkage, DNA fragmentation, anion superoxide production, but lithium prevented lead action. Moreover, apoptotic indexes such as PARP cleavage and release of HMGB1 induced by lead, were protected by lithium, suggesting anti-apoptotic effect of lithium. Immunoblot analysis of histone H3K9 acetylation indicated that lithium overcame lead effect on acetylation. In conclusion, lithium efficiently reduces lead toxicity suggesting new insight into lithium action which may contribute to increased cell survival. It also provides a potentially new therapeutic strategy for lithium and a cost-effective approach to minimize destructive effects of lead on bone marrow stem cells. Copyright © 2016 Elsevier GmbH. All rights reserved.

Olives and Bone: A Green Osteoporosis Prevention Option

PubMed Central

Chin, Kok-Yong; Ima-Nirwana, Soelaiman

2016-01-01

Skeletal degeneration due to aging, also known as osteoporosis, is a major health problem worldwide. Certain dietary components confer protection to our skeletal system against osteoporosis. Consumption of olives, olive oil and olive polyphenols has been shown to improve bone health. This review aims to summarize the current evidence from cellular, animal and human studies on the skeletal protective effects of olives, olive oil and olive polyphenols. Animal studies showed that supplementation of olives, olive oil or olive polyphenols could improve skeletal health assessed via bone mineral density, bone biomechanical strength and bone turnover markers in ovariectomized rats, especially those with inflammation. The beneficial effects of olive oil and olive polyphenols could be attributed to their ability to reduce oxidative stress and inflammation. However, variations in the bone protective, antioxidant and anti-inflammatory effects between studies were noted. Cellular studies demonstrated that olive polyphenols enhanced proliferation of pre-osteoblasts, differentiation of osteoblasts and decreased the formation of osteoclast-like cells. However, the exact molecular pathways for its bone health promoting effects are yet to be clearly elucidated. Human studies revealed that daily consumption of olive oil could prevent the decline in bone mineral density and improve bone turnover markers. As a conclusion, olives, olive oil and its polyphenols are potential dietary interventions to prevent osteoporosis among the elderly. PMID:27472350

Protective Effect of Ozone against Hemiscorpius lepturus Envenomation in Mice.

PubMed

Naserzadeh, Parvaneh; Shahi, Farshad; Shahbazzadeh, Delavar; Ghanei, Mostafa; Ashtari, Khadijeh; Panahi, Yoones; Hosseini, Mir-Jamal; Izadi, Morteza

2017-08-01

Scorpion (Hemiscorpius lepturus) stings are a public health concern in Iran, particularly in south and southwestern regions of Iran. The gold standard for the treatment of a scorpion sting is anti-venom therapy. However, immunotherapy can have serious side effects, such as anaphylactic shock (which can sometimes even lead to death). The aim of the current study was to demonstrate the protective effect of ozone against toxicity induced by Hemiscorpius lepturus (H. lepturus) venom in mice. Eight hours after the injection of ozone to the experimental design groups, the male mice were decapitated and mitochondria were isolated from five different tissues (liver, kidney, heart, brain, and spinal cord) using differential ultracentrifugation. Then, assessment of mitochondrial parameters including mitochondrial reactive oxidative species (ROS) production, mitochondrial membrane potential (MMP), ATP level, and the release of cytochrome c from the mitochondria was performed. Our results showed that H. lepturus venom-induced oxidative stress is related to ROS production and MMP collapse, which is correlated with cytochrome c release and ATP depletion, indicating the predisposition to the cell death signaling. In general, ozone therapy in moderate dose can be considered as clinically effective for the treatment of H. lepturus sting as a protective and antioxidant agent. Copyright © 2017 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.

A Critical Protection Level Derived from Dengue Infection Mathematical Model Considering Asymptomatic and Symptomatic Classes

NASA Astrophysics Data System (ADS)

Anggriani, N.; Supriatna, A. K.; Soewono, E.

2013-04-01

In this paper we formulate a model of dengue fever transmission by considering the presence of asymptomatic and symptomatic compartments. The model takes the form as a system of differential equations representing a host-vector SIR (Susceptible - Infective -Recovered) disease transmission. It is assumed that both host and vector populations are constant. It is also assumed that reinfection of recovered hosts by the disease is possible due to a wanning immunity in human body. We analyze the model to determine the qualitative behavior of the model solution and use the concept of effective basic reproduction number (fraktur Rp) as a control criteria of the disease transmission. The effect of mosquito biting protection (e.g. by using insect repellent) is also considered. We compute the long-term ratio of the asymptomatic and symptomatic classes and show a condition for which the iceberg phenomenon could appear.

Ethanol extract of Oenanthe javanica increases cell proliferation and neuroblast differentiation in the adolescent rat dentate gyrus

PubMed Central

Chen, Bai Hui; Park, Joon Ha; Cho, Jeong Hwi; Kim, In Hye; Shin, Bich Na; Ahn, Ji Hyeon; Hwang, Seok Joon; Yan, Bing Chun; Tae, Hyun Jin; Lee, Jae Chul; Bae, Eun Joo; Lee, Yun Lyul; Kim, Jong Dai; Won, Moo-Ho; Kang, Il Jun

2015-01-01

Oenanthe javanica is an aquatic perennial herb that belongs to the Oenanthe genus in Apiaceae family, and it displays well-known medicinal properties such as protective effects against glutamate-induced neurotoxicity. However, few studies regarding effects of Oenanthe javanica on neurogenesis in the brain have been reported. In this study, we examined the effects of a normal diet and a diet containing ethanol extract of Oenanthe javanica on cell proliferation and neuroblast differentiation in the subgranular zone of the hippocampal dentate gyrus of adolescent rats using Ki-67 (an endogenous marker for cell proliferation) and doublecortin (a marker for neuroblast). Our results showed that Oenanthe javanica extract significantly increased the number of Ki-67-immunoreactive cells and doublecortin-immunoreactive neuroblasts in the subgranular zone of the dentate gyrus in the adolescent rats. In addition, the immunoreactivity of brain-derived neurotrophic factor was significantly increased in the dentate gyrus of the Oenanthe javanica extract-treated group compared with the control group. However, we did not find that vascular endothelial growth factor expression was increased in the Oenanthe javanica extract-treated group compared with the control group. These results indicate that Oenanthe javanica extract improves cell proliferation and neuroblast differentiation by increasing brain-derived neurotrophic factor immunoreactivity in the rat dentate gyrus. PMID:25883627

Robustly detecting differential expression in RNA sequencing data using observation weights

PubMed Central

Zhou, Xiaobei; Lindsay, Helen; Robinson, Mark D.

2014-01-01

A popular approach for comparing gene expression levels between (replicated) conditions of RNA sequencing data relies on counting reads that map to features of interest. Within such count-based methods, many flexible and advanced statistical approaches now exist and offer the ability to adjust for covariates (e.g. batch effects). Often, these methods include some sort of ‘sharing of information’ across features to improve inferences in small samples. It is important to achieve an appropriate tradeoff between statistical power and protection against outliers. Here, we study the robustness of existing approaches for count-based differential expression analysis and propose a new strategy based on observation weights that can be used within existing frameworks. The results suggest that outliers can have a global effect on differential analyses. We demonstrate the effectiveness of our new approach with real data and simulated data that reflects properties of real datasets (e.g. dispersion-mean trend) and develop an extensible framework for comprehensive testing of current and future methods. In addition, we explore the origin of such outliers, in some cases highlighting additional biological or technical factors within the experiment. Further details can be downloaded from the project website: http://imlspenticton.uzh.ch/robinson_lab/edgeR_robust/. PMID:24753412

Insulin-Like Growth Factor 1 Mitigates Hematopoietic Toxicity After Lethal Total Body Irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhou, Dunhua; Deoliveira, Divino; Kang, Yubin

2013-03-15

Purpose: To investigate whether and how insulin-like growth factor 1 (IGF-1) mitigates hematopoietic toxicity after total body irradiation. Methods and Materials: BALB/c mice were irradiated with a lethal dose of radiation (7.5 Gy) and treated with IGF-1 at a dose of 100 μg/dose intravenously once a day for 5 consecutive days starting within 1 hour after exposure. Survival and hematopoietic recovery were monitored. The mechanisms by which IGF-1 promotes hematopoietic recovery were also studied by use of an in vitro culture system. Results: IGF-1 protected 8 of 20 mice (40%) from lethal irradiation, whereas only 2 of 20 mice (10%) inmore » the saline control group survived for more than 100 days after irradiation. A single dose of IGF-1 (500 μg) was as effective as daily dosing for 5 days. Positive effects were noted even when the initiation of treatment was delayed as long as 6 hours after irradiation. In comparison with the saline control group, treatment with IGF-1 significantly accelerated the recovery of both platelets and red blood cells in peripheral blood, total cell numbers, hematopoietic stem cells, and progenitor cells in the bone marrow when measured at day 14 after irradiation. IGF-1 protected both hematopoietic stem cells and progenitor cells from radiation-induced apoptosis and cell death. In addition, IGF-1 was able to facilitate the proliferation and differentiation of nonirradiated and irradiated hematopoietic progenitor cells. Conclusions: IGF-1 mitigates radiation-induced hematopoietic toxicity through protecting hematopoietic stem cells and progenitor cells from apoptosis and enhancing proliferation and differentiation of the surviving hematopoietic progenitor cells.« less

The Regulation of a Spatially Heterogeneous Externality: Tradable Groundwater Permits to Protect Streams

NASA Astrophysics Data System (ADS)

Kuwayama, Y.; Brozovic, N.

2012-12-01

Groundwater pumping from aquifers can reduce the flow of surface water in nearby streams through a process known as stream depletion. In the United States, recent awareness of this externality has led to intra- and inter-state conflict and rapidly-changing water management policies and institutions. A factor that complicates the design of groundwater management policies to protect streams is the spatial heterogeneity of the stream depletion externality; the marginal damage of groundwater use on stream flows depends crucially on the location of pumping relative to streams. Under these circumstances, economic theory predicts that spatially differentiated policies can achieve an aggregate reduction in stream depletion cost effectively. However, whether spatially differentiated policies offer significant abatement cost savings and environmental improvements over simpler, alternative policies is an empirical question. In this paper, we analyze whether adopting a spatially differentiated groundwater permit system can lead to significant savings in compliance costs while meeting targets on stream protection. Using a population data set of active groundwater wells in the Nebraska portion of the Republican River Basin, we implement an optimization model of each well owner's crop choice, land use, and irrigation decisions to determine the distribution of regulatory costs. We model the externality of pumping on streams by employing an analytical solution from the hydrology literature that determines reductions in stream flow caused by groundwater pumping over space and time. The economic and hydrologic model components are then combined into one optimization framework, which allows us to measure farmer abatement costs and stream flow benefits under a constrained optimal market that features spatially differentiated, tradable groundwater permits. We compare this outcome to the efficiency of alternative second-best policies, including spatially uniform permit markets and pumping restrictions based on geographic zones. Our analysis considers static policies for which abatement is fixed over time, as well as dynamic policies that allow abatement to vary over time and future compliance costs to be subject to a discount rate. We find that if current levels of stream flow in the Republican River Basin are held fixed, regulators can generate most of the potential abatement cost savings by establishing a one-to-one tradable permit system that does not account for spatial heterogeneity. We obtain this surprising result because the agronomic and climatic parameters in our data set that determine farmer abatement costs are spatially correlated with hydrologic parameters that determine the marginal damage of groundwater use on streams. However, we also find that if future legal or ecological circumstances require regulators to increase significantly the protection of streams from current levels, spatially differentiated policies will generate sizable cost savings compared to policies that ignore spatial heterogeneity.

Effect of selenium supplementation for protection of salivary glands from iodine-131 radiation damage in patients with differentiated thyroid cancer.

PubMed

Son, Haiyoung; Lee, Sang Mi; Yoon, Ra Gyoung; Lee, Hakmin; Lee, Ilkyun; Kim, Soon; Chung, Woong Youn; Lee, Jeong Won

2017-01-01

In the current study, we examined whether selenium supplementation during iodine-131 ( 131 I) treatment had a radio-protective effect on salivary glands. Sixteen patients with differentiated thyroid cancer were prospectively enrolled in the study. Patients after total thyroidectomy, before 131 I treatment, were divided into two groups; 8 patients in the selenium group and 8 patients in the control group. Patients in the selenium group received 300νg of selenium orally for 10 days, from 3 days before to 6 days after 131 I treatment. The control group received a placebo over the same period. To assess salivary gland function, salivary gland scintigraphy was performed before and 6 months after 131 I treatment. Serum amylase and whole blood selenium levels were measured before and 2 days and 6 months after 131 I treatment. Using salivary gland scintigraphy, maximum uptake ratio (MUR), maximum secretion percentage (MSP), and ejection fraction (EF) of each salivary gland were calculated. Baseline clinical characteristics, baseline amylase and selenium levels, and parameters of baseline salivary gland scintigraphy were not significantly different between selenium and control groups (P>0.05). On a blood test performed 2 days after 131 I treatment, the selenium group showed a significantly higher whole blood selenium level (P=0.008) and significantly lower serum amylase level (P=0.009) than the control group. On follow-up salivary gland scintigraphy, the control group showed significantly decreased, MUR of the bilateral parotid and left submandibular glands, MSP of the bilateral parotid and submandibular glands, and EF of the left submandibular glands (P<0.05), while the selenium group only had a significant decrease in MSP of the right submandibular gland and EF of the left submandibular gland (P<0.05). Selenium supplementation during 131 I treatment was effective to reduce salivary glands damage by 131 I radiation in patients with differentiated thyroid cancer.

Effects of atelocollagen on neural stem cell function and its migrating capacity into brain in psychiatric disease model.

PubMed

Yoshinaga, Toshihiro; Hashimoto, Eri; Ukai, Wataru; Ishii, Takao; Shirasaka, Tomohiro; Kigawa, Yoshiyasu; Tateno, Masaru; Kaneta, Hiroo; Watanabe, Kimihiko; Igarashi, Takeshi; Kobayashi, Seiju; Sohma, Hitoshi; Kato, Tadafumi; Saito, Toshikazu

2013-10-01

Stem cell therapy is well proposed as a potential method for the improvement of neurodegenerative damage in the brain. Among several different procedures to reach the cells into the injured lesion, the intravenous (IV) injection has benefit as a minimally invasive approach. However, for the brain disease, prompt development of the effective treatment way of cellular biodistribution of stem cells into the brain after IV injection is needed. Atelocollagen has been used as an adjunctive material in a gene, drug and cell delivery system because of its extremely low antigenicity and bioabsorbability to protect these transplants from intrabody environment. However, there is little work about the direct effect of atelocollagen on stem cells, we examined the functional change of survival, proliferation, migration and differentiation of cultured neural stem cells (NSCs) induced by atelocollagen in vitro. By 72-h treatment 0.01-0.05% atelocollagen showed no significant effects on survival, proliferation and migration of NSCs, while 0.03-0.05% atelocollagen induced significant reduction of neuronal differentiation and increase of astrocytic differentiation. Furthermore, IV treated NSCs complexed with atelocollagen (0.02%) could effectively migrate into the brain rather than NSC treated alone using chronic alcohol binge model rat. These experiments suggested that high dose of atelocollagen exerts direct influence on NSC function but under 0.03% of atelocollagen induces beneficial effect on regenerative approach of IV administration of NSCs for CNS disease.

Scoparone attenuates RANKL-induced osteoclastic differentiation through controlling reactive oxygen species production and scavenging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Sang-Hyun; Jang, Hae-Dong, E-mail: haedong@hnu.kr

Scoparone, one of the bioactive components of Artemisia capillaris Thunb, has various biological properties including immunosuppressive, hepatoprotective, anti-allergic, anti-inflammatory, and antioxidant effects. This study aims at evaluating the anti-osteoporotic effect of scoparone and its underlying mechanism in vitro. Scoparone demonstrated potent cellular antioxidant capacity. It was also found that scoparone inhibited the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation and suppressed cathepsin K and tartrate-resistant acid phosphatase (TRAP) expression via c-jun N-terminal kinase (JNK)/extracellular signal-regulated kinase (ERK)/p38-mediated c-Fos–nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) signaling pathway. During osteoclast differentiation, the production of general reactive oxygen speciesmore » (ROS) and superoxide anions was dose-dependently attenuated by scoparone. In addition, scoparone diminished NADPH (nicotinamide adenine dinucleotide phosphate) oxidase 1 (Nox1) expression and activation via the tumor necrosis factor receptor-associated factor 6 (TRAF6)–cSrc–phosphatidylinositol 3-kinase (PI3k) signaling pathway and prevented the disruption of mitochondrial electron transport chain system. Furthermore, scoparone augmented the expression of superoxide dismutase 1 (SOD1) and catalase (CAT). The overall results indicate that the inhibitory effect of scoparone on RANKL-induced osteoclast differentiation is attributed to the suppressive effect on ROS and superoxide anion production by inhibiting Nox1 expression and activation and protecting the mitochondrial electron transport chain system and the scavenging effect of ROS resulting from elevated SOD1 and CAT expression. - Highlights: • Scoparone dose-dependently inhibited RANKL-induced osteoclast differentiation. • Scoparone diminished general ROS and superoxide anions in a dose-dependent manner. • Scoparone inhibited Nox1 expression and activation. • Scoparone prevented the disruption of mitochondrial electron transport chain system. • Scoparone augmented superoxide dismutase and catalase expression.« less

Differential neuritogenic activities of two edible brown macroalgae, Undaria pinnatifida and Saccharina japonica.

PubMed

Hannan, Md Abdul; Mohibbullah, Md; Hwang, Seon-Yeong; Lee, Kyungyong; Kim, Yang-Chun; Hong, Yong-Ki; Moon, Il Soo

2014-01-01

Undaria pinnatifida (Harvey) Suringar and Saccharina japonica Areschoug are two common seaweeds, and both are known to have numerous pharmacological properties that include neuroprotective effects. In a previous study, we found that the ethanol extracts of U. pinnatifida (UPE) and S. japonica (SJE) had neurite promoting activities on developing hippocampal neurons. In the present study, we studied and compared the effects of UPE and SJE on neuronal maturation. Both UPE and SJE promoted neurite outgrowth in a dose-dependent manner with optimal concentrations of 5 and 15 μg/mL, respectively. Initial neuronal differentiation was significantly promoted by UPE and SJE. Subsequently, treatment with both increased indices of axonal and dendritic cytoarchitecture, such as, the numbers and lengths of primary processes, although only UPE had a significant effect on branching frequencies. In addition, UPE and SJE showed no evidence of cytotoxicity, rather they protected neurons from naturally occurring death in vitro. These results indicate that UPE and SJE promote axodendritic maturation and neuronal survival and suggest that these algal extracts, especially UPE, have beneficial effects on the nervous system.

Clopidogrel: A Case for Indication-Specific Pharmacogenetics

PubMed Central

Johnson, JA; Roden, DM; Lesko, LJ; Ashley, E; Klein, TE; Shuldiner, AR

2012-01-01

The CYP2C19*2 loss-of-function allele is associated with reduced generation of active metabolites of clopidogrel. However, meta-analyses have supported or discounted the impact of genotype on adverse cardiovascular outcomes during clopidogrel therapy, depending on studies included in the analysis. Here we review these data and conclude that evidence supports a differential effect of genotype on protection from major adverse cardiovascular outcomes following percutaneous coronary intervention (PCI), but not for other clopidogrel indications. PMID:22513313

Withholding differential risk information on legal consumer nicotine/tobacco products: The public health ethics of health information quarantines.

PubMed

Kozlowski, Lynn T; Sweanor, David

2016-06-01

The United States provides an example of a country with (a) legal tobacco/nicotine products (e.g., snus, other smokeless tobacco, cigarettes) differing greatly in risks to health and (b) respected health information websites that continue to omit or provide incorrect differential risk information. Concern for the principles of individual rights, health literacy, and personal autonomy (making decisions for oneself), which are key principles of public health ethics, has been countered by utilitarian arguments for the use of misleading or limited information to protect public health overall. We argue that omitting key health relevant information for current or prospective consumers represents a kind of quarantine of health-relevant information. As with disease quarantines, the coercive effects of quarantining information on differential risks need to be justified, not merely by fears of net negative public health effects, but by convincing evidence that such measures are actually warranted, that public health overall is in imminent danger and that the danger is sufficient to override principles of individual autonomy. Omitting such health-relevant information for consumers of such products effectively blindfolds them and impairs their making informed personal choices. Moral psychological issues that treat all tobacco/nicotine products similarly may also be influencing the reluctance to inform on differential risks. In countries where tobacco/nicotine products are legally sold and also differ greatly in disease risks compared to cigarettes (e.g., smokeless tobacco and vape), science-based, comprehensible, and actionable health information (consistent with health literacy principles) on differential risks should be available and only reconsidered if it is established that this information is causing losses to population health overall. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Phenotypic and functional characterization of herpes simplex virus glycoprotein B epitope-specific effector and memory CD8+ T cells from symptomatic and asymptomatic individuals with ocular herpes.

PubMed

Khan, Arif A; Srivastava, Ruchi; Spencer, Doran; Garg, Sumit; Fremgen, Daniel; Vahed, Hawa; Lopes, Patricia P; Pham, Thanh T; Hewett, Charlie; Kuang, Jasmine; Ong, Nicolas; Huang, Lei; Scarfone, Vanessa M; Nesburn, Anthony B; Wechsler, Steven L; BenMohamed, Lbachir

2015-04-01

Herpes simplex virus 1 (HSV-1) glycoprotein B (gB)-specific CD8(+) T cells protect mice from herpes infection and disease. However, whether and which HSV-1 gB-specific CD8(+) T cells play a key role in the "natural" protection seen in HSV-1-seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical herpes disease) remain to be determined. In this study, we have dissected the phenotypes and the functions of HSV-1 gB-specific CD8(+) T cells from HLA-A*02:01 positive, HSV-1 seropositive ASYMP and symptomatic (SYMP) individuals (with a history of numerous episodes of recurrent ocular herpes disease). We found the following. (i) Healthy ASYMP individuals maintained a significantly higher proportion of differentiated HSV-1 gB-specific effector memory CD8(+) T cells (TEM cells) (CD45RA(low) CCR7(low) CD44(high) CD62L(low)). In contrast, SYMP patients had frequent less-differentiated central memory CD8(+) T cells (TCM cells) (CD45RA(low) CCR7(high) CD44(low) CD62L(high)). (ii) ASYMP individuals had significantly higher proportions of multifunctional effector CD8(+) T cells which responded mainly to gB342-350 and gB561-569 "ASYMP" epitopes, and simultaneously produced IFN-γ, CD107(a/b), granzyme B, and perforin. In contrast, effector CD8(+) T cells from SYMP individuals were mostly monofunctional and were directed mainly against nonoverlapping gB17-25 and gB183-191 "SYMP" epitopes. (iii) Immunization of an HLA-A*02:01 transgenic mouse model of ocular herpes with "ASYMP" CD8(+) TEM cell epitopes, but not with "SYMP" CD8(+) TCM cell epitopes, induced a strong CD8(+) T cell-dependent protective immunity against ocular herpes infection and disease. Our findings provide insights into the role of HSV-specific CD8(+) TEM cells in protection against herpes and should be considered in the development of an effective vaccine. A significantly higher proportion of differentiated and multifunctional HSV-1 gB-specific effector memory CD8(+) T cells (TEM cells) (CD45RA(low) CCR7(low) CD44(high) CD62L(low)) were found in healthy ASYMP individuals who are seropositive for HSV-1 but never had any recurrent herpetic disease, while there were frequent less-differentiated and monofunctional central memory CD8(+) T cells (TCM cells) (CD45RA(low) CCR7(high) CD44(low) CD62L(high)) in SYMP patients. Immunization with "ASYMP" CD8(+) TEM cell epitopes, but not with "SYMP" CD8(+) TCM cell epitopes, induced a strong protective HSV-specific CD8(+) T cell response in HLA-A*02:01 transgenic mice. These findings are important for the development of a safe and effective T cell-based herpes vaccine. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Ouabain rescues rat nephrogenesis during intrauterine growth restriction by regulating the complement and coagulation cascades and calcium signaling pathway.

PubMed

Chen, L; Yue, J; Han, X; Li, J; Hu, Y

2016-02-01

Intrauterine growth restriction (IUGR) is associated with a reduction in the numbers of nephrons in neonates, which increases the risk of hypertension. Our previous study showed that ouabain protects the development of the embryonic kidney during IUGR. To explore this molecular mechanism, IUGR rats were induced by protein and calorie restriction throughout pregnancy, and ouabain was delivered using a mini osmotic pump. RNA sequencing technology was used to identify the differentially expressed genes (DEGs) of the embryonic kidneys. DEGs were submitted to the Database for Annotation and Visualization and Integrated Discovery, and gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted. Maternal malnutrition significantly reduced fetal weight, but ouabain treatment had no significant effect on body weight. A total of 322 (177 upregulated and 145 downregulated) DEGs were detected between control and the IUGR group. Meanwhile, 318 DEGs were found to be differentially expressed (180 increased and 138 decreased) between the IUGR group and the ouabain-treated group. KEGG pathway analysis indicated that maternal undernutrition mainly disrupts the complement and coagulation cascades and the calcium signaling pathway, which could be protected by ouabain treatment. Taken together, these two biological pathways may play an important role in nephrogenesis, indicating potential novel therapeutic targets against the unfavorable effects of IUGR.

Apoptosis in differentiating C2C12 muscle cells selectively targets Bcl-2-deficient myotubes

PubMed Central

Schoneich, Christian; Dremina, Elena; Galeva, Nadezhda; Sharov, Victor

2014-01-01

Muscle cell apoptosis accompanies normal muscle development and regeneration, as well as degenerative diseases and aging. C2C12 murine myoblast cells represent a common model to study muscle differentiation. Though it was already shown that myogenic differentiation of C2C12 cells is accompanied by enhanced apoptosis in a fraction of cells, either the cell population sensitive to apoptosis or regulatory mechanisms for the apoptotic response are unclear so far. In the current study we characterize apoptotic phenotypes of different types of C2C12 cells at all stages of differentiation, and report here that myotubes of differentiated C2C12 cells with low levels of anti-apoptotic Bcl-2 expression are particularly vulnerable to apoptosis even though they are displaying low levels of pro-apoptotic proteins Bax, Bak and Bad. In contrast, reserve cells exhibit higher levels of Bcl-2 and high resistance to apoptosis. The transfection of proliferating myoblasts with Bcl-2 prior to differentiation did not protect against spontaneous apoptosis accompanying differentiation of C2C12 cell but led to Bcl-2 overexpression in myotubes and to significant protection from apoptotic cell loss caused by exposure to hydrogen peroxide. Overall, our data advocate for a Bcl-2-dependent mechanism of apoptosis in differentiated muscle cells. However, downstream processes for spontaneous and hydrogen peroxide induced apoptosis are not completely similar. Apoptosis in differentiating myoblasts and myotubes is regulated not through interaction of Bcl-2 with pro-apoptotic Bcl-2 family proteins such as Bax, Bak, and Bad. PMID:24129924

The complex pericentriolar material 1 protein allows differentiation between myonuclei and nuclei of satellite cells of the skeletal muscle.

PubMed

Brunn, Anna

2018-05-27

The original article by Winje et al., entitled "Specific labelling of myonuclei by an antibody against pericentriolar material 1 (PCM1) on skeletal muscle tissue sections" 1 , sheds new light on the issue of heterogeneity of skeletal muscle and, thus, the problem to reliably distinguish between myonuclei versus nuclei of satellite cells of the skeletal muscle which are intimately associated. At the light microscopical level this differentiation is particularly difficult since only nuclei inside the muscle fiber are defined as true myonuclei. This is a major problem in analyses that use tissue homogenates, while in situ immunohistochemical studies using appropriate antibodies usually allow differentiation of cell populations. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Different requirements of functional telomeres in neural stem cells and terminally differentiated neurons.

PubMed

Lobanova, Anastasia; She, Robert; Pieraut, Simon; Clapp, Charlie; Maximov, Anton; Denchi, Eros Lazzerini

2017-04-01

Telomeres have been studied extensively in peripheral tissues, but their relevance in the nervous system remains poorly understood. Here, we examine the roles of telomeres at distinct stages of murine brain development by using lineage-specific genetic ablation of TRF2, an essential component of the shelterin complex that protects chromosome ends from the DNA damage response machinery. We found that functional telomeres are required for embryonic and adult neurogenesis, but their uncapping has surprisingly no detectable consequences on terminally differentiated neurons. Conditional knockout of TRF2 in post-mitotic immature neurons had virtually no detectable effect on circuit assembly, neuronal gene expression, and the behavior of adult animals despite triggering massive end-to-end chromosome fusions across the brain. These results suggest that telomeres are dispensable in terminally differentiated neurons and provide mechanistic insight into cognitive abnormalities associated with aberrant telomere length in humans. © 2017 Lobanova et al.; Published by Cold Spring Harbor Laboratory Press.

Moringa oleifera Lam. improves lipid metabolism during adipogenic differentiation of human stem cells.

PubMed

Barbagallo, I; Vanella, L; Distefano, A; Nicolosi, D; Maravigna, A; Lazzarino, G; Di Rosa, M; Tibullo, D; Acquaviva, R; Li Volti, G

2016-12-01

Moringa oleifera Lam., a multipurpose tree, is used traditionally for its nutritional and medicinal properties. It has been used for the treatment of a variety of conditions, including inflammation, cancer and metabolic disorders. We investigated the effect of Moringa oleifera Lam. on adipogenic differentiation of human adipose-derived mesenchymal stem cells and its impact on lipid metabolism and cellular antioxidant systems. We showed that Moringa oleifera Lam. treatment during adipogenic differentiation reduces inflammation, lipid accumulation and induces thermogenesis by activation of uncoupling protein 1 (UCP1), sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor alpha (PPARα), and coactivator 1 alpha (PGC1α). In addition, Moringa oleifera Lam. induces heme oxygenase-1 (HO-1), a well established protective and antioxidant enzyme. Finally Moringa oleifera Lam. significantly decreases the expression of molecules involved in adipogenesis and upregulates the expression of mediators involved in thermogenesis and lipid metabolism. Our results suggest that Moringa oleifera Lam. may promote the brown remodeling of white adipose tissue inducing thermogenesis and improving metabolic homeostasis.

Impact of heat processing on the detection of the major shellfish allergen tropomyosin in crustaceans and molluscs using specific monoclonal antibodies.

PubMed

Kamath, Sandip D; Abdel Rahman, Anas M; Komoda, Toshikazu; Lopata, Andreas L

2013-12-15

The major heat-stable shellfish allergen, tropomyosin, demonstrates immunological cross-reactivity, making specific differentiation of crustaceans and molluscs for food labelling very difficult. The aim of this study was to evaluate the application of allergen-specific monoclonal antibodies in differential detection of shellfish-derived tropomyosin in 11 crustacean and 7 mollusc species, and to study the impact of heating on its detection. Cross-reactive tropomyosin was detected in all crustacean species, with partial detection in molluscs: mussels, scallops and snails but none in oyster, octopus and squid. Furthermore, we have demonstrated that heating of shellfish has a profound effect on tropomyosin detection. This was evident by the enhanced recognition of multiple tropomyosin variants in the analysed shellfish species. Specific monoclonal antibodies, targetting the N-terminal region of tropomyosin, must therefore be developed to differentiate tropomyosins in crustaceans and molluscs. This can help in correct food labelling practices and thus protection of consumers. Copyright © 2013 Elsevier Ltd. All rights reserved.

Leptin receptor signaling in T cells is required for Th17 differentiation.

PubMed

Reis, Bernardo S; Lee, Kihyun; Fanok, Melania H; Mascaraque, Cristina; Amoury, Manal; Cohn, Lillian B; Rogoz, Aneta; Dallner, Olof S; Moraes-Vieira, Pedro M; Domingos, Ana I; Mucida, Daniel

2015-06-01

The hormone leptin plays a key role in energy homeostasis, and the absence of either leptin or its receptor (LepR) leads to severe obesity and metabolic disorders. To avoid indirect effects and to address the cell-intrinsic role of leptin signaling in the immune system, we conditionally targeted LepR in T cells. In contrast with pleiotropic immune disorders reported in obese mice with leptin or LepR deficiency, we found that LepR deficiency in CD4(+) T cells resulted in a selective defect in both autoimmune and protective Th17 responses. Reduced capacity for differentiation toward a Th17 phenotype by lepr-deficient T cells was attributed to reduced activation of the STAT3 and its downstream targets. This study establishes cell-intrinsic roles for LepR signaling in the immune system and suggests that leptin signaling during T cell differentiation plays a crucial role in T cell peripheral effector function. Copyright © 2015 by The American Association of Immunologists, Inc.

The organic osmolyte betaine induces keratin 2 expression in rat epidermal keratinocytes - A genome-wide study in UVB irradiated organotypic 3D cultures.

PubMed

Rauhala, Leena; Hämäläinen, Lasse; Dunlop, Thomas W; Pehkonen, Petri; Bart, Geneviève; Kokkonen, Maarit; Tammi, Markku; Tammi, Raija; Pasonen-Seppänen, Sanna

2015-12-25

The moisturizing and potentially protective properties of the organic osmolyte betaine (trimethylglycine) have made it an attractive component for skin care products. Its wide use despite the lack of comprehensive studies addressing its specific effects in skin led us to characterize the molecular targets of betaine in keratinocytes and to explore, whether it modifies the effects of acute UVB exposure. Genome-wide expression analysis was performed on organotypic cultures of rat epidermal keratinocytes, treated either with betaine (10mM), UVB (30 mJ/cm(2)) or their combination. Results were verified with qRT-PCR, western blotting and immunohistochemistry. Additionally, cell proliferation and differentiation were analyzed. Among the 89 genes influenced by betaine, the differentiation marker keratin 2 showed the highest upregulation, which was also confirmed at protein level. Expression of Egr1, a transcription factor, and Purkinje cell protein 4, a regulator of Ca(2+)/calmodulin metabolism, also increased, while downregulated genes included several ion-channel components, such as Fxyd2. Bioinformatics analyses suggest that genes modulated by betaine are involved in DNA replication, might counteract UV-induced processes, and include many targets of transcription factors associated with cell proliferation and differentiation. Our results indicate that betaine controls unique gene expression pathways in keratinocytes, including some involved in differentiation. Copyright © 2015 Elsevier B.V. All rights reserved.

Beneficial effect of a novel pentadecapeptide BPC 157 on gastric lesions induced by restraint stress, ethanol, indomethacin, and capsaicin neurotoxicity.

PubMed

Sikirić, P; Seiwerth, S; Grabarević, Z; Rucman, R; Petek, M; Jagić, V; Turković, B; Rotkvić, I; Mise, S; Zoricić, I; Gjurasin, M; Konjevoda, P; Separović, J; Ljubanović, D; Artuković, B; Bratulić, M; Tisljar, M; Jurina, L; Buljat, G; Miklić, P; Marović, A

1996-08-01

Very recently, the integrity of capsaicin somatosensory neurons and their protection were suggested to be related to the activity in nociception of a newly discovered 15-amino acid peptide, BPC 157, shown to have strong beneficial effect on intestinal and liver lesions. Therefore, from this viewpoint, we have studied the gastroprotective effect of the pentadecapeptide BPC 157, on gastric lesions produced in rats by 96% ethanol, restraint stress, and indomethacin. The possible involvement of sensory neurons in the salutary actions of BPC 157 (10 micrograms/kg, 10 ng/kg intraperitoneally) was studied with capsaicin, which has differential effects on sensory neurons: a high dose in adult (125 mg/kg subcutaneously, 3 months old) or administration (50 mg/kg subcutaneously) to neonatal animals (age of the 7 days) destroys sensory fibers, whereas a low dose (500 micrograms/kg intraperitoneally) activates neurotransmitter release and protective effects on the mucosa. In the absence of capsaicin, BPC 157 protected gastric mucosa against ethanol, restraint, and indomethacin application. In the presence of neurotoxic doses of capsaicin, the negative influence of capsaicin on restraint, ethanol, or indomethacin lesions consistently affected salutary activity of BPC 157. However, BPC 157 protection was still evident in the capsaicin-treated rats (either treated as adults or as newborns) in all of these assays. Interestingly, after neonatal capsaicin treatment, a complete abolition of BPC gastroprotection was noted if BPC 157 was applied as a single nanogram-regimen, but the mucosal protection was fully reversed when the same dose was used daily. In line with the excitatory dose of capsaicin the beneficial effectiveness of BPC 157 appears to be increased as well. Taken together, these data provide evidence for complex synergistic interaction between the beneficial effectiveness of BPC 157 and peptidergic sensory afferent neuron activity.

Formononetin, an isoflavone, activates AMP-activated protein kinase/β-catenin signalling to inhibit adipogenesis and rescues C57BL/6 mice from high-fat diet-induced obesity and bone loss.

PubMed

Gautam, Jyoti; Khedgikar, Vikram; Kushwaha, Priyanka; Choudhary, Dharmendra; Nagar, Geet Kumar; Dev, Kapil; Dixit, Preety; Singh, Divya; Maurya, Rakesh; Trivedi, Ritu

2017-03-01

Balance between adipocyte and osteoblast differentiation is the key link of disease progression in obesity and osteoporosis. We have previously reported that formononetin (FNT), an isoflavone extracted from Butea monosperma, stimulates osteoblast formation and protects against postmenopausal bone loss. The inverse relationship between osteoblasts and adipocytes prompted us to analyse the effect of FNT on adipogenesis and in vivo bone loss, triggered by high-fat diet (HFD)-induced obesity. The anti-obesity effect and mechanism of action of FNT was determined in 3T3-L1 cells and HFD-induced obese male mice. Our findings show that FNT suppresses the adipogenic differentiation of 3T3-L1 fibroblasts, through down-regulation of key adipogenic markers such as PPARγ, CCAAT/enhancer-binding protein alpha (C/EBPα) and sterol regulatory element-binding protein (SREBP) and inhibits intracellular TAG accumulation. Increased intracellular reactive oxygen species levels and AMP-activated protein kinase (AMPK) activation accompanied by stabilisation of β-catenin were attributed to the anti-adipogenic action of FNT. In vivo, 12 weeks of FNT treatment inhibited the development of obesity in mice by attenuating HFD-induced body weight gain and visceral fat accumulation. The anti-obesity effect of FNT results from increased energy expenditure. FNT also protects against HFD-induced dyslipidaemia and rescues deterioration of trabecular bone volume by increasing bone formation and decreasing bone resorbtion caused by HFD. FNT's rescuing action against obesity-induced osteoporosis commenced at the level of progenitors, as bone marrow progenitor cells, obtained from the HFD mice group supplemented with FNT, showed increased osteogenic and decreased adipogenic potentials. Our findings suggest that FNT inhibits adipogenesis through AMPK/β-catenin signal transduction pathways and protects against HFD-induced obesity and bone loss.

Effects of inequity on job satisfaction and self-evaluation in a national sample of African-American workers.

PubMed

Perry, L S

1993-08-01

Data from a national survey of African-American workers were used to test predictions from equity theory regarding the "distress" that results from negative inequity (below expected level) and positive inequity (above expected level) in pay and occupational prestige. The results showed differential effects of the two types of inequity on dependent variables of job satisfaction and self-report of job-related skill. Although those faced with opposite forms of inequity fostered different strategies for inequity reduction, in each case, workers chose a strategy that was self-protective.

Combinations of Ashwagandha Leaf Extracts Protect Brain-Derived Cells against Oxidative Stress and Induce Differentiation

PubMed Central

Shah, Navjot; Singh, Rumani; Sarangi, Upasana; Saxena, Nishant; Chaudhary, Anupama; Kaur, Gurcharan; Kaul, Sunil C.; Wadhwa, Renu

2015-01-01

Background Ashwagandha, a traditional Indian herb, has been known for its variety of therapeutic activities. We earlier demonstrated anticancer activities in the alcoholic and water extracts of the leaves that were mediated by activation of tumor suppressor functions and oxidative stress in cancer cells. Low doses of these extracts were shown to possess neuroprotective activities in vitro and in vivo assays. Methodology/Principal Findings We used cultured glioblastoma and neuroblastoma cells to examine the effect of extracts (alcoholic and water) as well as their bioactive components for neuroprotective activities against oxidative stress. Various biochemical and imaging assays on the marker proteins of glial and neuronal cells were performed along with their survival profiles in control, stressed and recovered conditions. We found that the extracts and one of the purified components, withanone, when used at a low dose, protected the glial and neuronal cells from oxidative as well as glutamate insult, and induced their differentiation per se. Furthermore, the combinations of extracts and active component were highly potent endorsing the therapeutic merit of the combinational approach. Conclusion Ashwagandha leaf derived bioactive compounds have neuroprotective potential and may serve as supplement for brain health. PMID:25789768

Black rice (Oryza sativa L.) extracts induce osteoblast differentiation and protect against bone loss in ovariectomized rats.

PubMed

Jang, Woo-Seok; Seo, Cho-Rong; Jang, Hwan Hee; Song, No-Joon; Kim, Jong-Keun; Ahn, Jee-Yin; Han, Jaejoon; Seo, Woo Duck; Lee, Young Min; Park, Kye Won

2015-01-01

Osteoporosis, an age associated skeletal disease, exhibits increased adipogenesis at the expense of osteogenesis from common osteoporotic bone marrow cells. In this study, black rice (Oryza sativa L.) extracts (BRE) were identified as osteogenic inducers. BRE stimulated the alkaline phosphatase (ALP) activity in both C3H10T1/2 and primary bone marrow cells. Similarly, BRE increased mRNA expression of ALP and osterix. Oral administration of BRE in OVX rats prevented decreases in bone density and strength. By contrast, BRE inhibited adipocyte differentiation of mesenchymal C3H10T1/2 cells and prevented increases in body weight and fat mass in high fat diet fed obese mice, further suggesting the dual effects of BRE on anti-adipogenesis and pro-osteogenesis. UPLC analysis identified cyanidin-3-O-glucoside and peonidin-3-O-glucoside as main anti-adipogenic effectors but not for pro-osteogenic induction. In mechanism studies, BRE selectively stimulated Wnt-driven luciferase activities. BRE treatment also induced Wnt-specific target genes such as Axin2, WISP2, and Cyclin D1. Taken together, these data suggest that BRE is a potentially useful ingredient to protect against age related osteoporosis and diet induced obesity.

Sustained Expression of Negative Regulators of Myelination Protects Schwann Cells from Dysmyelination in a Charcot-Marie-Tooth 1B Mouse Model.

PubMed

Florio, Francesca; Ferri, Cinzia; Scapin, Cristina; Feltri, M Laura; Wrabetz, Lawrence; D'Antonio, Maurizio

2018-05-02

Schwann cell differentiation and myelination in the PNS are the result of fine-tuning of positive and negative transcriptional regulators. As myelination starts, negative regulators are downregulated, whereas positive ones are upregulated. Fully differentiated Schwann cells maintain an extraordinary plasticity and can transdifferentiate into "repair" Schwann cells after nerve injury. Reactivation of negative regulators of myelination is essential to generate repair Schwann cells. Negative regulators have also been implicated in demyelinating neuropathies, although their role in disease remains elusive. Here, we used a mouse model of Charcot-Marie-Tooth neuropathy type 1B (CMT1B), the P0S63del mouse characterized by ER stress and the activation of the unfolded protein response, to show that adult Schwann cells are in a partial differentiation state because they overexpress transcription factors that are normally expressed only before myelination. We provide evidence that two of these factors, Sox2 and Id2, act as negative regulators of myelination in vivo However, their sustained expression in neuropathy is protective because ablation of Sox2 or/and Id2 from S63del mice of both sexes results in worsening of the dysmyelinating phenotype. This is accompanied by increased levels of mutant P0 expression and exacerbation of ER stress, suggesting that limited differentiation may represent a novel adaptive mechanism through which Schwann cells counter the toxic effect of a mutant terminal differentiation protein. SIGNIFICANCE STATEMENT In many neuropathies, Schwann cells express high levels of early differentiation genes, but the significance of these altered expression remained unclear. Because many of these factors may act as negative regulators of myelination, it was suggested that their misexpression could contribute to dysmyelination. Here, we show that the transcription factors Sox2 and Id2 act as negative regulators of myelination in vivo , but that their sustained expression in Charcot-Marie-Tooth type 1B (CMT1B) represents an adaptive response activated by the Schwann cells to reduce mutant protein toxicity and prevent demyelination. Copyright © 2018 the authors 0270-6474/18/384275-14$15.00/0.

Law and Equal Rights for Educational Opportunity.

ERIC Educational Resources Information Center

White, Sharon

Arguing violation of the equal protection clause of Federal and State constitutions, court actions in several States have challenged the method of financing public education. The issues raised concern interdistrict differentials in assessed valuation of properties. These differentials result in lower per-pupil funds for urban and rural districts…

Do we really need to differentiate mesenchymal stem cells into insulin-producing cells for attenuation of the autoimmune responses in type 1 diabetes: immunoprophylactic effects of precursors to insulin-producing cells.

PubMed

Sharma, Anshu; Rani, Rajni

2017-07-12

Type 1 diabetes (T1D) is a multifactorial autoimmune disorder where pancreatic beta cells are lost before the clinical manifestations of the disease. Administration of mesenchymal stem cells (MSCs) or MSCs differentiated into insulin-producing cells (IPCs) have yielded limited success when used therapeutically. We have evaluated the immunoprophylactic potentials of precursors to insulin-producing cells (pIPCs) and IPCs in nonobese diabetic (NOD) mice to ask a basic question: do we need to differentiate MSCs into IPCs or will pIPCs suffice to attenuate autoimmune responses in T1D? Bone marrow-derived MSCs from Balb/c mice were characterized following the International Society for Cellular Therapy (ISCT) guidelines. MSCs cultured in high-glucose media for 11 to 13 passages were characterized for the expression of pancreatic lineage genes using real-time polymerase chain reaction. Expression of the PDX1 gene in pIPCs was assessed using Western blot and fluorescence-activated cell sorting (FACS). Triple-positive MSCs were differentiated into IPCs using a three-step protocol after sorting them for cell surface markers, i.e. CD29, CD44, and SCA-1. Nonobese diabetic mice were administered pIPCs, IPCs, or phosphate-buffered saline (PBS) into the tail vein at weeks 9 or 10 and followed-up for 29-30 weeks for fasting blood glucose levels. Two consecutive blood sugar levels of more than 250 mg/dl were considered diabetic. MSCs grown in high-glucose media for 11 to 13 passages expressed genes of the pancreatic lineage such as PDX1, beta2, neurogenin, PAX4, Insulin, and glucagon. Furthermore, Western blot and FACS analysis for PDX-1, a transcription factor necessary for beta cell maturation, confirmed that these cells were precursors of insulin-producing cells (pIPCs). NOD mice administered with pIPCs were better protected from developing diabetes with a protective efficacy of 78.4% (p < 0.009); however, administration of IPCs gave protective efficacy of 55% at the end of 28-30 weeks. Precursors to insulin-producing cells seem to have better potential to arrest autoimmune response in type 1 diabetes when administered before the onset of the disease in NOD mice. When translated to humans, autologous mesenchymal stem cells grown in high-glucose media for 10 to 13 passages may have beneficial effects in individuals at high risk of developing type 1 diabetes.

Antagonism between granulocytic maturation and deacetylase inhibitor-induced apoptosis in acute promyelocytic leukaemia cells.

PubMed

Hennig, D; Müller, S; Wichmann, C; Drube, S; Pietschmann, K; Pelzl, L; Grez, M; Bug, G; Heinzel, T; Krämer, O H

2015-01-20

Transcriptional repression is a key mechanism driving leukaemogenesis. In acute promyelocytic leukaemia (APL), the fusion protein promyelocytic leukaemia-retinoic acid receptor-α fusion (PML-RARα) recruits transcriptional repressors to myeloid differentiation genes. All-trans-retinoic acid (ATRA) induces the proteasomal degradation of PML-RARα and granulocytic differentiation. Histone deacetylases (HDACs) fall into four classes (I-IV) and contribute to the transcription block caused by PML-RARα. Immunoblot, flow cytometry, and May-Grünwald-Giemsa staining were used to analyze differentiation and induction of apoptosis. A PML-RARα- and ATRA-dependent differentiation programme induces granulocytic maturation associated with an accumulation of the myeloid transcription factor CCAAT/enhancer binding protein (C/EBP)ɛ and of the surface protein CD11b. While this process protects APL cells from inhibitors of class I HDAC activity, inhibition of all Zinc-dependent HDACs (classes I, II, and IV) with the pan-HDACi (histone deacetylase inhibitor(s)) LBH589 induces apoptosis of immature and differentiated APL cells. LBH589 can eliminate C/EBPɛ and the mitochondrial apoptosis regulator B-cell lymphoma (BCL)-xL in immature and differentiated NB4 cells. Thus, BCL-xL and C/EBPɛ are newly identified molecular markers for the efficacy of HDACi against APL cells. Our results could explain the therapeutic limitations occurring with ATRA and class I HDACi combinations. Pro-apoptotic effects caused by pan-HDAC inhibition are not blunted by ATRA-induced differentiation and may provide a clinically interesting alternative.

Induced miR-99a expression represses Mtor cooperatively with miR-150 to promote regulatory T-cell differentiation

PubMed Central

Warth, Sebastian C; Hoefig, Kai P; Hiekel, Anian; Schallenberg, Sonja; Jovanovic, Ksenija; Klein, Ludger; Kretschmer, Karsten; Ansel, K Mark; Heissmeyer, Vigo

2015-01-01

Peripheral induction of regulatory T (Treg) cells provides essential protection from inappropriate immune responses. CD4+ T cells that lack endogenous miRNAs are impaired to differentiate into Treg cells, but the relevant miRNAs are unknown. We performed an overexpression screen with T-cell-expressed miRNAs in naive mouse CD4+ T cells undergoing Treg differentiation. Among 130 candidates, the screen identified 29 miRNAs with a negative and 10 miRNAs with a positive effect. Testing reciprocal Th17 differentiation revealed specific functions for miR-100, miR-99a and miR-10b, since all of these promoted the Treg and inhibited the Th17 program without impacting on viability, proliferation and activation. miR-99a cooperated with miR-150 to repress the expression of the Th17-promoting factor mTOR. The comparably low expression of miR-99a was strongly increased by the Treg cell inducer “retinoic acid”, and the abundantly expressed miR-150 could only repress Mtor in the presence of miR-99a. Our data suggest that induction of Treg cell differentiation is regulated by a miRNA network, which involves cooperation of constitutively expressed as well as inducible miRNAs. PMID:25712478

Reduction in radiation-induced brain injury by use of pentobarbital or lidocaine protection

DOE Office of Scientific and Technical Information (OSTI.GOV)

Oldfield, E.H.; Friedman, R.; Kinsella, T.

1990-05-01

To determine if barbiturates would protect brain at high doses of radiation, survival rates in rats that received whole-brain x-irradiation during pentobarbital- or lidocaine-induced anesthesia were compared with those of control animals that received no medication and of animals anesthetized with ketamine. The animals were shielded so that respiratory and digestive tissues would not be damaged by the radiation. Survival rates in rats that received whole-brain irradiation as a single 7500-rad dose under pentobarbital- or lidocaine-induced anesthesia was increased from between from 0% and 20% to between 45% and 69% over the 40 days of observation compared with the othermore » two groups (p less than 0.007). Ketamine anesthesia provided no protection. There were no notable differential effects upon non-neural tissues, suggesting that pentobarbital afforded protection through modulation of ambient neural activity during radiation exposure. Neural suppression during high-dose cranial irradiation protects brain from acute and early delayed radiation injury. Further development and application of this knowledge may reduce the incidence of radiation toxicity of the central nervous system (CNS) and may permit the safe use of otherwise unsafe doses of radiation in patients with CNS neoplasms.« less

Effects of cash transfers on Children's health and social protection in Sub-Saharan Africa: differences in outcomes based on orphan status and household assets.

PubMed

Crea, Thomas M; Reynolds, Andrew D; Sinha, Aakanksha; Eaton, Jeffrey W; Robertson, Laura A; Mushati, Phyllis; Dumba, Lovemore; Mavise, Gideon; Makoni, J C; Schumacher, Christina M; Nyamukapa, Constance A; Gregson, Simon

2015-05-28

Unconditional and conditional cash transfer programmes (UCT and CCT) show potential to improve the well-being of orphans and other children made vulnerable by HIV/AIDS (OVC). We address the gap in current understanding about the extent to which household-based cash transfers differentially impact individual children's outcomes, according to risk or protective factors such as orphan status and household assets. Data were obtained from a cluster-randomised controlled trial in eastern Zimbabwe, with random assignment to three study arms - UCT, CCT or control. The sample included 5,331 children ages 6-17 from 1,697 households. Generalized linear mixed models were specified to predict OVC health vulnerability (child chronic illness and disability) and social protection (birth registration and 90% school attendance). Models included child-level risk factors (age, orphan status); household risk factors (adults with chronic illnesses and disabilities, greater household size); and household protective factors (including asset-holding). Interactions were systematically tested. Orphan status was associated with decreased likelihood for birth registration, and paternal orphans and children for whom both parents' survival status was unknown were less likely to attend school. In the UCT arm, paternal orphans fared better in likelihood of birth registration compared with non-paternal orphans. Effects of study arms on outcomes were not moderated by any other risk or protective factors. High household asset-holding was associated with decreased likelihood of child's chronic illness and increased birth registration and school attendance, but household assets did not moderate the effects of cash transfers on risk or protective factors. Orphaned children are at higher risk for poor social protection outcomes even when cared for in family-based settings. UCT and CCT each produced direct effects on children's social protection which are not moderated by other child- and household-level risk factors, but orphans are less likely to attend school or obtain birth registration. The effects of UCT and CCT are not moderated by asset-holding, but greater household assets predict greater social protection outcomes. Intervention efforts need to focus on ameliorating the additional risk burden carried by orphaned children. These efforts might include caregiver education, and additional incentives based on efforts made specifically for orphaned children.

SNJ-1945, a calpain inhibitor, protects SH-SY5Y cells against MPP+ and rotenone

PubMed Central

Knaryan, Varduhi H.; Samantaray, Supriti; Sookyoung, Park; Azuma, Mitsuyoshi; Inoue, Jun; Banik, Naren L.

2014-01-01

Complex pathophysiology of Parkinson’s disease (PD) involves multiple CNS cell types. Degeneration in spinal cord neurons alongside brain has been shown to be involved in PD and evidenced in experimental parkinsonism. However, the mechanisms of these degenerative pathways are not well understood. In order to unravel these mechanisms SH-SY5Y neuroblastoma cells were differentiated into dopaminergic and cholinergic phenotypes respectively and used as cell culture model following exposure to two parkinsonian neurotoxicants MPP+ and rotenone. SNJ-1945, a cell-permeable calpain inhibitor was tested for its neuroprotective efficacy. MPP+ and rotenone dose-dependently elevated the levels of intracellular free Ca2+ and induced a concomitant rise in the levels of active calpain. SNJ-1945 pre-treatment significantly protected cell viability and preserved cellular morphology following MPP+ and rotenone exposure. The neurotoxicants elevated the levels of reactive oxygen species (ROS) more profoundly in SH-SY5Y cells differentiated into dopaminergic phenotype, and this effect could be attenuated with SNJ-1945 pre-treatment. In contrast, significant levels of inflammatory mediators (cyclooxygenase-2, Cox-2 and cleaved p10 fragment of caspase-1) were upregulated in the cholinergic phenotype, which could be dose-dependently attenuated by the calpain inhibitor. Overall, SNJ-1945 was efficacious against MPP+ or rotenone-induced ROS generation, inflammatory mediators, and proteolysis. A post-treatment regimen of SNJ-1945 was also examined in cells and partial protection was attained with calpain inhibitor administration 1–3 h after exposure to MPP+ or rotenone. Taken together these results indicate that calpain inhibition is a valid target for protection against parkinsonian neurotoxicants, and SNJ-1945 is an efficacious calpain inhibitor in this context. PMID:24341912

Differential inhibition of oxidized LDL-induced apoptosis in human endothelial cells treated with different flavonoids.

PubMed

Jeong, Yu-Jin; Choi, Yean-Jung; Kwon, Hyang-Mi; Kang, Sang-Wook; Park, Hyoung-Sook; Lee, Myungsook; Kang, Young-Hee

2005-05-01

High plasma level of cholesterol is a well-known risk factor for atherosclerotic diseases. Oxidized LDL induces cellular and nuclear damage that leads to apoptotic cell death. We tested the hypothesis that flavonoids may function as antioxidants with regard to LDL incubated with 5 microm-Cu(2+) alone or in combination with human umbilical vein endothelial cells (HUVEC). Cytotoxicity and formation of thiobarbituric acid-reactive substances induced by Cu(2+)-oxidized LDL were examined in the presence of various subtypes of flavonoid. Flavanols, flavonols and flavanones at a non-toxic dose of 50 microm markedly inhibited LDL oxidation by inhibiting the formation of peroxidative products. In contrast, the flavones luteolin and apigenin had no such effect, with >30 % of cells killed after exposure to 0.1 mg LDL/ml. Protective flavonoids, especially (-)-epigallocatechin gallate, quercetin, rutin and hesperetin, inhibited HUVEC nuclear condensation and fragmentation induced by Cu(2+)-oxidized LDL. In addition, immunochemical staining and Western blot analysis revealed that anti-apoptotic Bcl-2 expression was enhanced following treatment with these protective flavonoids. However, Bax expression and caspase-3 cleavage stimulated by 18 h incubation with oxidized LDL were reduced following treatment with these protective flavonoids. The down-regulation of Bcl-2 and up-regulation of caspase-3 activation were reversed by the cytoprotective flavonoids, (-)-epigallocatechin gallate, quercetin and hesperetin, at >/=10 microm. These results suggest that flavonoids may differentially prevent Cu(2+)-oxidized LDL-induced apoptosis and promote cell survival as potent antioxidants. Survival potentials of certain flavonoids against cytotoxic oxidized LDL appeared to stem from their disparate chemical structure. Furthermore, dietary flavonoids may have therapeutic potential for protecting the endothelium from oxidative stress and oxidized LDL-triggered atherogenesis.

Examining Differential Resilience Mechanisms by Comparing 'Tipping Points' of the Effects of Neighborhood Conditions on Anxiety by Race/Ethnicity.

PubMed

Coman, Emil Nicolae; Wu, Helen Zhao

2018-02-20

Exposure to adverse environmental and social conditions affects physical and mental health through complex mechanisms. Different racial/ethnic (R/E) groups may be more or less vulnerable to the same conditions, and the resilience mechanisms that can protect them likely operate differently in each population. We investigate how adverse neighborhood conditions (neighborhood disorder, NDis) differentially impact mental health (anxiety, Anx) in a sample of white and Black (African American) young women from Southeast Texas, USA. We illustrate a simple yet underutilized segmented regression model where linearity is relaxed to allow for a shift in the strength of the effect with the levels of the predictor. We compare how these effects change within R/E groups with the level of the predictor, but also how the "tipping points," where the effects change in strength, may differ by R/E. We find with classic linear regression that neighborhood disorder adversely affects Black women's anxiety, while in white women the effect seems negligible. Segmented regressions show that the Ndis → Anx effects in both groups of women appear to shift at similar levels, about one-fifth of a standard deviation below the mean of NDis, but the effect for Black women appears to start out as negative, then shifts in sign, i.e., to increase anxiety, while for white women, the opposite pattern emerges. Our findings can aid in devising better strategies for reducing health disparities that take into account different coping or resilience mechanisms operating differentially at distinct levels of adversity. We recommend that researchers investigate when adversity becomes exceedingly harmful and whether this happens differentially in distinct populations, so that intervention policies can be planned to reverse conditions that are more amenable to change, in effect pushing back the overall social risk factors below such tipping points.

Effects of Polymethoxyflavonoids on Bone Loss Induced by Estrogen Deficiency and by LPS-Dependent Inflammation in Mice.

PubMed

Matsumoto, Shigeru; Tominari, Tsukasa; Matsumoto, Chiho; Yoshinouchi, Shosei; Ichimaru, Ryota; Watanabe, Kenta; Hirata, Michiko; Grundler, Florian M W; Miyaura, Chisato; Inada, Masaki

2018-01-20

Polymethoxyflavonoids (PMFs) are a family of the natural compounds that mainly compise nobiletin, tangeretin, heptamethoxyflavone (HMF), and tetramethoxyflavone (TMF) in citrus fruits. PMFs have shown various biological functions, including anti-oxidative effects. We previously showed that nobiletin, tangeretin, and HMF all inhibited interleukin (IL)-1-mediated osteoclast differentiation via the inhibition of prostaglandin E2 synthesis. In this study, we created an original mixture of PMFs (nobiletin, tangeretin, HMF, and TMF) and examined whether or not PMFs exhibit co-operative inhibitory effects on osteoclastogenesis and bone resorption. In a coculture of bone marrow cells and osteoblasts, PMFs dose-dependently inhibited IL-1-induced osteoclast differentiation and bone resorption. The optimum concentration of PMFs was lower than that of nobiletin alone in the suppression of osteoclast differentiation, suggesting that the potency of PMFs was stronger than that of nobiletin in vitro. The oral administration of PMFs recovered the femoral bone loss induced by estrogen deficiency in ovariectomized mice. We further tested the effects of PMFs on lipopolysaccharide-induced bone resorption in mouse alveolar bone. In an ex vivo experimental model for periodontitis, PMFs significantly suppressed the bone-resorbing activity in organ cultures of mouse alveolar bone. These results indicate that a mixture of purified nobiletin, tangeretin, HMF, and TMF exhibits a co-operative inhibitory effect for the protection against bone loss in a mouse model of bone disease, suggesting that PMFs may be potential candidates for the prevention of bone resorption diseases, such as osteoporosis and periodontitis.

Integrated conservation and development: evaluating a community-based marine protected area project for equality of socioeconomic impacts.

PubMed

Gurney, Georgina G; Pressey, Robert L; Cinner, Joshua E; Pollnac, Richard; Campbell, Stuart J

2015-11-05

Despite the prevalence of protected areas, evidence of their impacts on people is weak and remains hotly contested in conservation policy. A key question in this debate is whether socioeconomic impacts vary according to social subgroup. Given that social inequity can create conflict and impede poverty reduction, understanding how protected areas differentially affect people is critical to designing them to achieve social and biological goals. Understanding heterogeneous responses to protected areas can improve targeting of management activities and help elucidate the pathways through which impacts of protected areas occur. Here, we assessed whether the socioeconomic impacts of marine protected areas (MPAs)-designed to achieve goals for both conservation and poverty alleviation-differed according to age, gender or religion in associated villages in North Sulawesi, Indonesia. Using data from pre-, mid- and post-implementation of the MPAs for control and project villages, we found little empirical evidence that impacts on five key socioeconomic indicators related to poverty differed according to social subgroup. We found suggestive empirical evidence that the effect of the MPAs on environmental knowledge differed by age and religion; over the medium and long terms, younger people and Muslims showed greater improvements compared with older people and Christians, respectively. © 2015 The Author(s).

Integrated conservation and development: evaluating a community-based marine protected area project for equality of socioeconomic impacts

PubMed Central

Gurney, Georgina G.; Pressey, Robert L.; Cinner, Joshua E.; Pollnac, Richard; Campbell, Stuart J.

2015-01-01

Despite the prevalence of protected areas, evidence of their impacts on people is weak and remains hotly contested in conservation policy. A key question in this debate is whether socioeconomic impacts vary according to social subgroup. Given that social inequity can create conflict and impede poverty reduction, understanding how protected areas differentially affect people is critical to designing them to achieve social and biological goals. Understanding heterogeneous responses to protected areas can improve targeting of management activities and help elucidate the pathways through which impacts of protected areas occur. Here, we assessed whether the socioeconomic impacts of marine protected areas (MPAs)—designed to achieve goals for both conservation and poverty alleviation—differed according to age, gender or religion in associated villages in North Sulawesi, Indonesia. Using data from pre-, mid- and post-implementation of the MPAs for control and project villages, we found little empirical evidence that impacts on five key socioeconomic indicators related to poverty differed according to social subgroup. We found suggestive empirical evidence that the effect of the MPAs on environmental knowledge differed by age and religion; over the medium and long terms, younger people and Muslims showed greater improvements compared with older people and Christians, respectively. PMID:26460130

Gastrodia and Uncaria (tianma gouteng) water extract exerts antioxidative and antiapoptotic effects against cerebral ischemia in vitro and in vivo.

PubMed

Xian, Jia Wen; Choi, Angus Yiu-Ting; Lau, Clara Bik-San; Leung, Wing Nang; Ng, Chun Fai; Chan, Chun Wai

2016-01-01

Gastrodia and Uncaria decoction (tianma gouteng yin) is commonly used in Chinese medicine to treat cerebral ischemia. The aim of this study was to investigate the neuroprotective effects of a water extract (GUW) of Gastrodia elata (tianma; GE) and Uncaria rhynchophylla (gouteng; UR) against ischemic insult using oxygen-glucose-deprived neuronal differentiated PC12 cells and rats subjected to middle cerebral artery occlusion (MCAO). GUW was prepared by boiling raw GE and UR in water, followed by the lyophilization of the resulting extract. Neuronal differentiated PC12 cells were subjected to oxygen-glucose deprivation with or without GUW. The neuroprotective effects of GUW were compared with those of the corresponding GE and UR extracts to tease apart the effects of the different herbs. The synergistic effect of GE and UR in GUW was measured using a modified version of Burgi's formulae. The neuroprotective mechanisms via Nrf2 and anti-apoptotic pathways were investigated using real time PCR and enzyme activity assays. The neuroprotective effects of GUW were studied in vivo using a rat MCAO model. Neurofunctional outcome and brain infarct volume we assessed. H&E staining, cresyl violet staining and immunohistochemistry were performed to assess the histological outcome. The results of lactate dehydrogenase assay showed that GUW protected cells in a concentration-dependent manner (P < 0.001). Moreover, the neuroprotective effects of GUW were greater than those of GE + UR (P = 0.018). Burgi's formula showed that the herbs in GUW acted synergistically to protect cells from ischemic injury. GUW significantly upregulated Bcl-2 expression (P = 0.0130) and reduced caspase-3 activity by 60 % (P < 0.001). GUW upregulated Nrf-2 expression (P = 0.0066) and the antioxidant response element pathway genes. The infarct volume was reduced by 55 % at day 7 of reperfusion (P < 0.001), and significant improvements were observed in the neurological deficit score and beam-walking test at 7 days (P < 0.001). H&E and cresyl violet staining revealed higher tissue integrity in the GUW treatment group compared with MCAO rats. GUW modulated the antioxidant system and antiapoptotic genes in oxygen-glucose deprived neuronal differentiated PC12 cells and MCAO sprague-dawley rats.

Implementation of Pilot Protection System for Large Scale Distribution System like The Future Renewable Electric Energy Distribution Management Project

NASA Astrophysics Data System (ADS)

Iigaya, Kiyohito

A robust, fast and accurate protection system based on pilot protection concept was developed previously and a few alterations in that algorithm were made to make it faster and more reliable and then was applied to smart distribution grids to verify the results for it. The new 10 sample window method was adapted into the pilot protection program and its performance for the test bed system operation was tabulated. Following that the system comparison between the hardware results for the same algorithm and the simulation results were compared. The development of the dual slope percentage differential method, its comparison with the 10 sample average window pilot protection system and the effects of CT saturation on the pilot protection system are also shown in this thesis. The implementation of the 10 sample average window pilot protection system is done to multiple distribution grids like Green Hub v4.3, IEEE 34, LSSS loop and modified LSSS loop. Case studies of these multi-terminal model are presented, and the results are also shown in this thesis. The result obtained shows that the new algorithm for the previously proposed protection system successfully identifies fault on the test bed and the results for both hardware and software simulations match and the response time is approximately less than quarter of a cycle which is fast as compared to the present commercial protection system and satisfies the FREEDM system requirement.

Differential Protection from Tobramycin by Extracellular Polymeric Substances from Acinetobacter baumannii and Staphylococcus aureus Biofilms

PubMed Central

Davenport, Emily K.; Call, Douglas R.

2014-01-01

We investigated biofilms of two pathogens, Acinetobacter baumannii and Staphylococcus aureus, to characterize mechanisms by which the extracellular polymeric substance (EPS) found in biofilms can protect bacteria against tobramycin exposure. To do so, it is critical to study EPS-antibiotic interactions in a homogeneous environment without mass transfer limitations. Consequently, we developed a method to grow biofilms, harvest EPS, and then augment planktonic cultures with isolated EPS and tobramycin. We demonstrated that planktonic cultures respond differently to being treated with different types of EPS (A. baumannii versus S. aureus) in the presence of tobramycin. By harvesting EPS from the biofilms, we found that A. baumannii EPS acts as a “universal protector” by inhibiting tobramycin activity against bacterial cells regardless of species; S. aureus EPS did not show any protective ability in cell cultures. Adding Mg2+ or Ca2+ reduced the protective effect of A. baumannii EPS. Finally, when we selectively digested the proteins or DNA of the EPS, we found that the protective ability did not change, suggesting that neither has a significant role in protection. To the best of our knowledge, this is the first study that demonstrates how EPS protects pathogens against antibiotics in a homogeneous system without mass transfer limitations. Our results suggest that EPS protects biofilm communities, in part, by adsorbing antibiotics near the surface. This may limit antibiotic diffusion to the bottom of the biofilms but is not likely to be the only mechanism of protection. PMID:24913166

Protective Effect of Pyruvate Against Radiation-Induced Damage in Collagenized Tissues

NASA Technical Reports Server (NTRS)

Griko, Y. V.; Yan, Xiaoli

2016-01-01

Exposure to high doses of ionizing radiation produces both acute and late effects on the collagenized tissues and have profound effects on wound healing. Because of the crucial practical importance for new radioprotective agents, our study has been focused on evaluation of the efficacy of non-toxic naturally occurring compounds to protect tissue integrity against high-dose gamma radiation. Here, we demonstrate that molecular integrity of collagen may serve as a sensitive biological marker for quantitative evaluation of molecular damage to collagenized tissue and efficacy of radioprotective agents. Increasing doses of gamma radiation (0-50kGy) result in progressive destruction of the native collagen fibrils, which provide a structural framework, strength, and proper milieu for the regenerating tissue. The strategy used in this study involved the thermodynamic specification of all structural changes in collagenized matrix of skin, aortic heart valve, and bone tissue induced by different doses and conditions of g-irradiation. This study describes a simple biophysical approach utilizing the Differential Scanning Calorimetry (DSC) to characterize the structural resistance of the aortic valve matrix exposed to different doses of g-irradiation. It allows us to identify the specific response of each constituent as well as to determine the influence of the different treatments on the characteristic parameters of protein structure. We found that pyruvate, a substance that naturally occurs in the body, provide significant protection (up to 80%) from biochemical and biomechanical damage to the collagenized tissue through the effective targeting of reactive oxygen species. The recently discovered role of pyruvate in the cell antioxidant defense to O2 oxidation, and its essential constituency in the daily human diet, indicate that the administration of pyruvate-based radioprotective formulations may provide safe and effective protection from deleterious effects of ionizing radiation.

Plasma Rich in Growth Factors Enhances Wound Healing and Protects from Photo-oxidative Stress in Dermal Fibroblasts and 3D Skin Models.

PubMed

Anitua, Eduardo; Pino, Ander; Jaen, Pedro; Orive, Gorka

2016-01-01

Optimal skin repair has been a desired goal for many researchers. Recently, plasma rich in growth factors (PRGF) has gained importance in dermatology proving it is beneficial effects in wound healing and cutaneous regeneration. The anti-fibrotic, pro-contractile and photo-protective effect of PRGF on dermal fibroblasts and 3D skin models has been evaluated. The effect against TGFβ1 induced myofibroblast differentiation was tested. Cell contractile activity over collagen gel matrices was analyzed and the effect against UV derived photo-oxidative stress was assessed. The effectiveness of PRGF obtained from young aged and middle aged donors was compared. Furthermore, 3D organotypic skin explants were used as human skin models with the aim of analyzing ex vivo cutaneous preventive and regenerative photo-protection after UV exposure. TGFβ1 induced myofibroblast levels decreased significantly after treatment with PRGF while the contractile activity increased compared to the control group. After UV irradiation, cell survival was promoted while apoptotic and ROS levels were noticeably reduced. Photo-exposed 3D explants showed higher levels of metabolic activity and lower levels of necrosis, cell damage, irritation and ROS formation when treated with PRGF. The histological integrity and connective tissue fibers showed lower signals of photodamage among PRGF injected skin models. No significant differences for the assessed biological outcomes were observed when PRGF obtained from young aged and middle aged donors were compared. These findings suggest that this autologous approach might be useful for antifibrotic wound healing and provide an effective protection against sun derived photo-oxidative stress regardless the age of the patient.

Effects of multiple viewings of an ultraviolet photo on sun protection behaviors.

PubMed

Mahler, H I M

2018-05-02

To determine whether multiple viewings of one's ultraviolet (UV) facial photo differentially affects subsequent sun protection behaviors relative to a single viewing. Pretest-posttest control group. Southern California college students (N = 151) were randomly assigned to be shown their UV facial photo one time, multiple times over the course of 2 weeks, or not at all. Emotional reactions, perceived susceptibility to skin damage, and sun protection intentions were assessed immediately, and sun protection behaviors were assessed during a surprise telephonic follow-up 1 month later. Immediately after viewing a UV photo of their face, participants reported significantly greater perceived susceptibility to skin damage, greater intentions to engage in future sun protection, and more negative emotions than those who had not seen a UV photo. Moreover, 1 month later, those who had viewed their UV photo were less likely to report having sunbathed and reported significantly greater sun protection than did controls. There were no differences in sun protection behaviors between those who had been shown their UV photo only once during the initial intervention session and those who had been sent their UV photo several times thereafter. However, among those who had been sent their UV photo several times, those who reported having viewed their photo on additional occasions reported significantly greater sun protection behaviors than those who had not. Being randomly assigned to view a UV facial photo multiple times generally neither strengthened nor weakened effects on subsequent sun protection behaviors relative to being shown the photo just once. However, among those who were sent their photo and thus had the option of viewing it more often than they had been assigned to, those who chose to view their photo more frequently also engaged in more sun protection behaviors. Copyright © 2018 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.

Chemoprevention of Breast Cancer by Mimicking the Protective Effect of Early First Birth

DTIC Science & Technology

2006-06-01

and differentiation in the rodent mammary gland. Mol Endocrinol 2002;16:2034–51. 7. Thordarson G, Jin E, Guzman RC, Swanson SM, Nandi S, Talamantes F...8. 11. Rajkumar L, Guzman RC, Yang J, Thordarson G, Talamantes F, Nandi S. Short-term exposure to preg- nancy levels of estrogen prevents mammary...carcino- genesis. Proc Natl Acad Sci U S A 2001;98:11755–9. 12. Guzman RC, Yang J, Rajkumar L, Thordarson G, Chen X, Nandi S. Hormonal prevention of

GPER activation is effective in protecting against inflammation-induced nigral dopaminergic loss and motor function impairment.

PubMed

Mendes-Oliveira, Julieta; Lopes Campos, Filipa; Videira, Rita Alexandra; Baltazar, Graça

2017-08-01

Increasing evidence suggest that excessive inflammatory responses from overactivated microglia play a critical role in Parkinson's disease (PD), contributing to, or exacerbating, nigral dopaminergic (DA) degeneration. Recent results from our group and others demonstrated that selective activation of G protein-coupled estrogen receptor (GPER) with the agonist G1 can protect DA neurons from 1-methyl-4-phenylpyridinium (MPP + ) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxins. However, it is not known whether modulation of microglial responses is one of the mechanisms by which G1 exerts its DA neuroprotective effects. We analyzed, in the N9 microglial cell line, the effect of G1 on microglial activation induced by lipopolysaccharide (LPS) exposure. The results revealed that G1 significantly decrease phagocytic activity, expression of inducible nitric oxide synthase (iNOS) and release of nitric oxide (NO) induced by LPS. To determine the relevance of this anti-inflammatory effect to the protection of nigral DA cells, the effect of G1 was analyzed in male mice injected unilaterally in the substantia nigra (SN) with LPS. Although G1 treatment did not decrease LPS-induced increase of ionized calcium binding adaptor molecule 1 (iba-1) positive cells it significantly reduced interleukin-1beta (IL-1β), cluster of differentiation 68 (CD68) and iNOS mRNA levels, and totally inhibited nigral DA cell loss and, as a consequence, protected the motor function. In summary, our findings demonstrated that the G1 agonist is able to modulate microglial responses and to protect DA neurons and motor functions against a lesion induced by an inflammatory insult. Since G1 lacks the feminizing effects associated with agonists of the classical estrogen receptors (ERs), the use of G1 to selectively activate the GPER may be a promising strategy for the development of new therapeutics for the treatment of PD and other neuroinflammatory diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

Human neural progenitors differentiate into astrocytes and protect motor neurons in aging rats.

PubMed

Das, Melanie M; Avalos, Pablo; Suezaki, Patrick; Godoy, Marlesa; Garcia, Leslie; Chang, Christine D; Vit, Jean-Philippe; Shelley, Brandon; Gowing, Genevieve; Svendsen, Clive N

2016-06-01

Age-associated health decline presents a significant challenge to healthcare, although there are few animal models that can be used to test potential treatments. Here, we show that there is a significant reduction in both spinal cord motor neurons and motor function over time in the aging rat. One explanation for this motor neuron loss could be reduced support from surrounding aging astrocytes. Indeed, we have previously shown using in vitro models that aging rat astrocytes are less supportive to rat motor neuron function and survival over time. Here, we test whether rejuvenating the astrocyte niche can improve the survival of motor neurons in an aging spinal cord. We transplanted fetal-derived human neural progenitor cells (hNPCs) into the aging rat spinal cord and found that the cells survive and differentiate into astrocytes with a much higher efficiency than when transplanted into younger animals, suggesting that the aging environment stimulates astrocyte maturation. Importantly, the engrafted astrocytes were able to protect against motor neuron loss associated with aging, although this did not result in an increase in motor function based on behavioral assays. We also transplanted hNPCs genetically modified to secrete glial cell line-derived neurotrophic factor (GDNF) into the aging rat spinal cord, as this combination of cell and protein delivery can protect motor neurons in animal models of ALS. During aging, GDNF-expressing hNPCs protected motor neurons, though to the same extent as hNPCs alone, and again had no effect on motor function. We conclude that hNPCs can survive well in the aging spinal cord, protect motor neurons and mature faster into astrocytes when compared to transplantation into the young spinal cord. While there was no functional improvement, there were no functional deficits either, further supporting a good safety profile of hNPC transplantation even into the older patient population. Copyright © 2016 Elsevier Inc. All rights reserved.

Role of Phosphatidylinositol-3 Kinase Pathway in NMDA Preconditioning: Different Mechanisms for Seizures and Hippocampal Neuronal Degeneration Induced by Quinolinic Acid.

PubMed

Constantino, Leandra C; Binder, Luisa B; Vandresen-Filho, Samuel; Viola, Giordano G; Ludka, Fabiana K; Lopes, Mark W; Leal, Rodrigo B; Tasca, Carla I

2018-04-20

N-methyl D-aspartate (NMDA) preconditioning is evoked by the administration of a subtoxic dose of NMDA and is protective against neuronal excitotoxicity. This effect may involve a diversity of targets and cell signaling cascades associated to neuroprotection. Phosphatidylinositol-3 kinase/protein kinase B (PI3K/Akt) and mitogen-activated protein kinases (MAPKs) such as extracellular regulated protein kinase 1/2 (ERK1/2) and p38 MAPK pathways play a major role in neuroprotective mechanisms. However, their involvement in NMDA preconditioning was not yet fully investigated. The present study aimed to evaluate the effect of NMDA preconditioning on PI3K/Akt, ERK1/2, and p38 MAPK pathways in the hippocampus of mice and characterize the involvement of PI3K on NMDA preconditioning-evoked prevention of seizures and hippocampal cell damage induced by quinolinic acid (QA). Thus, mice received wortmannin (a PI3K inhibitor) and 15 min later a subconvulsant dose of NMDA (preconditioning) or saline. After 24 h of this treatment, an intracerebroventricular QA infusion was administered. Phosphorylation levels and total content of Akt, glycogen synthase protein kinase-3β (GSK-3β), ERK1/2, and p38 MAPK were not altered after 24 h of NMDA preconditioning with or without wortmmanin pretreatment. Moreover, after QA administration, behavioral seizures, hippocampal neuronal degeneration, and Akt activation were evaluated. Inhibition of PI3K pathway was effective in abolishing the protective effect of NMDA preconditioning against QA-induced seizures, but did not modify neuronal protection promoted by preconditioning as evaluated by Fluoro-Jade B staining. The study confirms that PI3K participates in the mechanism of protection induced by NMDA preconditioning against QA-induced seizures. Conversely, NMDA preconditioning-evoked protection against neuronal degeneration is not altered by PI3K signaling pathway inhibition. These results point to differential mechanisms regarding protection against a behavioral and cellular manifestation of neural damage.

Transcriptomic Profiling during the Post-Harvest of Heat-Treated Dixiland Prunus persica Fruits: Common and Distinct Response to Heat and Cold

PubMed Central

Lauxmann, Martin A.; Brun, Bianca; Borsani, Julia; Bustamante, Claudia A.; Budde, Claudio O.; Lara, María V.; Drincovich, María F.

2012-01-01

Cold storage is extensively used to slow the rapid deterioration of peach (Prunus persica L. Batsch) fruit after harvest. However, peach fruit subjected to long periods of cold storage develop chilling injury (CI) symptoms. Post-harvest heat treatment (HT) of peach fruit prior to cold storage is effective in reducing some CI symptoms, maintaining fruit quality, preventing softening and controlling post-harvest diseases. To identify the molecular changes induced by HT, which may be associated to CI protection, the differential transcriptome of peach fruit subjected to HT was characterized by the differential display technique. A total of 127 differentially expressed unigenes (DEUs), with a presence-absence pattern, were identified comparing peach fruit ripening at 20°C with those exposed to a 39°C-HT for 3 days. The 127 DEUs were divided into four expression profile clusters, among which the heat-induced (47%) and heat-repressed (36%) groups resulted the most represented, including genes with unknown function, or involved in protein modification, transcription or RNA metabolism. Considering the CI-protection induced by HT, 23-heat-responsive genes were selected and analyzed during and after short-term cold storage of peach fruit. More than 90% of the genes selected resulted modified by cold, from which nearly 60% followed the same and nearly 40% opposite response to heat and cold. Moreover, by using available Arabidopsis microarray data, it was found that nearly 70% of the peach-heat responsive genes also respond to cold in Arabidopsis, either following the same trend or showing an opposite response. Overall, the high number of common responsive genes to heat and cold identified in the present work indicates that HT of peach fruit after harvest induces a cold response involving complex cellular processes; identifying genes that are involved in the better preparation of peach fruit for cold-storage and unraveling the basis for the CI protection induced by HT. PMID:23236430

Selenium protects reproductive system and foetus development in a rat model of gestational lead exposure.

PubMed

Shen, W; Chen, J; Yin, J; Wang, S-L

2016-01-01

Lead is a common environmental contaminant. Lead accumulation in the body is especially dangerous for pregnant women and newborns. Selenium is a trace element which may rectify the damaging effects of lead. Here we tested potential protective effects of selenium against gestational lead exposure. Pregnant SD rats were exposed to 200 mg/L of lead acetate (given with water), with or without sodium selenite supplementation (2-8 mg/kg/day via intragastric administration). Pregnant rats not exposed to lead or selenium served as control animals. The outcomes in pregnant rats were serum lead and selenium levels, reproductive hormone (follicle-stimulating hormone, luteinizing hormone, prolactin, oestradiol, progesterone) levels, and uterine and ovarian morphological changes. The outcomes in the offspring were sex differentiation, survival rates (day 21 after birth), weight (days 0-35 after birth), weight of reproductive organs, and puberty onset (foreskin separation or vaginal opening). Selenium supplementation dose-dependently decreased serum lead levels, rectified reproductive hormone levels, and attenuated reproductive morphological changes caused by lead exposure. Lead exposure did not affect sex differentiation, but significantly (p < 0.05 vs. control animals) decreased the offspring weight on days 0-28 and the weight of their reproductive organs. Furthermore, lead exposure delayed the onset of puberty. These pathological changes were dose-dependently rectified or attenuated by selenium supplementation. Gestational lead exposure causes damages to the reproductive system of pregnant rats, and negatively modulates growth and reproductive system development of the offspring. These adverse effects are rectified or attenuated by selenium supplementation.

Nasal mucosa and blood cell transcriptome profiles do not reflect respiratory symptoms associated with moisture-damage.

PubMed

Ndika, Joseph; Suojalehto, Hille; Täubel, Martin; Lehto, Maili; Karvala, Kirsi; Pallasaho, Paula; Sund, Jukka; Auvinen, Petri; Järvi, Kati; Pekkanen, Juha; Kinaret, Pia; Greco, Dario; Hyvärinen, Anne; Alenius, Harri

2018-05-04

Upper and lower respiratory symptoms and asthma are adverse health effects associated with moisture-damaged buildings. Quantitative measures to detect adverse health effects related to exposure to dampness and mold are needed. Here, we investigate differences in gene expression between occupants of moisture-damaged and reference buildings. Moisture-damaged (N=11) and control (N=5) buildings were evaluated for dampness and mold by trained inspectors. The transcriptomics cohort consisted of nasal brushings and peripheral blood mononuclear cells (PBMCs) from 86 teachers, with/without self-perceived respiratory symptoms. Subject categories comprised reference (R) and damaged (D) buildings with (S) or without (NS) symptoms; i.e. R-S, R-NS, DS and D-NS. Component analyses and k-means clustering of transcriptome profiles did not distinguish building status (R/D) or presence of respiratory symptoms (S/NS). Only one nasal mucosa gene (YBX3P1) exhibited a significant change in expression between D-S and D-NS. Nine other nasal mucosa genes were differentially expressed between R-S and D-S teachers. No differentially expressed genes were identified in PBMCs. We conclude that the observed mRNA differences provide very weak biological evidence for adverse health effects associated with subject occupancy of the specified moisture-damaged buildings. This emphasizes the need to evaluate all potential factors (including those not related to toxicity) influencing perceived/self-reported ill-health in moisture-damaged buildings. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

The gender gap in student engagement: The role of teachers' autonomy support, structure, and involvement.

PubMed

Lietaert, Sofie; Roorda, Debora; Laevers, Ferre; Verschueren, Karine; De Fraine, Bieke

2015-12-01

The gender gap in education in favour of girls is a widely known phenomenon. Boys generally have higher dropout rates, obtain lower grades, and show lower engagement. Insight into factors related to these academic outcomes could help to address the gender gap. This study investigated, for Dutch language classes, (1) how boys and girls differ in behavioural engagement, (2) which teacher support dimensions (autonomy support, structure, involvement) may explain gender differences in engagement (mediation hypothesis), and (3) whether and which of these teacher support dimensions matter more for boys' as opposed to girls' engagement (moderation or differential effects hypothesis). A total of 385 Grade 7 students and their 15 language teachers participated in this study. Teacher support was assessed through student reports. Student engagement was measured using student, teacher, and observer reports. By means of structural equation modelling, the mediating role of the teacher support dimensions for gender differences in behavioural engagement was tested. The potential differential role of the teacher support dimensions for boys' and girls' engagement was investigated through multigroup analysis. Boys were less engaged than girls and reported lower support from their teacher. Autonomy support and involvement partially mediated the relationship between gender and behavioural engagement. Autonomy support was demonstrated to be a protective factor for boys' engagement but not for girls'. Structure and involvement contributed equally to engagement for both sexes. Although involvement and autonomy support partly explained the gender gap in engagement (mediation hypothesis), more support was found for differential effects of autonomy support on boys' versus girls' engagement (differential effects hypothesis). © 2015 The British Psychological Society.

Wage differentials between college graduates with and without learning disabilities.

PubMed

Dickinson, David L; Verbeek, Roelant L

2002-01-01

Wage differential studies examining legally protected groups typically focus on gender or racial differences. Legislation also fully protects individuals with learning disabilities (LD). This article is the first to decompose wage differentials between adults with and without LD. An original data set of college graduates with documented LD was constructed, and these individuals were compared to a control group from the National Longitudinal Survey of Youth (NLSY). Our results show that much of the observed lower wages for individuals with LD is due to differences in productivity characteristics. However, there is an unexplained portion of the wage gap that could possibly be considered wage discrimination against individuals with LD. This possibility seems smaller due to the fact that the subsample of the employers who knew of the employee's learning disabilities did not appear to pay significantly lower wages to these individuals. Alternative hypotheses are discussed, as are sample-specific issues.

Is Your Center Burglar/Vandal Proofed? Guidelines for Protecting Your Center.

ERIC Educational Resources Information Center

Adams, Shawn

1998-01-01

Identifies specific steps that child care centers can take to reduce the chances of burglary and vandalism. Differentiates loss prevention, loss control, and risk financing. Includes discussion of layering defenses, perimeter protection, security lighting, building surface security, locks, and alarm systems. Discusses the importance of reducing…

Parity induces differentiation and reduces Wnt/Notch signaling ratio and proliferation potential of basal stem/progenitor cells isolated from mouse mammary epithelium

PubMed Central

2013-01-01

Introduction Early pregnancy has a strong protective effect against breast cancer in humans and rodents, but the underlying mechanism is unknown. Because breast cancers are thought to arise from specific cell subpopulations of mammary epithelia, we studied the effect of parity on the transcriptome and the differentiation/proliferation potential of specific luminal and basal mammary cells in mice. Methods Mammary epithelial cell subpopulations (luminal Sca1-, luminal Sca1+, basal stem/progenitor, and basal myoepithelial cells) were isolated by flow cytometry from parous and age-matched virgin mice and examined by using a combination of unbiased genomics, bioinformatics, in vitro colony formation, and in vivo limiting dilution transplantation assays. Specific findings were further investigated with immunohistochemistry in entire glands of parous and age-matched virgin mice. Results Transcriptome analysis revealed an upregulation of differentiation genes and a marked decrease in the Wnt/Notch signaling ratio in basal stem/progenitor cells of parous mice. Separate bioinformatics analyses showed reduced activity for the canonical Wnt transcription factor LEF1/TCF7 and increased activity for the Wnt repressor TCF3. This finding was specific for basal stem/progenitor cells and was associated with downregulation of potentially carcinogenic pathways and a reduction in the proliferation potential of this cell subpopulation in vitro and in vivo. As a possible mechanism for decreased Wnt signaling in basal stem/progenitor cells, we found a more than threefold reduction in the expression of the secreted Wnt ligand Wnt4 in total mammary cells from parous mice, which corresponded to a similar decrease in the proportion of Wnt4-secreting and estrogen/progesterone receptor-positive cells. Because recombinant Wnt4 rescued the proliferation defect of basal stem/progenitor cells in vitro, reduced Wnt4 secretion appears to be causally related to parity-induced alterations of basal stem/progenitor cell properties in mice. Conclusions By revealing that parity induces differentiation and downregulates the Wnt/Notch signaling ratio and the in vitro and in vivo proliferation potential of basal stem/progenitor cells in mice, our study sheds light on the long-term consequences of an early pregnancy. Furthermore, it opens the door to future studies assessing whether inhibitors of the Wnt pathway may be used to mimic the parity-induced protective effect against breast cancer. PMID:23621987

Survival and differentiation defects contribute to neutropenia in glucose-6-phosphatase-β (G6PC3) deficiency in a model of mouse neutrophil granulocyte differentiation.

PubMed

Gautam, S; Kirschnek, S; Gentle, I E; Kopiniok, C; Henneke, P; Häcker, H; Malleret, L; Belaaouaj, A; Häcker, G

2013-08-01

Differentiation of neutrophil granulocytes (neutrophils) occurs through several steps in the bone marrow and requires a coordinate regulation of factors determining survival and lineage-specific development. A number of genes are known whose deficiency disrupts neutrophil generation in humans and in mice. One of the proteins encoded by these genes, glucose-6-phosphatase-β (G6PC3), is involved in glucose metabolism. G6PC3 deficiency causes neutropenia in humans and in mice, linked to enhanced apoptosis and ER stress. We used a model of conditional Hoxb8 expression to test molecular and functional differentiation as well as survival defects in neutrophils from G6PC3(-/-) mice. Progenitor lines were established and differentiated into neutrophils when Hoxb8 was turned off. G6PC3(-/-) progenitor cells underwent substantial apoptosis when differentiation was started. Transgenic expression of Bcl-XL rescued survival; however, Bcl-XL-protected differentiated cells showed reduced proliferation, immaturity and functional deficiency such as altered MAP kinase signaling and reduced cytokine secretion. Impaired glucose utilization was found and was associated with ER stress and apoptosis, associated with the upregulation of Bim and Bax; downregulation of Bim protected against apoptosis during differentiation. ER-stress further caused a profound loss of expression and secretion of the main neutrophil product neutrophil elastase during differentiation. Transplantation of wild-type Hoxb8-progenitor cells into irradiated mice allowed differentiation into neutrophils in the bone marrow in vivo. Transplantation of G6PC3(-/-) cells yielded few mature neutrophils in bone marrow and peripheral blood. Transgenic Bcl-XL permitted differentiation of G6PC3(-/-) cells in vivo. However, functional deficiencies and differentiation abnormalities remained. Differentiation of macrophages from Hoxb8-dependent progenitors was only slightly disturbed. A combination of defects in differentiation and survival thus underlies neutropenia in G6PC3(-/-) deficiency, both originating from a reduced ability to utilize glucose. Hoxb8-dependent cells are a model to study differentiation and survival of the neutrophil lineage.

The differentiation and protective function of cytolytic CD4 T cells in influenza infection

USDA-ARS?s Scientific Manuscript database

CD4 T cells that recognize peptide antigen in the context of Class II MHC can differentiate into various subsets that are characterized by their helper functions. However, increasing evidence indicates that CD4 cells with direct cytolytic activity play a role in chronic, as well as, acute infections...

The Manifest and Latent Functions of Differential Response in Child Welfare

ERIC Educational Resources Information Center

Ji, Daniel; Sullivan, Richard

2016-01-01

Although previous research has explored the efficacy of differential response (DR) programs in child welfare, there have been no studies to date about coding decisions between designations by child protection service agencies. Research has explored client satisfaction with DR as well as rates of recidivism and removal/placement but with limited…

Eriodictyol protects against H(2)O(2)-induced neuron-like PC12 cell death through activation of Nrf2/ARE signaling pathway.

PubMed

Lou, Haiyan; Jing, Xu; Ren, Dongmei; Wei, Xinbing; Zhang, Xiumei

2012-07-01

Eriodictyol, a flavonoid isolated from the Chinese herb Dracocephalum rupestre has long been established as an antioxidant. The present study was designed to explore the protective effects of eriodictyol against hydrogen peroxide (H(2)O(2))-induced neurotoxicity with cultured rat pheochromocytoma cells (PC12 cells) and the possible mechanisms involved. For this purpose, differentiated PC12 cells were cultured and exposed to 200 μM H(2)O(2) in the absence or presence of eriodictyol (20, 40 and 80 μM). In addition, the potential contribution of the Nrf2/ARE neuroprotective pathway in eriodictyol-mediated protection against H(2)O(2)-induced neurotoxicity was also investigated. The results showed that H(2)O(2)-induced cell death can be inhibited in the presence of eriodictyol as measured by assays for MTT and apoptosis. Further study revealed that eriodictyol induced the nuclear translocation of Nrf2, enhanced the expression of heme oxygenase (HO-1) and γ-glutamylcysteine synthetase (γ-GCS), and increased the levels of intracellular glutathione. Treatment of PC12 cells with Nrf2 small interference RNA abolished eriodictyol-induced HO-1 and γ-GCS expression and its protective effects. In conclusion, these results suggest that eriodictyol upregulates HO-1 and γ-GCS expression through the activation of Nrf2/ARE pathway and protects PC12 cells against H(2)O(2)-induced oxidative stress. Copyright © 2012 Elsevier Ltd. All rights reserved.

Social support differentially moderates the impact of neuroticism and extraversion on mental wellbeing among community-dwelling older adults.

PubMed

McHugh, J E; Lawlor, B A

2012-10-01

Personality affects psychological wellbeing, and social support networks may mediate this effect. This may be particularly pertinent in later life, when social structures change significantly, and can lead to a decline in psychological wellbeing. To examine, in an older population, whether the relationships between neuroticism and extraversion and mental wellbeing are moderated by available social support networks. We gathered information from 536 community-dwelling older adults, regarding personality, social support networks, depressive symptomatology, anxiety and perceived stress, as well as controlling for age and gender. Neuroticism and extraversion interacted with social support networks to determine psychological wellbeing (depression, stress and anxiety). High scores on the social support networks measure appear to be protective against the deleterious effects of high scores on the neuroticism scale on psychological wellbeing. Meanwhile, individuals high in extraversion appear to require large social support networks in order to maintain psychological wellbeing. Large familial and friendship social support networks are associated with good psychological wellbeing. To optimise psychological wellbeing in older adults, improving social support networks may be differentially effective for different personality types.

Age and motives for volunteering: testing hypotheses derived from socioemotional selectivity theory.

PubMed

Okun, Morris A; Schultz, Amy

2003-06-01

Following a meta-analysis of the relations between age and volunteer motives (career, understanding, enhancement, protective, making friends, social, and values), the authors tested hypotheses derived from socioemotional selectivity theory regarding the effects of age on these volunteer motives. The Volunteer Functions Inventory was completed by 523 volunteers from 2 affiliates of the International Habitat for Humanity. Multiple regression analyses revealed, as predicted, that as age increases, career and understanding volunteer motivation decrease and social volunteer motivation increases. Contrary to expectations, age did not contribute to the prediction of enhancement, protective, and values volunteer motivations and the relation between age and making friends volunteer motivation was nonlinear. The results were discussed in the context of age-differential and age-similarity perspectives on volunteer motivation.

Differential Requirements for T Cells in Viruslike Particle- and Rotavirus-Induced Protective Immunity▿

PubMed Central

Blutt, Sarah E.; Warfield, Kelly L.; Estes, Mary K.; Conner, Margaret E.

2008-01-01

Correlates of protection from rotavirus infection are controversial. We compared the roles of B and T lymphocytes in protective immunity induced either by intranasally administered nonreplicating viruslike particles or inactivated virus or by orally administered murine rotavirus. We found that protection induced by nonreplicating vaccines requires CD4+ T cells and CD40/CD40L. In contrast, T cells were not required for short-term protective immunity induced by infection, but both T-cell-dependent and -independent mechanisms contributed to long-term maintenance of protection. Our findings indicate that more than one marker of protective immunity exists and that these markers depend on the vaccine that is administered. PMID:18184712

DNA-damage-induced differentiation of leukaemic cells as an anti-cancer barrier.

PubMed

Santos, Margarida A; Faryabi, Robert B; Ergen, Aysegul V; Day, Amanda M; Malhowski, Amy; Canela, Andres; Onozawa, Masahiro; Lee, Ji-Eun; Callen, Elsa; Gutierrez-Martinez, Paula; Chen, Hua-Tang; Wong, Nancy; Finkel, Nadia; Deshpande, Aniruddha; Sharrow, Susan; Rossi, Derrick J; Ito, Keisuke; Ge, Kai; Aplan, Peter D; Armstrong, Scott A; Nussenzweig, André

2014-10-02

Self-renewal is the hallmark feature both of normal stem cells and cancer stem cells. Since the regenerative capacity of normal haematopoietic stem cells is limited by the accumulation of reactive oxygen species and DNA double-strand breaks, we speculated that DNA damage might also constrain leukaemic self-renewal and malignant haematopoiesis. Here we show that the histone methyl-transferase MLL4, a suppressor of B-cell lymphoma, is required for stem-cell activity and an aggressive form of acute myeloid leukaemia harbouring the MLL-AF9 oncogene. Deletion of MLL4 enhances myelopoiesis and myeloid differentiation of leukaemic blasts, which protects mice from death related to acute myeloid leukaemia. MLL4 exerts its function by regulating transcriptional programs associated with the antioxidant response. Addition of reactive oxygen species scavengers or ectopic expression of FOXO3 protects MLL4(-/-) MLL-AF9 cells from DNA damage and inhibits myeloid maturation. Similar to MLL4 deficiency, loss of ATM or BRCA1 sensitizes transformed cells to differentiation, suggesting that myeloid differentiation is promoted by loss of genome integrity. Indeed, we show that restriction-enzyme-induced double-strand breaks are sufficient to induce differentiation of MLL-AF9 blasts, which requires cyclin-dependent kinase inhibitor p21(Cip1) (Cdkn1a) activity. In summary, we have uncovered an unexpected tumour-promoting role of genome guardians in enforcing the oncogene-induced differentiation blockade in acute myeloid leukaemia.

Parental practices and political violence: the protective role of parental warmth and authority-control in Jewish and Arab Israeli children.

PubMed

Lavi, Iris; Slone, Michelle

2012-10-01

Parental warmth and parental authority-control patterns have been documented as practices with highest significance for children's well-being and development in a variety of life areas. Various forms of these practices have been shown to have a direct positive effect on children and also to protect children from adverse effects of numerous stressors. However, surprisingly, few studies have examined the role of these practices as possible protective factors for children exposed to intractable conflict and political violence. Participants in this study were Jewish (n = 88) and Arab (n = 105) Israeli families, with children aged 7-12.5 (M = 10.73, SD = 0.99). Children completed questionnaires assessing political violence exposure, behavioral, psychological, and social difficulties, and perceived paternal and maternal warmth. Mothers and fathers completed questionnaires assessing parental warmth, parental authority-control, and the child's difficulties. Results showed parental warmth to be a significant moderator of political violence, related to low levels of behavioral and social difficulties of children. Parental authority-control patterns were not protectors from adverse effects of political violence exposure. Maternal authoritarian authority-control showed an effect resembling a risk factor. Differential roles of parental warmth and authority-control, fathers' versus mothers' roles, and ethnic differences are discussed, and practical clinical implications are proposed. © 2012 American Orthopsychiatric Association.

Metformin Improves Ileal Epithelial Barrier Function in Interleukin-10 Deficient Mice

PubMed Central

Xue, Yansong; Zhang, Hanying; Sun, Xiaofei; Zhu, Mei-Jun

2016-01-01

Background and aims The impairment of intestinal epithelial barrier is the main etiologic factor of inflammatory bowel disease. The proper intestinal epithelial proliferation and differentiation is crucial for maintaining intestinal integrity. Metformin is a common anti-diabetic drug. The objective is to evaluate the protective effects of metformin on ileal epithelial barrier integrity using interleukin-10 deficient (IL10KO) mice. Methods Wild-type and IL10KO mice were fed with/without metformin for 6 weeks and then ileum was collected for analyses. The mediatory role of AMP-activated protein kinase (AMPK) was further examined by gain and loss of function study in vitro. Results Compared to wild-type mice, IL10KO mice had increased proliferation, reduced goblet cell and Paneth cell lineage differentiation in the ileum tissue, which was accompanied with increased crypt expansion. Metformin supplementation mitigated intestinal cell proliferation, restored villus/crypt ratio, increased goblet cell and Paneth cell differentiation and improved barrier function. In addition, metformin supplementation in IL10KO mice suppressed macrophage pro-inflammatory activity as indicated by reduced M1 macrophage abundance and decreased pro-inflammatory cytokine IL-1β, TNF-α and IFN-γ expressions. As a target of metformin, AMPK phosphorylation was enhanced in mice treated with metformin, regardless of mouse genotypes. In correlation, the mRNA level of differentiation regulator including bmp4, bmpr2 and math1 were also increased in IL10KO mice supplemented with metformin, which likely explains the enhanced epithelial differentiation in IL10KO mice with metformin. Consistently, in Caco-2 cells, metformin promoted claudin-3 and E-cadherin assembly and mitigated TNF-α-induced fragmentation of tight junction proteins. Gain and loss of function assay also demonstrated AMPK was correlated with epithelial differentiation and proliferation. Conclusions Metformin supplementation promotes secretory cell lineage differentiation, suppresses inflammation and improves epithelial barrier function in IL10KO mice likely through activation of AMPK, showing its beneficial effects on gut epithelial. PMID:28002460

Inhibitory effects of hepatocyte growth factor and interleukin-6 on transforming growth factor-beta1 mediated vocal fold fibroblast-myofibroblast differentiation.

PubMed

Vyas, Bimal; Ishikawa, Keiko; Duflo, Suzy; Chen, Xia; Thibeault, Susan L

2010-05-01

The role of myofibroblasts in vocal fold scarring has not been extensively studied, partly because of the lack of a robust in vitro model. The objective of this investigation was to develop and characterize a myofibroblast in vitro model that could be utilized to investigate the molecular mechanism of myofibroblast differentiation and function in injured vocal fold tissue. Differentiation of human primary vocal fold fibroblasts (hVFFs) to myofibroblasts was stimulated with 5, 10, or 20 ng/mL of recombinant transforming growth factor-beta1 (TGF-beta1). Cultures were analyzed by immunofluorescence and Western blotting, with an alpha-smooth muscle actin (alpha-SMA) antibody used as a myofibroblast marker. Normal rabbit vocal folds were treated with 10 ng/mL of TGF-beta1 for 7 days for in vivo corroboration. The effects of interleukin-6 (IL-6) and hepatocyte growth factor (HGF) on myofibroblast differentiation were studied with Western blots. The hVFFs demonstrated positive alpha-SMA labeling in cells stimulated by 10 and 20 ng/mL TGF-beta1, indicating that hVFFs were capable of differentiation to myofibroblasts. Transforming growth factor-beta1 induced the largest increase in alpha-SMA at 10 ng/mL on day 5 of treatment. Both HGF and IL-6 suppressed the expression of TGF-beta1-induced alpha-SMA. Our work characterizes a useful in vitro model of TGF-beta1-mediated vocal fold fibroblast-myofibroblast differentiation. The extent of differentiation appears to be attenuated by HGF, suggesting a potential mechanism to support prior work indicating that HGF plays a protective role in reducing scar formation in vocal fold injuries. Paradoxically, IL-6, which has been shown to play a profibrotic role in dermal studies, also attenuated the TGF-beta1 response.

Hyperbaric oxygen modalities are differentially effective in distinct brain ischemia models

PubMed Central

Ostrowski, Robert P.; Stępień, Katarzyna; Pucko, Emanuela; Matyja, Ewa

2016-01-01

The effectiveness and efficacy of hyperbaric oxygen (HBO) preconditioning and post-treatment modalities have been demonstrated in experimental models of ischemic cerebrovascular diseases, including global brain ischemia, transient focal and permanent focal cerebral ischemia, and experimental neonatal hypoxia-ischemia encephalopathy. In general, early and repetitive post-treatment of HBO appears to create enhanced protection against brain ischemia whereas delayed HBO treatment after transient focal ischemia may even aggravate brain injury. This review advocates the level of injury reduction upon HBO as an important component for translational evaluation of HBO based treatment modalities. The combined preconditioning and HBO post-treatment that would provide synergistic effects is also worth considering. PMID:27826422

The Mental Capacity Act--a balance between protection and liberty.

PubMed

Walters, Thomas Paul

The stated aim of the Mental Capacity Act is to provide greater protection to those who may lose their mental capacities, particularly in terms of informed consent, patient affairs, advanced decisions and research. This article attempts to explore this new statute by way of examining the scope to which the Act departs from the previous Common Law. Three key themes are identified within this new Act, which differentiate it from Common Law: patients' best interests, which is paramount to any care or treatment; proxy consent, whereby donees can now be appointed to take charge of medical decisions; and advanced directives, where so-called living wills can be enforced provided that they are specific, written, signed and witnessed. However, upon examining the statute it appears that rather than increasing patient autonomy and self-determination, evidence suggests that power is still being held by the medical profession. Whether patients have full autonomy or not, the main issue could be how to strike an effective and workable balance between protection and liberty.

Synthetic Consolidants Attacked by Melanin-Producing Fungi: Case Study of the Biodeterioration of Milan (Italy) Cathedral Marble Treated with Acrylics▿

PubMed Central

Cappitelli, Francesca; Nosanchuk, Joshua D.; Casadevall, Arturo; Toniolo, Lucia; Brusetti, Lorenzo; Florio, Sofia; Principi, Pamela; Borin, Sara; Sorlini, Claudia

2007-01-01

Monuments and artistic stone surfaces are often consolidated and protected with synthetic polymers, in particular, acrylics. Although it is generally thought that acrylic polymers are resistant to biodeterioration, we report for the first time the systematic occurrence of dematiaceous meristematic fungi on many marble samples of the cathedral in Milan (Italy) previously treated with this material. Fourier transform infrared spectroscopy applied to the Milan cathedral stone samples revealed characteristic features of biodeteriorated synthetic resins that differentiated them from the aged but nonbiodeteriorated samples. Samples showing biological colonization were analyzed for the presence of fungi. Cultivation and morphological characterization and methods independent from cultivation, such as denaturing gradient gel electrophoresis coupled with partial 18S rRNA gene sequencing and immunofluorescence staining with melanin-binding antibodies, showed that melanin-producing species are heavily present on stone surfaces protected with acrylic resins. This observation raises the question of the effectiveness of acrylics in protecting stone artworks. PMID:17071788

Synthetic consolidants attacked by melanin-producing fungi: case study of the biodeterioration of Milan (Italy) cathedral marble treated with acrylics.

PubMed

Cappitelli, Francesca; Nosanchuk, Joshua D; Casadevall, Arturo; Toniolo, Lucia; Brusetti, Lorenzo; Florio, Sofia; Principi, Pamela; Borin, Sara; Sorlini, Claudia

2007-01-01

Monuments and artistic stone surfaces are often consolidated and protected with synthetic polymers, in particular, acrylics. Although it is generally thought that acrylic polymers are resistant to biodeterioration, we report for the first time the systematic occurrence of dematiaceous meristematic fungi on many marble samples of the cathedral in Milan (Italy) previously treated with this material. Fourier transform infrared spectroscopy applied to the Milan cathedral stone samples revealed characteristic features of biodeteriorated synthetic resins that differentiated them from the aged but nonbiodeteriorated samples. Samples showing biological colonization were analyzed for the presence of fungi. Cultivation and morphological characterization and methods independent from cultivation, such as denaturing gradient gel electrophoresis coupled with partial 18S rRNA gene sequencing and immunofluorescence staining with melanin-binding antibodies, showed that melanin-producing species are heavily present on stone surfaces protected with acrylic resins. This observation raises the question of the effectiveness of acrylics in protecting stone artworks.

Far infrared radiation promotes rabbit renal proximal tubule cell proliferation and functional characteristics, and protects against cisplatin-induced nephrotoxicity.

PubMed

Chiang, I-Ni; Pu, Yeong-Shiau; Huang, Chao-Yuan; Young, Tai-Horng

2017-01-01

Far infrared radiation, a subdivision of the electromagnetic spectrum, is beneficial for long-term tissue healing, anti-inflammatory effects, growth promotion, sleep modulation, acceleration of microcirculation, and pain relief. We investigated if far infrared radiation is beneficial for renal proximal tubule cell cultivation and renal tissue engineering. We observed the effects of far infrared radiation on renal proximal tubules cells, including its effects on cell proliferation, gene and protein expression, and viability. We also examined the protective effects of far infrared radiation against cisplatin, a nephrotoxic agent, using the human proximal tubule cell line HK-2. We found that daily exposure to far infrared radiation for 30 min significantly increased rabbit renal proximal tubule cell proliferation in vitro, as assessed by MTT assay. Far infrared radiation was not only beneficial to renal proximal tubule cell proliferation, it also increased the expression of ATPase Na+/K+ subunit alpha 1 and glucose transporter 1, as determined by western blotting. Using quantitative polymerase chain reaction, we found that far infrared radiation enhanced CDK5R1, GNAS, NPPB, and TEK expression. In the proximal tubule cell line HK-2, far infrared radiation protected against cisplatin-mediated nephrotoxicity by reducing apoptosis. Renal proximal tubule cell cultivation with far infrared radiation exposure resulted in better cell proliferation, significantly higher ATPase Na+/K+ subunit alpha 1 and glucose transporter 1 expression, and significantly enhanced expression of CDK5R1, GNAS, NPPB, and TEK. These results suggest that far infrared radiation improves cell proliferation and differentiation. In HK-2 cells, far infrared radiation mediated protective effects against cisplatin-induced nephrotoxicity by reducing apoptosis, as indicated by flow cytometry and caspase-3 assay.

Scalable privacy-preserving data sharing methodology for genome-wide association studies.

PubMed

Yu, Fei; Fienberg, Stephen E; Slavković, Aleksandra B; Uhler, Caroline

2014-08-01

The protection of privacy of individual-level information in genome-wide association study (GWAS) databases has been a major concern of researchers following the publication of "an attack" on GWAS data by Homer et al. (2008). Traditional statistical methods for confidentiality and privacy protection of statistical databases do not scale well to deal with GWAS data, especially in terms of guarantees regarding protection from linkage to external information. The more recent concept of differential privacy, introduced by the cryptographic community, is an approach that provides a rigorous definition of privacy with meaningful privacy guarantees in the presence of arbitrary external information, although the guarantees may come at a serious price in terms of data utility. Building on such notions, Uhler et al. (2013) proposed new methods to release aggregate GWAS data without compromising an individual's privacy. We extend the methods developed in Uhler et al. (2013) for releasing differentially-private χ(2)-statistics by allowing for arbitrary number of cases and controls, and for releasing differentially-private allelic test statistics. We also provide a new interpretation by assuming the controls' data are known, which is a realistic assumption because some GWAS use publicly available data as controls. We assess the performance of the proposed methods through a risk-utility analysis on a real data set consisting of DNA samples collected by the Wellcome Trust Case Control Consortium and compare the methods with the differentially-private release mechanism proposed by Johnson and Shmatikov (2013). Copyright © 2014 Elsevier Inc. All rights reserved.

Epidermal fatty acid-binding protein protects nerve growth factor-differentiated PC12 cells from lipotoxic injury

PubMed Central

Liu, Jo-Wen; Montero, Manuel; Bu, Liming; De Leon, Marino

2015-01-01

Epidermal fatty acid-binding protein (E-FABP/FABP5/DA11) binds and transport long-chain fatty acids in the cytoplasm and may play a protecting role during neuronal injury. We examined whether E-FABP protects nerve growth factor-differentiated PC12 cells (NGFDPC12 cells) from lipotoxic injury observed after palmitic acid (C16:0; PAM) overload. NGFDPC12 cells cultures treated with PAM/bovine serum albumin at 0.3 mM/0.15 mM show PAM-induced lipotoxicity (PAM-LTx) and apoptosis. The apoptosis was preceded by a cellular accumulation of reactive oxygen species (ROS) and higher levels of E-FABP. Antioxidants MCI-186 and N-acetyl cysteine prevented E-FABP's induction in expression by PAM-LTx, while tert-butyl hydroperoxide increased ROS and E-FABP expression. Non-metabolized methyl ester of PAM, methyl palmitic acid (mPAM), failed to increase cellular ROS, E-FABP gene expression, or trigger apoptosis. Treatment of NGFDPC12 cultures with siE-FABP showed reduced E-FABP levels correlating with higher accumulation of ROS and cell death after exposure to PAM. In contrast, increasing E-FABP cellular levels by pre-loading the cells with recombinant E-FABP diminished the PAM-induced ROS and cell death. Finally, agonists for PPARβ (GW0742) or PPARγ (GW1929) increased E-FABP expression and enhanced the resistance of NGFDPC12 cells to PAM-LTx. We conclude that E-FABP protects NGFDPC12 cells from lipotoxic injury through mechanisms that involve reduction of ROS. Epidermal fatty acid-binding protein (E-FABP) may protect nerve cells from the damaging exposure to high levels of free fatty acids (FA). We show that E-FABP can neutralize the effects of reactive oxygen species (ROS) generated by the high levels of FA in the cell and protect PC12 cells from lipotoxic injuries common in Type 2 diabetes neuropathy. Potentially, E-FABP gene up-regulation may be mediated through the NFkB pathway and future studies are needed to further evaluate this proposition. PMID:25147052

Effects of the 1, 4-dihydropyridine L-type calcium channel blocker benidipine on bone marrow stromal cells.

PubMed

Ma, Zhong-ping; Liao, Jia-cheng; Zhao, Chang; Cai, Dao-zhang

2015-08-01

Osteoporosis (OP) often increases the risk of bone fracture and other complications and is a major clinical problem. Previous studies have found that high blood pressure is associated with bone formation abnormalities, resulting in increased calcium loss. We have investigated the effect of the antihypertensive drug benidipine on bone marrow stromal cell (BMSC) differentiation into osteoblasts and bone formation under osteoporotic conditions. We used a combination of in vitro and in vivo approaches to test the hypothesis that benidipine promotes murine BMSC differentiation into osteoblasts. Alkaline phosphatase (ALP), osteocalcin (OCN), runt-related transcription factor 2 (RUNX2), β-catenin, and low-density lipoprotein receptor-related protein 5 (LRP5) protein expression was evaluated in primary femoral BMSCs from C57/BL6 mice cultured under osteogenic conditions for 2 weeks to examine the effects of benidipine. An ovariectomized (OVX) mouse model was used to investigate the effect of benidipine treatment for 3 months in vivo. We found that ALP, OCN, and RUNX2 expression was up-regulated and WNT/β-catenin signaling was enhanced in vitro and in vivo. In OVX mice that were intragastrically administered benidipine, bone parameters (trabecular thickness, bone mineral density, and trabecular number) in the distal femoral metaphysis were significantly increased compared with control OVX mice. Consistently, benidipine promoted BMSC differentiation into osteoblasts and protected against bone loss in OVX mice. Therefore, benidipine might be a suitable candidate for the treatment of patients with postmenopausal osteoporosis and hypertension.

Pharmaceutical Activation or Genetic Absence of ClC-2 Alters Tight Junctions During Experimental Colitis.

PubMed

Jin, Younggeon; Pridgen, Tiffany A; Blikslager, Anthony T

2015-12-01

We have previously reported that the ClC-2 chloride channel has an important role in regulation of tight junction barrier function during experimental colitis, and the pharmaceutical ClC-2 activator lubiprostone initiates intestinal barrier repair in ischemic-injured intestine. Thus, we hypothesized that pharmaceutical ClC-2 activation would have a protective and therapeutic effect in murine models of colitis, which would be absent in ClC-2 mice. We administered lubiprostone to wild-type or ClC-2 mice with dextran sulfate sodium (DSS) or 2, 4, 5-trinitrobenzene sulfonic acid-induced colitis. We determined the severity of colitis and assessed intestinal permeability. Selected tight junction proteins were analyzed by Western blotting and immunofluorescence/confocal microscopy, whereas proliferative and differentiated cells were examined with special staining and immunohistochemistry. Oral preventive or therapeutic administration of lubiprostone significantly reduced the severity of colitis and reduced intestinal permeability in both DSS and trinitrobenzene sulfonic acid-induced colitis. Preventive treatment with lubiprostone induced significant recovery of the expression and distribution of selected sealing tight junction proteins in mice with DSS-induced colitis. In addition, lubiprostone reduced crypt proliferation and increased the number of differentiated epithelial cells. Alternatively, when lubiprostone was administered to ClC-2 mice, the protective effect against DSS colitis was limited. This study suggests a central role for ClC-2 in restoration of barrier function and tight junction architecture in experimental murine colitis, which can be therapeutically targeted with lubiprostone.

Ischemic preconditioning modulates the expression of several genes, leading to the overproduction of IL-1Ra, iNOS, and Bcl-2 in a human model of liver ischemia-reperfusion.

PubMed

Barrier, Alain; Olaya, Natalia; Chiappini, Franck; Roser, François; Scatton, Olivier; Artus, Cédric; Franc, Brigitte; Dudoit, Sandrine; Flahault, Antoine; Debuire, Brigitte; Azoulay, Daniel; Lemoine, Antoinette

2005-10-01

Ischemia triggers an inflammatory response that precipitates cell death during reperfusion. Several studies have shown that tissues are protected by ischemic preconditioning (IP) consisting of 10 min of ischemia followed by 10 min of reperfusion just before ischemia. The molecular basis of this protective effect is poorly understood. We used cDNA arrays (20K) to compare global gene expression in liver biopsies from living human liver donors who underwent IP (n=7) or not (n=7) just before liver devascularization. Microarray data were analyzed using pairedt test with a type I error rate fixed at alpha = 2.5 10(6) (Bonferroni correction). We found that 60 genes were differentially expressed (36 over- and 24 underexpressed in preconditioning group). After IP, the most significantly overexpressed gene was IL-1Ra. This was confirmed by immunoblotting. Differentially expressed were genes involved in apoptosis (NOD2, ephrin-A1, and calpain) and in the carbohydrate metabolism. A significant increase in the amount of the anti-apoptotic protein Bcl-2 in preconditioned livers but no change in the cleavage of procaspase-3, -8, and -9 was observed. We also observed an increase in the amount in the inducible nitric oxide synthase. Therefore, the benefits of IP may be associated with the overproduction of IL-1Ra, Bcl-2, and NO countering the proinflammatory and proapoptotic effects generated during ischemia-reperfusion.

Treatment of Guillain-Barré syndrome with Bifidobacterium infantis through regulation of T helper cells subsets.

PubMed

Shi, Peng; Qu, Hongdang; Nian, Di; Chen, Yuhua; Liu, Xiaolin; Li, Qiang; Li, Qianqian; Wang, Chun; Ye, Ming; Ma, Bo

2018-06-13

Guillain-Barré syndrome (GBS) is a rare, autoimmune-mediated disease. The use of Bifidobacterium is reportedly effective in alleviating GBS since they act by regulating T helper (Th) cells. In this study, we explored the differentiation of T helper cell subsets in patients with GBS. We also evaluated the effect of GBS on Bifidobacterium levels in patients and the likely protective influence of this bacterium in alleviating the disease in an animal model. We used flow cytometry, and real-time polymerase chain reaction (PCR) to determine the T cell subsets differentiation among 30 GBS patients and 20 healthy controls (HC). The concentration of Bifidobacterium was assayed by real-time PCR. Experimental autoimmune neuritis (EAN) animal model was established to support the protective role of Bifidobacterium in GBS. The expression of Th cells, Th2 and Th17 in the patients was significantly higher than that in the HC, while Treg cells decreased substantially. Moreover, the levels of Bifidobacterium in the GBS patients were considerably lower than those in the HC, the concentration of Bifidobacterium correlating with Th2 and Th17 subsets negatively. Treatment with Bifidobacterium significantly reduced the levels of Th2 and Th17 and promoted the levels of Treg cells. We concluded from this study that Bifidobacterium alleviated GBS by regulating Th cells, although in-depth studies might be required to fully understand the mechanism of action. Copyright © 2018. Published by Elsevier B.V.

The tools of competition: Differentiation, segmentation and the microprocessor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Piepmeier, J.M.; Jermain, D.O.; Egnor, T.L.

1993-11-01

The microprocessor enables electric utilities to recover product differentiation and market segmentation tools that they relinquished decades ago. These tools present a [open quotes]double-edged[close quotes] opportunity to the industry. Product differentiation and market segmentation are deeply and permanently embedded in the corporate strategy and culture of virtually every successful firm. Most electric utilities, however, continue to promote a generic product to an undifferentiated captive audience. This approach was also common in the pre-Yeltsin USSR, where advertisements simply read, Buy Beer, or Eat Potatoes'. Electric utilities relinquished the differentiation/segmentation function in the far distant past to the suppliers of end-use energymore » appliances such as GE and Carrier. By default they assigned themselves the role of commodity supplier. Historically, this role has been protected in the marketplace and insulated from competition by two strong barriers: economies of scale and status as a legally franchised monopoly in a well-defined geographic territory. These two barriers do not exist independently; the second depends on the first. When scale economies cease and then reverse, the industry's legally protected position in the marketplace begins to erode. The lack of product differentiation and market segmentation, which was inconsequential before, now becomes a serious handicap: These same relinquished tools seem to be essential for success in a competitive environment.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Prokop'ev, I.A.; Churshukov, E.S.; Maiko, L.P.

This article evaluates the stability of the protective properties of preservative oils when they are oxidized in the bulk and in a thin layer. Proposes a method based on a quantitative evaluation of the changes in protective properties of the oils after artificial oxidation in the bulk and in a thin layer on a metal surface. Finds that the proposed method makes it possible to establish the character of changes in protective properties of preservative oils during storage and application, and to differentiate oils with respect to this index over a broad range of protective levels.

40 CFR 798.5500 - Differential growth inhibition of repair proficient and repair deficient bacteria: “Bacterial DNA...

Code of Federal Regulations, 2010 CFR

2010-07-01

... should be documented and should be adequate for the experimental design. (5) Metabolic activation... 40 Protection of Environment 31 2010-07-01 2010-07-01 true Differential growth inhibition of... titers (cells per ml). Transformed data alone in the absence of experimental data are not acceptable (i.e...

Molecular basis of the potential of vitamin D to prevent cancer.

PubMed

Ingraham, Betty A; Bragdon, Beth; Nohe, Anja

2008-01-01

To review current research findings in cell biology, epidemiology, preclinical, and clinical trials on the protective effects of vitamin D against the development of cancers of the breast, colon, prostate, lung, and ovary. Current recommendations for optimal vitamin D status, the movement towards revision of standards, and reflections on healthy exposure to sunlight are also reviewed. Search methodology: A literature search was conducted in April and updated in September 2007. The Medline and Web of Knowledge databases were searched for primary and review articles published between 1970 and 2007, using the search terms 'vitamin D', 'calcitriol', 'cancer', 'chemoprevention', 'nuclear receptor', 'vitamin D receptor', 'apoptosis', 'cell cycle', 'epidemiology', and 'cell adhesion molecule'. Articles that focused on epidemiological, preclinical, and clinical evidence for vitamin D's effects were selected and additional articles were obtained from reference lists of the retrieved articles. An increasing body of research supports the hypothesis that the active form of vitamin D has significant, protective effects against the development of cancer. Epidemiological studies show an inverse association between sun exposure, serum levels of 25(OH)D, and intakes of vitamin D and risk of developing and/or surviving cancer. The protective effects of vitamin D result from its role as a nuclear transcription factor that regulates cell growth, differentiation, apoptosis and a wide range of cellular mechanisms central to the development of cancer. A significant number of individuals have serum vitamin D levels lower than what appears to protect against cancer, and the research community is currently revising the guidelines for optimal health. This will lead to improved public health policies and to reduced risk of cancer. Research strongly supports the view that efforts to improve vitamin D status would have significant protective effects against the development of cancer. The clinical research community is currently revising recommendations for optimal serum levels and for sensible levels of sun exposure, to levels greater than previously thought. Currently, most experts in the field believe that intakes of between 1000 and 4000 IU will lead to a more healthy level of serum 25(OH)D, at approximately 75 nmol/L that will offer significant protection effects against cancers of the breast, colon, prostate, ovary, lungs, and pancreas. The first randomized trial has shown significant protection against breast cancer, and other clinical trials will follow and ultimately lead to improved public health policies and significantly fewer cancers.

Cordyceps sinensis health supplement enhances recovery from taxol-induced leukopenia.

PubMed

Liu, Wei-Chung; Chuang, Wei-Ling; Tsai, Min-Lung; Hong, Ji-Hong; McBride, William H; Chiang, Chi-Shiun

2008-04-01

This study aimed to evaluate the ability of the health food supplement Cordyceps sinensis (CS) to ameliorate suppressive effects of chemotherapy on bone marrow function as a model for cancer treatment. Mice were treated with Taxol (17 mg/kg body wt) one day before oral administration of a hot-water extract of CS (50 mg/kg daily) that was given daily for 3 weeks. White blood cell counts in peripheral blood of mice receiving Taxol were at 50% of normal levels on day 28 but had recovered completely in mice treated with CS. In vitro assays showed that CS enhanced the colony-forming ability of both granulocyte macrophage colony forming unit (GM-CFU) and osteogenic cells from bone marrow preparations and promoted the differentiation of bone marrow mesenchymal stromal cells into adipocytes, alkaline phosphatase-positive osteoblasts, and bone tissue. This result could be attributed to enhanced expression of Cbfa1 (core binding factor a) and BMP-2 (bone morphogenetic protein) with concurrent suppression of ODF (osteoclast differentiation factor/RANK [receptor activator of NF-kappaB]) ligand. In summary, CS enhances recovery of mice from leukopenia caused by Taxol treatment. It appears to do so by protecting both hematopoietic progenitor cells directly and the bone marrow stem cell niche through its effects on osteoblast differentiation.

Combining NT3-overexpressing MSCs and PLGA microcarriers for brain tissue engineering: A potential tool for treatment of Parkinson's disease.

PubMed

Moradian, Hanieh; Keshvari, Hamid; Fasehee, Hamidreza; Dinarvand, Rassoul; Faghihi, Shahab

2017-07-01

Parkinson's disease (PD) is a progressive neurodegenerative disorder that characterized by destruction of substantia nigrostriatal pathway due to the loss of dopaminergic (DA) neurons. Regardless of substantial efforts for treatment of PD in recent years, an effective therapeutic strategy is still missing. In a multidisciplinary approach, bone marrow derived mesenchymal stem cells (BMSCs) are genetically engineered to overexpress neurotrophin-3 (nt-3 gene) that protect central nervous system tissues and stimulates neuronal-like differentiation of BMSCs. Poly(lactic-co-glycolic acid) (PLGA) microcarriers are designed as an injectable scaffold and synthesized via double emulsion method. The surface of PLGA microcarriers are functionalized by collagen as a bioadhesive agent for improved cell attachment. The results demonstrate effective overexpression of NT-3. The expression of tyrosine hydroxylase (TH) in transfected BMSCs reveal that NT-3 promotes the intracellular signaling pathway of DA neuron differentiation. It is also shown that transfected BMSCs are successfully attached to the surface of microcarriers. The presence of dopamine in peripheral media of cell/microcarrier complex reveals that BMSCs are successfully differentiated into dopaminergic neuron. Our approach that sustains presence of growth factor can be suggested as a novel complementary therapeutic strategy for treatment of Parkinson disease. Copyright © 2017 Elsevier B.V. All rights reserved.

Analysis on Behaviour of Wavelet Coefficient during Fault Occurrence in Transformer

NASA Astrophysics Data System (ADS)

Sreewirote, Bancha; Ngaopitakkul, Atthapol

2018-03-01

The protection system for transformer has play significant role in avoiding severe damage to equipment when disturbance occur and ensure overall system reliability. One of the methodology that widely used in protection scheme and algorithm is discrete wavelet transform. However, characteristic of coefficient under fault condition must be analyzed to ensure its effectiveness. So, this paper proposed study and analysis on wavelet coefficient characteristic when fault occur in transformer in both high- and low-frequency component from discrete wavelet transform. The effect of internal and external fault on wavelet coefficient of both fault and normal phase has been taken into consideration. The fault signal has been simulate using transmission connected to transformer experimental setup on laboratory level that modelled after actual system. The result in term of wavelet coefficient shown a clearly differentiate between wavelet characteristic in both high and low frequency component that can be used to further design and improve detection and classification algorithm that based on discrete wavelet transform methodology in the future.

Evaluation of dispersion strengthened nickel-base alloy heat shields for space shuttle application

NASA Technical Reports Server (NTRS)

Johnson, R., Jr.; Killpatrick, D. H.

1973-01-01

The work reported constitutes the first phase of a two-phase program. Vehicle environments having critical effects on the thermal protection system are defined; TD Ni-20Cr material characteristics are reviewed and compared with TD Ni-20Cr produced in previous development efforts; cyclic load, temperature, and pressure effects on TD Ni-20Cr sheet material are investigated; the effects of braze reinforcement in improving the efficiency of spotwelded, diffusion-bonded, or seam-welded joints are evaluated through tests of simple lap-shear joint samples; parametric studies of metallic radiative thermal protection systems are reported; and the design, instrumentation, and testing of full-scale subsize heat shield panels are described. Tests of full-scale subsize panels included simulated meteoroid impact tests; simulated entry flight aerodynamic heating in an arc-heated plasma stream; programmed differential pressure loads and temperatures simulating mission conditions; and acoustic tests simulating sound levels experienced by heat shields during about boost flight. Test results are described, and the performances of two heat shield designs are compared and evaluated.

The effects of gallic/ferulic/caffeic acids on colour intensification and anthocyanin stability.

PubMed

Qian, Bing-Jun; Liu, Jian-Hua; Zhao, Shu-Juan; Cai, Jian-Xiong; Jing, Pu

2017-08-01

The mechanism by which copigments stabilize colour, by protecting anthocyanin chromophores from nucleophilic attack, seems well accepted. This study was to determine effects of gallic/ferulic/caffeic acids on colour intensification and anthocyanin stability. Molecular dynamics simulations were applied to explore molecular interactions. Phenolic acids intensified the colour by 19%∼27%. Colour fading during heating followed first-order reactions with half-lives of 3.66, 9.64, 3.50, and 3.39h, whereas anthocyanin degradation, determined by the pH differential method (or HPLC-PDA), followed second-order reactions with half-lives of 3.29 (3.40), 3.43 (3.39), 2.29 (0.39), and 2.72 (0.32)h alone or with gallic/ferulic/caffeic acids, respectively, suggesting that anthocyanin degradation was faster than the colour fading. The strongest protection of gallic acids might be attributed to the shortest distance (4.37Å) of its aromatic ring to the anthocyanin (AC) panel. Hyperchromic effects induced by phenolic acids were pronounced and they obscured the accelerated anthocyanin degradation due to self-association interruption. Copyright © 2017 Elsevier Ltd. All rights reserved.

Human neuroblastoma SH-SY5Y cells show increased resistance to hyperthermic stress after differentiation, associated with elevated levels of Hsp72.

PubMed

Cheng, Lesley; Smith, Danielle J; Anderson, Robin L; Nagley, Phillip

2011-01-01

Terminally differentiated neurones in the central nervous system need to be protected from stress. We ask here whether differentiation of progenitor cells to neurones is accompanied by up-regulation of Hsp72, with acquisition of enhanced thermotolerance. Human neuroblastoma SH-SY5Y cells were propagated in an undifferentiated form and subsequently differentiated into neurone-like cells. Thermotolerance tests were carried out by exposure of cells to various temperatures, monitoring nuclear morphology as index of cell death. Abundance of Hsp72 was measured in cell lysates by western immunoblotting. The differentiation of SH-SY5Y cells was accompanied by increased expression of Hsp72. Further, in both cell states, exposure to mild hyperthermic stress (43°C for 30 min) increased Hsp72 expression. After differentiation, SH-SY5Y cells were more resistant to hyperthermic stress compared to their undifferentiated state, correlating with levels of Hsp72. Stable exogenous expression of Hsp72 in SH-SY5Y cells (transfected line 5YHSP72.1, containing mildly elevated levels of Hsp72), led to enhanced resistance to hyperthermic stress. Hsp72 was found to be inducible in undifferentiated 5YHSP72.1 cells; such heat-treated cells displayed enhanced thermotolerance. Treatment of cells with KNK437, a suppressor of Hsp72 induction, resulted in acute thermosensitisation of all cell types tested here. Hsp72 has a major role in the enhanced hyperthermic resistance acquired during neuronal differentiation of SH-SY5Y cells. These findings model the requirement in intact organisms for highly differentiated neurones to be specially protected against thermal stress.

Disparity in disability between native-born non-Hispanic white and foreign-born Asian older adults in the United States: effects of educational attainment and age at immigration.

PubMed

Lee, Min-Ah

2011-04-01

It is widely known that educational attainment has considerable influence on the prevalence of disability among native-born non-Hispanic older adults in the US. However, few studies have examined whether educational attainment has a similar effect on disability among foreign-born Asian older adults. If it does not have a similar effect on these adults, why not, and is its effect influenced by the age at which they immigrated to the US? This study addresses these questions by using the 2006 American Community Survey Public Use Microdata Sample (ACS PUMS). Logistic regression analyses reveal that education has differential effects on the two racial groups. Education protects foreign-born Asians less than native-born non-Hispanic whites. In addition, Asian adults who immigrated earlier are less likely to experience disability. Interestingly, the interaction between age at immigration and educational attainment for foreign-born Asian older adults indicates that less educated Asians are more likely to benefit from early immigration. Heterogeneity within the Asian group is also examined. The findings suggest that educational attainment has differential effects not only on the two racial groups but also on the foreign-born Asian group depending on age at immigration. Copyright © 2011 Elsevier Ltd. All rights reserved.

Effect of sulphur mustard on human skin cell lines with differential agent sensitivity.

PubMed

Simpson, Rachel; Lindsay, Christopher D

2005-01-01

The ability of sulphur mustard (HD) to induce DNA damage places limits on the efficacy of approaches aimed at protecting human cells from the cytotoxic effects of HD using a variety of protective agents such as thiol-containing esters and protease inhibitors. In the present study, potential alternative strategies were investigated by examining the differential effects of HD on G361, SVK14, HaCaT and NCTC 2544 human skin cells. The G361 cell line was more resistant to the cytotoxic effects of HD than the NCTC, HaCaT and SVK14 cell lines at HD doses of >3 and <100 microM HD as determined by the MTT assay. At 72 h after exposure to 60 microM HD there was up to an 8.8-fold difference (P < 0.0001) between G361 and SVK14 cell culture viability. Buthionine sulphoximine (BSO) pretreatment increased the sensitivity of all four cell lines to HD. A substantial proportion of the resistance of G361 cells to HD was attributable to BSO-mediated effects on antioxidant-mediated metabolism, although G361 cultures still retained a high degree of viability at 30 microM HD following BSO pretreatment. Cell cycle analysis confirmed that SVK14 cells were relatively more sensitive to HD, as shown by the 2.1-fold reduction (P < 0.0001) in the percentage of cells in G0/G1 phase 24 h after HD exposure compared with control cultures. This compared well with a 1.2-fold increase (P < 0.05) in the percentage of G361 cells in G0/G1 phase following HD exposure, suggesting the existence of a more efficient G0/G1 checkpoint control mechanism in this cell line. Manipulation of the cell cycle using various modulating agents did not increase the resistance of cell lines to the cytotoxic effects of HD. Crown copyright 2005

RNA sequencing supports distinct reactive oxygen species-mediated pathways of apoptosis by high and low size mass fractions of Bay leaf (Lauris nobilis) in HT-29 cells.

PubMed

Rodd, Annabelle L; Ververis, Katherine; Sayakkarage, Dheeshana; Khan, Abdul W; Rafehi, Haloom; Ziemann, Mark; Loveridge, Shanon J; Lazarus, Ross; Kerr, Caroline; Lockett, Trevor; El-Osta, Assam; Karagiannis, Tom C; Bennett, Louise E

2015-08-01

Anti-proliferative and pro-apoptotic effects of Bay leaf (Laurus nobilis) in mammalian cancer and HT-29 adenocarcinoma cells have been previously attributed to effects of polyphenolic and essential oil chemical species. Recently, we demonstrated differentiated growth-regulating effects of high (HFBL) versus low molecular mass (LFBL) aqueous fractions of bay leaf and now confirm by comparative effects on gene expression, that HFBL and LFBL suppress HT-29 growth by distinct mechanisms. Induction of intra-cellular lesions including DNA strand breakage by extra-cellular HFBL, invoked the hypothesis that iron-mediated reactive oxygen species with capacity to penetrate cell membrane, were responsible for HFBL-mediated effects, supported by equivalent effects of HFBL in combination with γ radiation. Activities of HFBL and LFBL were interpreted to reflect differentiated responses to iron-mediated reactive oxygen species (ROS), occurring either outside or inside cells. In the presence of LFBL, apoptotic death was relatively delayed compared with HFBL. ROS production by LFBL mediated p53-dependent apoptosis and recovery was suppressed by promoting G1/S phase arrest and failure of cellular tight junctions. In comparison, intra-cellular anti-oxidant protection exerted by LFBL was absent for extra-cellular HFBL (likely polysaccharide-rich), which potentiated more rapid apoptosis by producing DNA double strand breaks. Differentiated effects on expression of genes regulating ROS defense and chromatic condensation by LFBL versus HFBL, were observed. The results support ferrous iron in cell culture systems and potentially in vivo, can invoke different extra-cellular versus intra-cellular ROS-mediated chemistries, that may be regulated by exogenous, including dietary species.

PDGF is Required for Remyelination-Promoting IgM Stimulation of Oligodendrocyte Progenitor Cell Proliferation

PubMed Central

Watzlawik, Jens O.; Warrington, Arthur E.; Rodriguez, Moses

2013-01-01

Background Promotion of remyelination is a major goal in treating demyelinating diseases such as multiple sclerosis (MS). The recombinant human monoclonal IgM, rHIgM22, targets myelin and oligodendrocytes (OLs) and promotes remyelination in animal models of MS. It is unclear whether rHIgM22-mediated stimulation of lesion repair is due to promotion of oligodendrocyte progenitor cell (OPC) proliferation and survival, OPC differentiation into myelinating OLs or protection of mature OLs. It is also unknown whether astrocytes or microglia play a functional role in IgM-mediated lesion repair. Methods We assessed the effect of rHIgM22 on cell proliferation in mixed CNS glial and OPC cultures by tritiated-thymidine uptake and by double-label immunocytochemistry using the proliferation marker, Ki-67. Antibody-mediated signaling events, OPC differentiation and OPC survival were investigated and quantified by Western blots. Results rHIgM22 stimulates OPC proliferation in mixed glial cultures but not in purified OPCs. There is no proliferative response in astrocytes or microglia. rHIgM22 activates PDGFαR in OPCs in mixed glial cultures. Blocking PDGFR-kinase inhibits rHIgM22-mediated OPC proliferation in mixed glia. We confirm in isolated OPCs that rHIgM22-mediated anti-apoptotic signaling and inhibition of OPC differentiation requires PDGF and FGF-2. We observed no IgM-mediated effect in mature OLs in the absence of PDGF and FGF-2. Conclusion Stimulation of OPC proliferation by rHIgM22 depends on co-stimulatory astrocytic and/or microglial factors. We demonstrate that rHIgM22-mediated activation of PDGFαR is required for stimulation of OPC proliferation. We propose that rHIgM22 lowers the PDGF threshold required for OPC proliferation and protection, which can result in remyelination of CNS lesions. PMID:23383310

Enhanced acquired antibodies to a chimeric Plasmodium falciparum antigen; UB05-09 is associated with protective immunity against malaria.

PubMed

Dinga, J N; Gamua, S D; Titanji, V P K

2017-08-01

It has been shown that covalently linking two antigens could enhance the immunogenicity of the chimeric construct. To prioritize such a chimera for malaria vaccine development, it is necessary to demonstrate that naturally acquired antibodies against the chimera are associated with protection from malaria. Here, we probe the ability of a chimeric construct of UB05 and UB09 antigens (UB05-09) to better differentiate between acquired immune protection and susceptibility to malaria. In a cross-sectional study, recombinant UB05-09 chimera and the constituent antigens were used to probe for specific antibodies in the plasma from children and adults resident in a malaria-endemic zone, using the enzyme-linked immunosorbent assay (ELISA). Anti-UB05-09 antibody levels doubled that of its constituent antigens, UB09 and UB05, and this correlated with protection against malaria. The presence of enhanced UB05-09-specific antibody correlated with the absence of fever and parasitaemia, which are the main symptoms of malaria infection. The chimera is more effective in detecting and distinguishing acquired protective immunity against malaria than any of its constituents taken alone. Online B-cell epitope prediction tools confirmed the presence of B-cell epitopes in the study antigens. UB05-09 chimera is a marker of protective immunity against malaria that needs to be studied further. © 2017 John Wiley & Sons Ltd.

Incensole acetate prevents beta-amyloid-induced neurotoxicity in human olfactory bulb neural stem cells.

PubMed

El-Magd, Mohammed A; Khalifa, Sara F; A Alzahrani, Faisal Abdulrahman; Badawy, Abdelnaser A; El-Shetry, Eman S; Dawood, Lamess M; Alruwaili, Mohammed M; Alrawaili, Hedib A; Risha, Engi F; El-Taweel, Fathy M; Marei, Hany E

2018-06-15

β-Amyloid peptide (Aβ) is a potent neurotoxic protein associated with Alzheimer's disease (AD) which causes oxidative damage to neurons. Incensole acetate (IA) is a major constituent of Boswellia carterii resin, which has anti-inflammatory and protective properties against damage of a large verity of neural subtypes. However, this neuroprotective effect was not studied on human olfactory bulb neural stem cells (hOBNSCs). Herein, we evaluated this effect and studied the underlying mechanisms. Exposure to Aβ 25-35 (5 and 10 μM for 24 h) inhibited proliferation (revealed by downregulation of Nestin and Sox2 gene expression), and induced differentiation (marked by increased expression of the immature neuronal marker Map2 and the astrocyte marker Gfap) of hOBNSCs. However, pre-treatment with IA (100 μM for 4 h) stimulated proliferation and differentiation of neuronal, rather than astrocyte, markers. Moreover, IA pretreatment significantly decreased the Aβ 25-35 -induced viability loss, apoptotic rate (revealed by decreased caspase 3 activity and protein expression, downregulated expression of Bax, caspase 8, cyto c, caspase3, and upregulated expression of Bcl2 mRNAs and proteins, in addition to elevated mitochondrial membrane potential and lowered intracellular Ca +2 ). IA reduced Aβ-mediated ROS production (revealed by decreased intracellular ROS and MDA level, and increased SOD, CAT, and GPX contents), and inhibited Aβ-induced inflammation (marked by down-regulated expression of IL1b, TNFa, NfKb, and Cox2 genes). IA also significantly upregulated mRNA and protein expression of Erk1/2 and Nrf2. Notably, IA increased the antioxidant enzyme heme oxygenase-1 (HO-1) expression and this effect was reversed by HO-1 inhibitor zinc protoporphyrin (ZnPP) leading to reduction of the neuroprotective effect of IA against Aβ-induced neurotoxicity. These findings clearly show the ability of IA to initiate proliferation and differentiation of neuronal progenitors in hOBNSCs and induce HO-1 expression, thereby protecting the hOBNSCs cells from Aβ 25-35 -induced oxidative cell death. Thus, IA may be applicable as a potential preventive agent for AD by its effect on hOBNSCs and could also be used as an adjuvant to hOBNSCs in cellular therapy of neurodegenerative diseases. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Connectivity of the habitat-forming kelp, Ecklonia radiata within and among estuaries and open coast.

PubMed

Coleman, Melinda A

2013-01-01

With marine protected areas being established worldwide there is a pressing need to understand how the physical setting in which these areas are placed influences patterns of dispersal and connectivity of important marine organisms. This is particularly critical for dynamic and complex nearshore marine environments where patterns of genetic structure of organisms are often chaotic and uncoupled from broad scale physical processes. This study determines the influence of habitat heterogeneity (presence of estuaries) on patterns of genetic structure and connectivity of the common kelp, Ecklonia radiata. There was no genetic differentiation of kelp between estuaries and the open coast and the presence of estuaries did not increase genetic differentiation among open coast populations. Similarly, there were no differences in level of inbreeding or genetic diversity between estuarine and open coast populations. The presence of large estuaries along rocky coastlines does not appear to influence genetic structure of this kelp and factors other than physical heterogeneity of habitat are likely more important determinants of regional connectivity. Marine reserves are currently lacking in this bioregion and may be designated in the future. Knowledge of the factors that influence important habitat forming organisms such as kelp contribute to informed and effective marine protected area design and conservation initiatives to maintain resilience of important marine habitats.

Redox biology response in germinating Phaseolus vulgaris seeds exposed to copper: Evidence for differential redox buffering in seedlings and cotyledon.

PubMed

Karmous, Inès; Trevisan, Rafael; El Ferjani, Ezzeddine; Chaoui, Abdelilah; Sheehan, David

2017-01-01

In agriculture, heavy metal contamination of soil interferes with processes associated with plant growth, development and productivity. Here, we describe oxidative and redox changes, and deleterious injury within cotyledons and seedlings caused by exposure of germinating (Phaseolus vulgaris L. var. soisson nain hâtif) seeds to copper (Cu). Cu induced a marked delay in seedling growth, and was associated with biochemical disturbances in terms of intracellular oxidative status, redox regulation and energy metabolism. In response to these alterations, modulation of activities of antioxidant proteins (thioredoxin and glutathione reductase, peroxiredoxin) occurred, thus preventing oxidative damage. In addition, oxidative modification of proteins was detected in both cotyledons and seedlings by one- and two-dimensional electrophoresis. These modified proteins may play roles in redox buffering. The changes in activities of redox proteins underline their fundamental roles in controlling redox homeostasis. However, observed differential redox responses in cotyledon and seedling tissues showed a major capacity of the seedlings' redox systems to protect the reduced status of protein thiols, thus suggesting quantitatively greater antioxidant protection of proteins in seedlings compared to cotyledon. To our knowledge, this is the first comprehensive redox biology investigation of the effect of Cu on seed germination.

Can marital selection explain the differences in health between married and divorced people? From a longitudinal study of a British birth cohort.

PubMed

Cheung, Y B

1998-03-01

In view of the rising divorce rates, the impact of divorce on health has an increasing importance in public health. The differentials in health between the married and the divorced may be explained by 'marital selection' and 'marital protection'. Using longitudinal data from a study of the 1958 British birth cohort, factors that select people into divorce were identified from the areas of socio-economic status, health, and attractiveness, which included physical attractiveness, health-related behaviour and temperament. Evidence for both positive and adverse selection is found. The different sets of selection factors for females and males appear to be in line with gender role expectations. The health differentials between married and divorced men were weak and can be explained away by the selection factors. Having controlled for the selection effects, there were still significant associations between divorce and physical and psychological health in women. Though these unexplained differentials cannot be definitely interpreted as the consequences of marital dissolution, this interpretation remains plausible.

Implications for the Self Determine Benevolence and Self-Protection in Intergroup Relations

PubMed Central

Malloy, Thomas E.; Kinney, Lorin

2017-01-01

People often favor groups they belong to over those beyond the in-group boundary. Yet, in-group favoritism does not always occur, and people will sometimes favor an out-group over the in-group. We delineate theoretically when in-group favoritism (i.e., self-protection) and out-group favoritism (i.e., benevolence) should occur. In two experiments, groups’ relative status and competence stereotypes were manipulated; groups’ outcomes were non-contingent in Experiment 1 and contingent in Experiment 2. When allocating reward, members of a low status group were self-protective, favoring the in-group over the out-group under both non-contingent and contingent outcomes. Those with high status benevolently favored the out-group when outcomes were non-contingent, but were self-protective with contingent outcomes. People were willing to engage in social activities with an out-group member regardless of competence. However, when task collaboration had implications for the self, those with low status preferred competent over less competent out-group members. Traits of high status targets were differentiated by those with low status in both experiments, whereas those with high status differentiated low status members’ traits only when outcomes were contingent. A general principle fits the data: the implications of intergroup responses for the self determine benevolence and self-protection. Implications for the Self Determine Benevolence and Self Protection in Intergroup Relations PMID:29225518

Implications for the Self Determine Benevolence and Self-Protection in Intergroup Relations.

PubMed

Malloy, Thomas E; Kinney, Lorin

2017-01-01

People often favor groups they belong to over those beyond the in-group boundary. Yet, in-group favoritism does not always occur, and people will sometimes favor an out-group over the in-group. We delineate theoretically when in-group favoritism (i.e., self-protection) and out-group favoritism (i.e., benevolence) should occur. In two experiments, groups' relative status and competence stereotypes were manipulated; groups' outcomes were non-contingent in Experiment 1 and contingent in Experiment 2. When allocating reward, members of a low status group were self-protective, favoring the in-group over the out-group under both non-contingent and contingent outcomes. Those with high status benevolently favored the out-group when outcomes were non-contingent, but were self-protective with contingent outcomes. People were willing to engage in social activities with an out-group member regardless of competence. However, when task collaboration had implications for the self, those with low status preferred competent over less competent out-group members. Traits of high status targets were differentiated by those with low status in both experiments, whereas those with high status differentiated low status members' traits only when outcomes were contingent. A general principle fits the data: the implications of intergroup responses for the self determine benevolence and self-protection. Implications for the Self Determine Benevolence and Self Protection in Intergroup Relations.

Antibody treatment against pulmonary exposure to abrin confers significantly higher levels of protection than treatment against ricin intoxication.

PubMed

Sabo, Tamar; Gal, Yoav; Elhanany, Eitan; Sapoznikov, Anita; Falach, Reut; Mazor, Ohad; Kronman, Chanoch

2015-09-02

Abrin, a potent plant-derived toxin bearing strong resemblance to ricin, irreversibly inactivates ribosomes by site-specific depurination, thereby precipitating cessation of protein synthesis in cells. Due to its high availability and ease of preparation, abrin is considered a biological threat, especially in context of bioterror warfare. To date, there is no established therapeutic countermeasure against abrin intoxication. In the present study, we examined the progress of pulmonary abrin intoxication in mice, evaluated the protective effect of antibody-based post-exposure therapy, and compared these findings to those observed for ricin intoxication and therapy. Salient features of abrin intoxication were found to be similar to those of ricin and include massive recruitment of neutrophils to the lungs, high levels of pro-inflammatory markers in the bronchoalveolar lavage fluid and damage of the alveolar-capillary barrier. In contrast, the protective effect of anti-abrin antibody treatment was found to differ significantly from that of anti-ricin treatment. While anti-ricin treatment efficiency was quite limited even at 24h post-exposure (34% protection), administration of polyclonal anti-abrin antibodies even as late as 72h post-exposure, conferred exceedingly high-level protection (>70%). While both anti-toxin antibody treatments caused neutrophil and macrophage levels in the lungs to revert to normal, only anti-abrin treatment brought about a significant decline in the pulmonary levels of the pro-inflammatory cytokine IL-6. The differential ability of the anti-toxin treatments to dampen inflammation caused by the two similar toxins, abrin and ricin, could explain the radically different levels of protection achieved following antibody treatment. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

DNA-damage-induced differentiation of leukaemic cells as an anti-cancer barrier

PubMed Central

Santos, Margarida A.; Faryabi, Robert B.; Ergen, Aysegul V.; Day, Amanda M.; Malhowski, Amy; Canela, Andres; Onozawa, Masahiro; Lee, Ji-Eun; Callen, Elsa; Gutierrez-Martinez, Paula; Chen, Hua-Tang; Wong, Nancy; Finkel, Nadia; Deshpande, Aniruddha; Sharrow, Susan; Rossi, Derrick J.; Ito, Keisuke; Ge, Kai; Aplan, Peter D.; Armstrong, Scott A.; Nussenzweig, André

2015-01-01

Self-renewal is the hallmark feature both of normal stem cells and cancer stem cells1. Since the regenerative capacity of normal haematopoietic stem cells is limited by the accumulation of reactive oxygen species and DNA double-strand breaks2–4, we speculated that DNA damage might also constrain leukaemic self-renewal and malignant haematopoiesis. Here we show that the histone methyl-transferase MLL4, a suppressor of B-cell lymphoma5,6, is required for stem-cell activity and an aggressive form of acute myeloid leukaemia harbouring the MLL–AF9 oncogene. Deletion of MLL4 enhances myelopoiesis and myeloid differentiation of leukaemic blasts, which protects mice from death related to acute myeloid leukaemia. MLL4 exerts its function by regulating transcriptional programs associated with the antioxidant response. Addition of reactive oxygen species scavengers or ectopic expression of FOXO3 protects MLL4−/− MLL–AF9 cells from DNA damage and inhibits myeloid maturation. Similar to MLL4 deficiency, loss of ATM or BRCA1 sensitizes transformed cells to differentiation, suggesting that myeloid differentiation is promoted by loss of genome integrity. Indeed, we show that restriction-enzyme-induced double-strand breaks are sufficient to induce differentiation of MLL–AF9 blasts, which requires cyclin-dependent kinase inhibitor p21Cip1 (Cdkn1a) activity. In summary, we have uncovered an unexpected tumour-promoting role of genome guardians in enforcing the oncogene-induced differentiation blockade in acute myeloid leukaemia. PMID:25079327

Assessment of radiation protection awareness and knowledge about radiological examination doses among Italian radiographers.

PubMed

Paolicchi, F; Miniati, F; Bastiani, L; Faggioni, L; Ciaramella, A; Creonti, I; Sottocornola, C; Dionisi, C; Caramella, D

2016-04-01

To evaluate radiation protection basic knowledge and dose assessment for radiological procedures among Italian radiographers A validated questionnaire was distributed to 780 participants with balanced demographic characteristics and geographic distribution. Only 12.1 % of participants attended radiation protection courses on a regular basis. Despite 90 % of radiographers stating to have sufficient awareness of radiation protection issues, most of them underestimated the radiation dose of almost all radiological procedures. About 5 % and 4 % of the participants, respectively, claimed that pelvis magnetic resonance imaging and abdominal ultrasound exposed patients to radiation. On the contrary, 7.0 % of the radiographers stated that mammography does not use ionising radiation. About half of participants believed that radiation-induced cancer is not dependent on age or gender and were not able to differentiate between deterministic and stochastic effects. Young radiographers (with less than 3 years of experience) showed a higher level of knowledge compared with the more experienced radiographers. There is a substantial need for radiographers to improve their awareness of radiation protection issues and their knowledge of radiological procedures. Specific actions such as regular training courses for both undergraduate and postgraduate students as well as for working radiographers must be considered in order to assure patient safety during radiological examinations. • Radiographers should improve their knowledge on radiation protection issues. • Only 12.1 % of participants attended radiation protection courses on a regular basis. • Specific actions must be considered in order to increase knowledge and awareness.

Ecotoxicological effects of the herbicide glyphosate in non-target aquatic species: Transcriptional responses in the mussel Mytilus galloprovincialis.

PubMed

Milan, M; Dalla Rovere, G; Smits, M; Ferraresso, S; Pastore, P; Marin, M G; Bogialli, S; Patarnello, T; Bargelloni, L; Matozzo, V

2018-06-01

Glyphosate has been the most widely used herbicide worldwide over the last three decades, raising increasing concerns for its potential impacts on environmental and human health. Recent studies revealed that glyphosate occurs in soil, surface water, and groundwater, and residues are found at all levels of the food chain, such as drinking water, plants, animals, and even in humans. While research has demonstrated that glyphosate can induce a broad range of biological effects in exposed organisms, the global molecular mechanisms of action still need to be elucidated, in particular for marine species. In this study, we characterized for the first time the molecular mechanisms of action of glyphosate in a marine bivalve species after exposure to environmentally realistic concentrations. To reach such a goal, Mediterranean mussels Mytilus galloprovincialis, an ecologically and economically relevant species, were exposed for 21 days to 10, 100, and 1000 μg/L and digestive gland transcriptional profiles were investigated through RNA-seq. Differential expression analysis identified a total of 111, 124, and 211 differentially regulated transcripts at glyphosate concentrations of 10, 100, and 1000 μg/L, respectively. Five genes were found consistently differentially expressed at all investigated concentrations, including SERP2, which plays a role in the protection of unfolded target proteins against degradation, the antiapoptotic protein GIMAP5, and MTMR14, which is involved in macroautophagy. Functional analysis of differentially expressed genes reveals the disruption of several key biological processes, such as energy metabolism and Ca 2+ homeostasis, cell signalling, and endoplasmic reticulum stress response. Together, the results obtained suggest that the presence of glyphosate in the marine ecosystem should raise particular concern because of its significant effects even at the lowest concentration. Copyright © 2018 Elsevier Ltd. All rights reserved.

Relationship beliefs and illness appraisals are differentially associated with specific ways of coping in spouses of patients with type 2 diabetes.

PubMed

Johnson, Matthew D; Anderson, Jared R; Wilcox, Allison; Walker, Ann; Robbins, David C; Lewis, Virginia L

2013-01-01

Using data from 117 spouses of patients diagnosed with type 2 diabetes and multiple-group path analysis, the current study explored the association of four relationship beliefs (satisfaction, sacrifice, confidence and instability) and four diabetes appraisals (consequences, distress, control and efficacy) with illness-specific coping behaviour: active engagement, protective buffering and overprotection. The potential moderating effect of gender was also tested. Results indicated gender did moderate the associations among the variables in the model, with the association of relationship satisfaction and active engagement being significantly stronger for men, while diabetes control was more strongly related to protective buffering for women. The only variables associated with active engagement were three relationship-specific cognitions: higher levels of relationship satisfaction (for men only), satisfaction with sacrifice and relationship confidence were all related to higher active engagement. The diabetes appraisals were the only variables associated with protective buffering and overprotection. Higher diabetes distress and diabetes control (for women only) and lower diabetes efficacy were predictive of greater protective buffering. Lower diabetes efficacy and higher diabetes control were associated with greater overprotection. Implications for theory, research and practice are discussed.

Regulation of the orexigenic neuropeptide, enkephalin, by PPARδ and fatty acids in neurons of the hypothalamus and forebrain.

PubMed

Poon, Kinning; Alam, Mohammad; Karatayev, Olga; Barson, Jessica R; Leibowitz, Sarah F

2015-12-01

Ingestion of a high-fat diet composed mainly of the saturated fatty acid, palmitic (PA), and the unsaturated fatty acid, oleic (OA), stimulates transcription in the brain of the opioid neuropeptide, enkephalin (ENK), which promotes intake of substances of abuse. To understand possible underlying mechanisms, this study examined the nuclear receptors, peroxisome proliferator-activated receptors (PPARs), and tested in hypothalamic and forebrain neurons from rat embryos whether PPARs regulate endogenous ENK and the fatty acids themselves affect these PPARs and ENK. The first set of experiments demonstrated that knocking down PPARδ, but not PPARα or PPARγ, increased ENK transcription, activation of PPARδ by an agonist decreased ENK levels, and PPARδ neurons coexpressed ENK, suggesting that PPARδ negatively regulates ENK. In the second set of experiments, PA treatment of hypothalamic and forebrain neurons had no effect on PPARδ protein while stimulating ENK mRNA and protein, whereas OA increased both mRNA and protein levels of PPARδ in forebrain neurons while having no effect on ENK mRNA and increasing ENK levels. These findings show that PA has a strong, stimulatory effect on ENK and weak effect on PPARδ protein, whereas OA has a strong stimulatory effect on PPARδ and weak effect on ENK, consistent with the inhibitory effect of PPARδ on ENK. They suggest a function for PPARδ, perhaps protective in nature, in embryonic neurons exposed to fatty acids from a fat-rich diet and provide evidence for a mechanism contributing to differential effects of saturated and monounsaturated fatty acids on neurochemical systems involved in consummatory behavior. Our findings show that PPARδ in forebrain and hypothalamic neurons negatively regulates enkephalin (ENK), a peptide known to promote ingestive behavior. This inverse relationship is consistent with our additional findings, that a saturated (palmitic; PA) compared to a monounsaturated fatty acid (oleic; OA) has a strong stimulatory effect on ENK and weak effect on PPARδ. These results suggest that PPARδ protects against the neuronal effects of fatty acids, which differentially affect neurochemical systems involved in ingestive behavior. © 2015 International Society for Neurochemistry.

Chemoprevention of Breast Cancer by Mimicking the Protective Effect of Early First Birth. Addendum

DTIC Science & Technology

2013-03-01

changes in growth factors, TGF-h3, and differentiation in the rodent mammary gland. Mol Endocrinol 2002;16:2034–51. 7. Thordarson G, Jin E, Guzman RC...rats. Carcinogenesis 1999;20:623–8. 11. Rajkumar L, Guzman RC, Yang J, Thordarson G, Talamantes F, Nandi S. Short-term exposure to preg- nancy levels of...estrogen prevents mammary carcino- genesis. Proc Natl Acad Sci U S A 2001;98:11755–9. 12. Guzman RC, Yang J, Rajkumar L, Thordarson G, Chen X, Nandi S

Chemoprevention of Breast Cancer by Mimicking the Protective Effect of Early First Birth

DTIC Science & Technology

2008-06-01

growth factors, TGF-h3, and differentiation in the rodent mammary gland. Mol Endocrinol 2002;16:2034–51. 7. Thordarson G, Jin E, Guzman RC, Swanson...Carcinogenesis 1999;20:623–8. 11. Rajkumar L, Guzman RC, Yang J, Thordarson G, Talamantes F, Nandi S. Short-term exposure to preg- nancy levels of...estrogen prevents mammary carcino- genesis. Proc Natl Acad Sci U S A 2001;98:11755–9. 12. Guzman RC, Yang J, Rajkumar L, Thordarson G, Chen X, Nandi S

Analysis of the Catecholaminergic Phenotype in Human SH-SY5Y and BE(2)-M17 Neuroblastoma Cell Lines upon Differentiation

PubMed Central

Filograna, Roberta; Civiero, Laura; Ferrari, Vanni; Codolo, Gaia; Greggio, Elisa; Bubacco, Luigi; Beltramini, Mariano; Bisaglia, Marco

2015-01-01

Human cell lines are often used to investigate cellular pathways relevant for physiological or pathological processes or to evaluate cell toxicity or protection induced by different compounds, including potential drugs. In this study, we analyzed and compared the differentiating activities of three agents (retinoic acid, staurosporine and 12-O-tetradecanoylphorbol-13-acetate) on the human neuroblastoma SH-SY5Y and BE(2)-M17 cell lines; the first cell line is largely used in the field of neuroscience, while the second is still poorly characterized. After evaluating their effects in terms of cell proliferation and morphology, we investigated their catecholaminergic properties by assessing the expression profiles of the major genes involved in catecholamine synthesis and storage and the cellular concentrations of the neurotransmitters dopamine and noradrenaline. Our results demonstrate that the two cell lines possess similar abilities to differentiate and acquire a neuron-like morphology. The most evident effects in SH-SY5Y cells were observed in the presence of staurosporine, while in BE(2)-M17 cells, retinoic acid induced the strongest effects. Undifferentiated SH-SY5Y and BE(2)-M17 cells are characterized by the production of both NA and DA, but their levels are considerably higher in BE(2)-M17 cells. Moreover, the NAergic phenotype appears to be more pronounced in SH-SY5Y cells, while BE(2)-M17 cells have a more prominent DAergic phenotype. Finally, the catecholamine concentration strongly increases upon differentiation induced by staurosporine in both cell lines. In conclusion, in this work the catecholaminergic phenotype of the human BE(2)-M17 cell line upon differentiation was characterized for the first time. Our data suggest that SH-SY5Y and BE(2)-M17 represent two alternative cell models for the neuroscience field. PMID:26317353

Analysis of the Catecholaminergic Phenotype in Human SH-SY5Y and BE(2)-M17 Neuroblastoma Cell Lines upon Differentiation.

PubMed

Filograna, Roberta; Civiero, Laura; Ferrari, Vanni; Codolo, Gaia; Greggio, Elisa; Bubacco, Luigi; Beltramini, Mariano; Bisaglia, Marco

2015-01-01

Human cell lines are often used to investigate cellular pathways relevant for physiological or pathological processes or to evaluate cell toxicity or protection induced by different compounds, including potential drugs. In this study, we analyzed and compared the differentiating activities of three agents (retinoic acid, staurosporine and 12-O-tetradecanoylphorbol-13-acetate) on the human neuroblastoma SH-SY5Y and BE(2)-M17 cell lines; the first cell line is largely used in the field of neuroscience, while the second is still poorly characterized. After evaluating their effects in terms of cell proliferation and morphology, we investigated their catecholaminergic properties by assessing the expression profiles of the major genes involved in catecholamine synthesis and storage and the cellular concentrations of the neurotransmitters dopamine and noradrenaline. Our results demonstrate that the two cell lines possess similar abilities to differentiate and acquire a neuron-like morphology. The most evident effects in SH-SY5Y cells were observed in the presence of staurosporine, while in BE(2)-M17 cells, retinoic acid induced the strongest effects. Undifferentiated SH-SY5Y and BE(2)-M17 cells are characterized by the production of both NA and DA, but their levels are considerably higher in BE(2)-M17 cells. Moreover, the NAergic phenotype appears to be more pronounced in SH-SY5Y cells, while BE(2)-M17 cells have a more prominent DAergic phenotype. Finally, the catecholamine concentration strongly increases upon differentiation induced by staurosporine in both cell lines. In conclusion, in this work the catecholaminergic phenotype of the human BE(2)-M17 cell line upon differentiation was characterized for the first time. Our data suggest that SH-SY5Y and BE(2)-M17 represent two alternative cell models for the neuroscience field.

Institutional deliveries weakly associated with improved neonatal survival in developing countries: evidence from 192 Demographic and Health Surveys.

PubMed

Fink, Günther; Ross, Rebecca; Hill, Kenneth

2015-12-01

Child and maternal mortality remain high in many developing countries. A principal strategy used in low- and middle-income countries is increasing the proportion of pregnancies delivered at facilities. Although this strategy is reasonable with high quality facilities, evidence for the protective effects of facility deliveries is mixed. We pooled 1.47 million birth records collected by the Demographic and Health Surveys to estimate the association between institutional deliveries and early neonatal mortality. Subsample analysis and instrumental variable estimation were used to assess and correct the extent to which mortality differentials are biased by an increased likelihood of facility attendance for high-risk deliveries. No associations between institutional deliveries and early neonatal mortality were found in the pooled sample [adjusted odds ratio (aOR) 0.995, 95% confidence interval (CI) 0.966-1.025)]. When stratified by facility type, protective effects were found for private facilities (aOR 0.876, 95% CI 0.840-0.914), but not for public hospitals or health centres. Significant protective effects were found when past behaviour was used to eliminate selection bias generated by short-term responses to medical need (aOR 0.884, 95% CI 0.814-0.961). At the community and country levels, strong positive associations were found between early neonatal mortality among facility deliveries and the prevalence of institutional deliveries. Facility deliveries have the potential to reduce early neonatal mortality in developing countries. The results presented suggest that the quality, utilization and protective effects of institutional deliveries vary widely across countries; major improvements in both utilization and quality of care will be needed to achieve further improvements in maternal and child health. © The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

Protective effects of myricitrin against osteoporosis via reducing reactive oxygen species and bone-resorbing cytokines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, Qiang; Gao, Bo; Wang, Long

Oxidative stress is a crucial pathogenic factor in the development of osteoporosis. Myricitrin, isolated from Myrica cerifera, is a potent antioxidant. We hypothesized that myricitrin possessed protective effects against osteoporosis by partially reducing reactive oxygen species (ROS) and bone-resorbing cytokines in osteoblastic MC3T3-E1 cells and human bone marrow stromal cells (hBMSCs). We investigated myricitrin on osteogenic differentiation under oxidative stress. Hydrogen peroxide (H{sub 2}O{sub 2}) was used to establish an oxidative cell injury model. Our results revealed that myricitrin significantly improved some osteogenic markers in these cells. Myricitrin decreased lipid production and reduced peroxisome proliferator-activated receptor gamma-2 (PPARγ2) expression inmore » hBMSCs. Moreover, myricitrin reduced the expression of receptor activator of nuclear factor kappa-B ligand (RANKL) and IL-6 and partially suppressed ROS production. In vivo, we established a murine ovariectomized (OVX) osteoporosis model. Our results demonstrated that myricitrin supplementation reduced serum malondialdehyde (MDA) activity and increased reduced glutathione (GSH) activity. Importantly, it ameliorated the micro-architecture of trabecular bones in the 4th lumbar vertebrae (L4) and distal femur. Taken together, these results indicated that the protective effects of myricitrin against osteoporosis are linked to a reduction in ROS and bone-resorbing cytokines, suggesting that myricitrin may be useful in bone metabolism diseases, particularly osteoporosis. - Highlights: • Myricitrin protects MC3T3-E1 cells and hBMSCs from oxidative stress. • It is accompanied by a decrease in oxidative stress and bone-resorbing cytokines. • Myricitrin decreases serum reactive oxygen species to some degree. • Myricitrin partly reverses ovariectomy effects in vivo. • Myricitrin may represent a beneficial anti-osteoporosis treatment method.« less

Protective and Risk Influences of Drug Use among a Multiethnic Sample of Adolescent Boys

ERIC Educational Resources Information Center

Galaif, E. R.; Newcomb, M. D.; Vega, W. A.; Krell, R. D.

2007-01-01

A measurement model was analyzed to demonstrate a differential distribution and cumulative exposure to psychosocial risk and protective influences of adolescent drug use among ethnically-diverse adolescent samples. The sample included U.S.-born (US) Latino (N = 837), foreign-born (FB) Latino (N = 447), White (N = 632), and African American (N =…

47 CFR 80.385 - Frequencies for automated systems.

Code of Federal Regulations, 2010 CFR

2010-10-01

... must notify the American Radio Relay League in writing at least 30 days prior to initiation of... protection will be provided to a site-based licensee's predicted 38 dBu signal level contour. The site-based... differential. The 18 dB protection to the site-based licensee's predicted 38 dBu signal level contour shall be...

47 CFR 80.385 - Frequencies for automated systems.

Code of Federal Regulations, 2011 CFR

2011-10-01

... must notify the American Radio Relay League in writing at least 30 days prior to initiation of... protection will be provided to a site-based licensee's predicted 38 dBu signal level contour. The site-based... differential. The 18 dB protection to the site-based licensee's predicted 38 dBu signal level contour shall be...

African American Students' Perceptions of Differential Treatment in Learning Environments: Examining the Moderating Role of Peer Support, Connection to Heritage, and Discrimination Efficacy

ERIC Educational Resources Information Center

Brittian, Aerika S.; Gray, DeLeon L.

2014-01-01

This study examined the relationship between African American students' perceptions of differential treatment by teachers and educational outcomes, and the factors that promote these outcomes in the context of perceived discrimination, focusing on the protective value of youth's cultural heritage, as well as individual characteristics. The…

Alterations in Factors Involved in Differentiation and Barrier Function in the Epithelium in Oral and Genital Lichen Planus.

PubMed

Danielsson, Karin; Ebrahimi, Majid; Nylander, Elisabet; Wahlin, Ylva Britt; Nylander, Karin

2017-02-08

Lichen planus is a chronic recurrent inflammatory disease affecting both skin and mucosa, mainly in oral and/or genital regions. Keratinocytes go through a well-regulated process of proliferation and differentiation, alterations in which may result in defects in the protective epithelial barrier. Long-term barrier impairment might lead to chronic inflammation. In order to broaden our understanding of the differentiation process in mucosal lichen planus, we mapped the expression of 4 factors known to be involved in differentiation. Biopsies were collected from oral and genital lichen planus lesions and normal controls. Altered expression of all 4 factors in epithelium from lichen planus lesions was found, clearly indicating disturbed epithelial differentiation in lichen planus lesions.

Minority and Immigrant Youth Exposure to Community Violence: The Differential Effects of Family Management and Peers.

PubMed

Antunes, Maria João Lobo; Ahlin, Eileen M

2018-02-01

Experiences with neighborhood violence can produce negative consequences in youth, including stress, anxiety, and deviant behavior. Studies report that immigrant and minority youth are more likely to be exposed to violence but less likely to perpetrate it. Similarly, research shows parenting practices are differentially adopted by Blacks, Whites, and Hispanics. Although family management strategies can often act as a barrier to the detrimental effects of exposure to community violence (ETV-C), there is a paucity of investigation on how Hispanic subgroups (e.g., Puerto Rican, Mexican) and immigrant families employ such practices in protecting their children against victimization and violence in the community. Applying an ecological framework, we use data from the Project on Human Development in Chicago Neighborhoods to examine the role of parenting and peer relationships on youth ETV-C, across race/ethnicity and immigrant generational status. Our sample is drawn from Cohorts 9, 12, and 15, and is over 40% Hispanic-Latino. We investigate the differences in within and outside the home family management strategies in terms of both race/ethnicity and immigrant generational status. Our work also seeks to determine the effects of race/ethnicity and immigrant status on youth ETV-C, while examining the influence of family management and peer relations. Results indicate that the adoption of family management practices is not homogeneous across Hispanic subgroups or immigrant generational status, and parenting practices seem to mediate the relationship between these characteristics and exposure to violence. Variations in parenting practices underscore the need to disentangle the cultural plurality of racial/ethnic grouping and how immigrant generational status influences parenting choices that protect children from exposure to violence in the community.

Neuroprotective effects of human mesenchymal stem cells on neural cultures exposed to 6-hydroxydopamine: implications for reparative therapy in Parkinson's disease.

PubMed

Cova, Lidia; Bossolasco, Patrizia; Armentero, Marie-Therese; Diana, Valentina; Zennaro, Eleonora; Mellone, Manuela; Calzarossa, Cinzia; Cerri, Silvia; Deliliers, Giorgio Lambertenghi; Polli, Elio; Blandini, Fabio; Silani, Vincenzo

2012-03-01

Stem cell (SC) transplantation represents a promising tool to treat neurodegenerative disorders, such as Parkinson's disease (PD), but positive therapeutic outcomes require elucidation of the biological mechanisms involved. Therefore, we investigated human Mesenchymal SCs (hMSCs) ability to protect murine differentiated Neural SCs (mdNSCs) against the cytotoxic effects of 6-hydroxydopamine (6-OHDA) in a co-culture model mimicking the in vivo neurovascular niche. The internalization of 6-OHDA mainly relies on its uptake by the dopamine active transporter (DAT), but its toxicity could also involve other pathways. We demonstrated that mdNSCs consistently expressed DAT along the differentiative process. Exposure to 6-OHDA did not affect hMSCs, but induced DAT-independent apoptosis in mdNSCs with generation of reactive oxygen species and caspases 3/7 activation. The potential neuroprotective action of hMSCs on mdNSCs exposed to 6-OHDA was tested in different co-culture conditions, in which hMSCs were added to mdNSCs prior to, simultaneously, or after 6-OHDA treatment. In the presence of the neurotoxin, the majority of mdNSCs acquired an apoptotic phenotype, while co-cultures with hMSCs significantly increased their survival (up to 70%) in all conditions. Multiplex human angiogenic array analysis on the conditioned media demonstrated that cytokine release by hMSCs was finely modulated. Moreover, sole growth factor addition yielded a similar neuroprotective effect on mdNSCs. In conclusion, our findings demonstrate that hMSCs protect mdNSCs against 6-OHDA neurotoxicity, and rescue cells from ongoing neurodegeneration likely through the release of multiple cytokines. Our findings provide novel insights for the development of therapeutic strategies designed to counteract the neurodegenerative processes of PD.

The protective roles of TiO2 nanoparticles against UV-B toxicity in Daphnia magna.

PubMed

Liu, Jie; Wang, Wen-Xiong

2017-09-01

Aquatic environments are increasingly under environmental stress due to ultraviolet (UV) radiation and potential inputs of nanoparticles with intense application of nanotechnology. In this study, we investigated the interaction between UV-B radiation and titanium nanoparticles (TiO 2 -NPs) in a model freshwater cladoceran Daphnia magna. UV-B toxicity to Daphnia magna was examined when the daphnids were exposed to a range of TiO 2 -NPs concentrations with an initial 5 or 10min of 200μW/cm 2 UV-B radiation. In addition, UV-B toxicity was also examined in the presence of TiO 2 -NPs in the body of daphnids. Our results demonstrated that the daphnid mortality under UV-B radiation decreased significantly in the presence of TiO 2 -NPs both in the water and in the body, indicating that TiO 2 -NPs had some protective effects on D. magna against UV-B. Such protective effect was mainly caused by the blockage of UV-B by TiO 2 -NPs adsorption. UV-B produced reactive oxygen species (ROS) in the water and in the daphnids, which was not sufficient to cause mortality of daphnids over short periods of radiation. Previous studies focused on the effects of TiO 2 -NPs on the toxicity of total UV radiation, and did not attempt to differentiate the potential diverse roles of UV-A and UV-B. Our study indicated that TiO 2 -NPs may conversely protect the UV-B toxicity to daphnids. Copyright © 2017 Elsevier B.V. All rights reserved.

Simultaneous Overexpression of Functional Human HO-1, E5NT and ENTPD1 Protects Murine Fibroblasts against TNF-α-Induced Injury In Vitro

PubMed Central

Cinti, Alessandro; De Giorgi, Marco; Chisci, Elisa; Arena, Claudia; Galimberti, Gloria; Farina, Laura; Bugarin, Cristina; Rivolta, Ilaria; Gaipa, Giuseppe; Smolenski, Ryszard Tom; Cerrito, Maria Grazia; Lavitrano, Marialuisa; Giovannoni, Roberto

2015-01-01

Several biomedical applications, such as xenotransplantation, require multiple genes simultaneously expressed in eukaryotic cells. Advances in genetic engineering technologies have led to the development of efficient polycistronic vectors based on the use of the 2A self-processing oligopeptide. The aim of this work was to evaluate the protective effects of the simultaneous expression of a novel combination of anti-inflammatory human genes, ENTPD1, E5NT and HO-1, in eukaryotic cells. We produced an F2A system-based multicistronic construct to express three human proteins in NIH3T3 cells exposed to an inflammatory stimulus represented by tumor necrosis factor alpha (TNF-α), a pro-inflammatory cytokine which plays an important role during inflammation, cell proliferation, differentiation and apoptosis and in the inflammatory response during ischemia/reperfusion injury in several organ transplantation settings. The protective effects against TNF-α-induced cytotoxicity and cell death, mediated by HO-1, ENTPD1 and E5NT genes were better observed in cells expressing the combination of genes as compared to cells expressing each single gene and the effect was further improved by administrating enzymatic substrates of the human genes to the cells. Moreover, a gene expression analyses demonstrated that the expression of the three genes has a role in modulating key regulators of TNF-α signalling pathway, namely Nemo and Tnfaip3, that promoted pro-survival phenotype in TNF-α injured cells. These results could provide new insights in the research of protective mechanisms in transplantation settings. PMID:26513260

Omentin protects against LPS-induced ARDS through suppressing pulmonary inflammation and promoting endothelial barrier via an Akt/eNOS-dependent mechanism.

PubMed

Qi, Di; Tang, Xumao; He, Jing; Wang, Daoxin; Zhao, Yan; Deng, Wang; Deng, Xinyu; Zhou, Guoqi; Xia, Jing; Zhong, Xi; Pu, Shenglan

2016-09-08

Acute respiratory distress syndrome (ARDS) is characterized by increased pulmonary inflammation and endothelial barrier permeability. Omentin has been shown to benefit obesity-related systemic vascular diseases; however, its effects on ARDS are unknown. In the present study, the level of circulating omentin in patients with ARDS was assessed to appraise its clinical significance in ARDS. Mice were subjected to systemic administration of adenoviral vector expressing omentin (Ad-omentin) and one-shot treatment of recombinant human omentin (rh-omentin) to examine omentin's effects on lipopolysaccharide (LPS)-induced ARDS. Pulmonary endothelial cells (ECs) were treated with rh-omentin to further investigate its underlying mechanism. We found that a decreased level of circulating omentin negatively correlated with white blood cells and procalcitonin in patients with ARDS. Ad-omentin protected against LPS-induced ARDS by alleviating the pulmonary inflammatory response and endothelial barrier injury in mice, accompanied by Akt/eNOS pathway activation. Treatment of pulmonary ECs with rh-omentin attenuated inflammatory response and restored adherens junctions (AJs), and cytoskeleton organization promoted endothelial barrier after LPS insult. Moreover, the omentin-mediated enhancement of EC survival and differentiation was blocked by the Akt/eNOS pathway inactivation. Therapeutic rh-omentin treatment also effectively protected against LPS-induced ARDS via the Akt/eNOS pathway. Collectively, these data indicated that omentin protects against LPS-induced ARDS by suppressing inflammation and promoting the pulmonary endothelial barrier, at least partially, through an Akt/eNOS-dependent mechanism. Therapeutic strategies aiming to restore omentin levels may be valuable for the prevention or treatment of ARDS.

Preparation and Characterization of Pyrotechnics Binder-Coated Nano-Aluminum Composite Particles

NASA Astrophysics Data System (ADS)

Ye, Mingquan; Zhang, Shuting; Liu, Songsong; Han, Aijun; Chen, Xin

2017-07-01

The aim of this article is to protect the activity of nano-aluminum (Al) particles in solid rocket propellants and pyrotechnics. The morphology, structure, active aluminum content, and thermal and catalytic properties of the coated samples were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), thermogravimetry-differential scanning calorimetry (TG-DSC), and oxidation-reduction titration methods. The results indicated that nano-Al particles could be effectively coated with phenolic resin (PF), fluororubber (Viton B), and shellac through a solvent/nonsolvent method. The energetic composite particles have core-shell structures and the thickness of the coating film is about 5-15 nm. Analysis of the active Al content revealed that Viton B coating had a much better protective effect. The TG-DSC results showed that the energy amount and energy release rate of PF-, Viton B-, and shellac-coated Al particles were larger than those of the raw nano-Al particles. The catalytic effects of coated Al particles on the thermal decomposition of ammonium perchlorate (AP) were better than those of raw nano-Al particles, and the effect of shellac-coated Al particles was significantly better than that of Viton B-coated Al particles.

Differential effects of grape juice on gastric emptying and renal function from cisplatin-induced acute adverse toxicity.

PubMed

Ko, J-L; Tsai, C-H; Liu, T-C; Lin, M-Y; Lin, H-L; Ou, C-C

2016-08-01

Grape skin and seeds contain large amounts of phytochemicals such as polyphenols, resveratrol, and proanthocyanidins, which possess antioxidant activities. Cisplatin is widely used in the treatment of cancer. High doses of cisplatin have also been known to produce acute adverse effects. The aim of this study was to investigate the protective effects of antioxidant properties of whole grape juice (with skin and seeds) on cisplatin-induced acute gastrointestinal tract disorders and nephrotoxicity in Wistar rats. Gastric emptying is significantly increased in whole grape juice-pretreated rats when compared to cisplatin treatment alone. The expression of ghrelin mRNA of stomach is increased in rats with whole grape juice. However, pretreatment with whole grape juice did not reduce renal function markers in acute renal toxicity. No significant changes were recorded in the oxidative stress/antioxidant status parameters of any study group. In contrast, pretreatment with whole grape juice slightly improved tubular cell vacuolization, tubular dilatation, and cast formation in renal tubules. These results show that consumption of whole grape juice induces somewhat beneficial effects in preventing cisplatin-mediated dyspepsia but does not offer protection against cisplatin-induced acute renal toxicity. © The Author(s) 2015.

Modulation of transcription factors by curcumin.

PubMed

Shishodia, Shishir; Singh, Tulika; Chaturvedi, Madan M

2007-01-01

Curcumin is the active ingredient of turmeric that has been consumed as a dietary spice for ages. Turmeric is widely used in traditional Indian medicine to cure biliary disorders, anorexia, cough, diabetic wounds, hepatic disorders, rheumatism, and sinusitis. Extensive investigation over the last five decades has indicated that curcumin reduces blood cholesterol, prevents low-density lipoprotein oxidation, inhibits platelet aggregation, suppresses thrombosis and myocardial infarction, suppresses symptoms associated with type II diabetes, rheumatoid arthritis, multiple sclerosis, and Alzheimer's disease, inhibits HIV replication, enhances wound healing, protects from liver injury, increases bile secretion, protects from cataract formation, and protects from pulmonary toxicity and fibrosis. Evidence indicates that the divergent effects of curcumin are dependent on its pleiotropic molecular effects. These include the regulation of signal transduction pathways and direct modulation of several enzymatic activities. Most of these signaling cascades lead to the activation of transcription factors. Curcumin has been found to modulate the activity of several key transcription factors and, in turn, the cellular expression profiles. Curcumin has been shown to elicit vital cellular responses such as cell cycle arrest, apoptosis, and differentiation by activating a cascade of molecular events. In this chapter, we briefly review the effects of curcumin on transcription factors NF-KB, AP-1, Egr-1, STATs, PPAR-gamma, beta-catenin, nrf2, EpRE, p53, CBP, and androgen receptor (AR) and AR-related cofactors giving major emphasis to the molecular mechanisms of its action.

Effects of pre-radiation exposure to LLLT of normal and malignant cells.

PubMed

Barasch, Andrei; Raber-Durlacher, Judith; Epstein, Joel B; Carroll, James

2016-06-01

Low-level laser therapy (LLLT) efficacy for the prevention of cancer treatment-induced oral mucositis (OM) has been amply described. However, potential protection of malignant cells remains a legitimate concern for clinicians. We tested LLLT-induced protection from ionizing radiation killing in both malignant and normal cells. We treated six groups each of normal human lymphoblasts (TK6) and human leukemia cells (HL60) with He-Ne LLLT (632.8 nm, 35 mW, CW, 1 cm(2), 35 mW/cm(2) for 3-343 s, 0.1-12 J/cm(2)) prior to exposure to ionizing radiation (IR). Cells were then incubated and counted daily to determine their survival. Optimization of IR dose and incubation time was established prior to testing the effect of LLLT. Growth curves for both cell lines showed significant declines after exposure to 50-200 cGy IR when compared to controls. Pre-radiation exposure to LLLT (4.0 J/cm(2)) followed by 1-h incubation blocked this decline in TK6 but not in HL60 cells. The latter cells were sensitized to the killing effects of IR in a dose-dependent manner. This study shows that pre-IR LLLT treatment results in a differential response of normal vs. malignant cells, suggesting that LLLT does not confer protection and may even sensitize cancer cells to IR killing.

N-ras couples antigen receptor signaling to Eomesodermin and to functional CD8+ T cell memory but not to effector differentiation

PubMed Central

Iborra, Salvador; Ramos, Manuel; Arana, David M.; Lázaro, Silvia; Aguilar, Francisco; Santos, Eugenio; López, Daniel

2013-01-01

Signals from the TCR that specifically contribute to effector versus memory CD8+ T cell differentiation are poorly understood. Using mice and adoptively transferred T lymphocytes lacking the small GTPase N-ras, we found that N-ras–deficient CD8+ T cells differentiate efficiently into antiviral primary effectors but have a severe defect in generating protective memory cells. This defect was rescued, although only partly, by rapamycin-mediated inhibition of mammalian target of rapamycin (mTOR) in vivo. The memory defect correlated with a marked impairment in vitro and in vivo of the antigen-mediated early induction of T-box transcription factor Eomesodermin (Eomes), whereas T-bet was unaffected. Besides N-ras, early Eomes induction in vitro required phosphoinositide 3-kinase (PI3K)–AKT but not extracellular signal-regulated kinase (ERK) activation, and it was largely insensitive to rapamycin. Consistent with N-ras coupling Eomes to T cell memory, retrovirally enforced expression of Eomes in N-ras–deficient CD8+ T cells effectively rescued their memory differentiation. Thus, our study identifies a critical role for N-ras as a TCR-proximal regulator of Eomes for early determination of the CD8+ T cell memory fate. PMID:23776078

Low osmolality and shear stress during liposuction impair cell viability in autologous fat grafting.

PubMed

Ismail, T; Bürgin, J; Todorov, A; Osinga, R; Menzi, N; Largo, R D; Haug, M; Martin, I; Scherberich, A; Schaefer, D J

2017-05-01

Liposuction and subsequent autologous fat grafting have become essential techniques for fat augmentation in plastic surgery. However, standard harvesting techniques that ensure the survival of adipocytes and stromal vascular fraction (SVF) cells and thus preserve the transplanted fat volume are lacking. In particular, the effect of different parameters of the tumescent solution has not been studied in this context. We hypothesized that the osmolality of the tumescent solution could have a significant effect on the survival of adipocytes and SVF cells. We developed two distinct in vitro models based on freshly harvested excision fat from patients undergoing surgical treatment. First, we investigated the effect of osmolality by incubating excision fat in different tumescent solutions and analyzed the total cell survival and the differentiation potential of SVF cells. Vital whole-mount staining, isolation yield of SVF cells, clonogenicity, and osteogenic and adipogenic differentiation capacities were analyzed. Second, we addressed the additional effect of mechanical stress by simulating a liposuction on pieces of excision fat after incubation with the tumescent solutions. Osmolality of the tumescent solution by itself did not have a significant effect on adipocyte and SVF viability or SVF differentiation. However, when osmolality was combined with liposuction, a significant trend toward lower viability and more lipid droplets with lower osmolality was observed. Especially, SVF viability was significantly lower after liposuction with a hypotonic (150 mOsm/kg) solution. This study demonstrates the considerable effect of osmolality during liposuction and may lead to the development of "cell-protective" tumescent solutions. Copyright © 2017 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

Beyond drinking: differential effects of demographic and socioeconomic factors on alcohol-related adverse consequences across European countries.

PubMed

Kuendig, Hervé; Plant, Moira L; Plant, Martin A; Kuntsche, Sandra; Miller, Patrick; Gmel, Gerhard; Ahlström, Salme; Bergmark, Karin Helmersson; Olafsdóttir, Hildigunnur; Elekes, Zsuzsanna; Csemy, Ladislav; Knibbe, Ronald

2008-01-01

Evidence underlines the importance of drinking patterns and individual characteristics in experiencing adverse alcohol-related consequences; however, little research has been conducted to explore who does and who does not experience consequences with similar drinking patterns. Using data from seven European countries, this study assesses the association between demographic and socioeconomic characteristics and six adverse consequences. Conditional logistic regression models were estimated, cases (experiencing a consequence) being matched to controls (not experiencing the consequence) by drinking patterns. In general, protective effects with increasing age and being in a partnership were consistent. Gender effects were mixed, but mainly protective for women. Educational achievement and economic status showed consistent effects across countries, but different directions of effect across consequences. Consequences mostly associated with individual drinking pattern (injury, blackout, and loss of control over drinking) exhibited similar patterns of associations, but varying ones arose for consequences additionally influenced by societal reaction to drinking (guilt, role failure, and pressure to cut down drinking). Differences in strengths and directions of effects across consequences pointed to the possibility that the reporting of adverse consequences is not only influenced by alcohol consumption, but also by attributional processes related to demographic and socioeconomic statuses. Copyright 2008 S. Karger AG, Basel.

[Cutaneous lupus erythematosus and skin manifestations in systemic lupus erythematosus].

PubMed

Sticherling, M

2013-06-01

Skin manifestations are frequently observed in lupus erythematosus (LE) and are manifold. Nonspecific and specific symptoms can be differentiated with the latter belonging to the dermatologically well-characterized clinical entities of acute cutaneous, subacute cutaneous, chronic cutaneous as well as intermittent cutaneous LE. These forms are differentially related to systemic LE. Patient history and clinical examinations, laboratory and immunoserological findings as well as organ imaging results determine the time point as well as the intensity of therapy. Apart from cessation of smoking and alcohol consumption as well as stringent UV protection, topical therapy with corticosteroids or calcineurin inhibitors may suffice with limited forms of the disease. In many cases, however, systemic treatment with antimalarial drugs as a basic treatment is mandatory. Several immunosuppressive agents can alternatively be used in conjunction with systemic corticosteroids. Early and effective therapy is important to prevent irreversible scarring of the skin and to avoid internal organ damage.

Modulation of stress-induced neurobehavioral changes and brain oxidative injury by nitric oxide (NO) mimetics in rats.

PubMed

Gulati, Kavita; Chakraborti, Ayanabha; Ray, Arunabha

2007-11-02

The present study evaluated the effects of NO mimetics on stress-induced neurobehavioral changes and the possible involvement of ROS-RNS interactions in rats. Restraint stress (RS) suppressed both percent open arm entries and time spent in the open arms in the elevated plus maze (EPM) test. These RS-induced changes in EPM activity were attenuated by the NO mimetics, l-arginine, isosorbide dinitrate and molsidomine, in a differential manner. RS-exposed rats showed (a) increased lipid peroxidation (MDA) and (b) lowered reduced glutathione (GSH) and NO metabolites (NOx), in brain homogenates of these animals. Pretreatment with the NO mimetics also differentially influenced RS-induced changes in brain oxidative stress markers. The results suggest that NO may protect against stress-induced anxiogenic behavior and oxidative injury in the brain and highlight the significance of ROS-RNS interactions.

Study of antioxidant properties of a water-soluble Vitamin E derivative-tocopherol monoglucoside (TMG) by differential pulse voltammetry.

PubMed

Korotkova, E I; Avramchik, O A; Kagiya, T V; Karbainov, Y A; Tcherdyntseva, N V

2004-06-17

Study of antioxidant properties of tocopherol monoglucoside (TMG), a water-soluble Vitamin E derivative, by differential pulse voltammetry has been carried out in this work. The pH influence on the antioxidant properties of TMG has been also investigated. It was observed that the antioxidant activity of TMG is greater at 6.90

Attachment representations and anxiety: differential relationships among mothers of sexually abused and comparison girls.

PubMed

Kim, Kihyun; Trickett, Penelope K; Putnam, Frank W

2011-02-01

The present study sought to document an example of how childhood sexual abuse and attachment representation interact while contributing to the trait anxiety of nonoffending mothers following the disclosure of their daughters' sexual abuse. The study sample consisted of 57 ethnically diverse mothers of sexually abused girls aged 6 to 16 and 47 mothers of comparison girls who were matched with the abused girls on age, socioeconomic status, and family constellation. Results indicate that the mothers' representations of past attachment relationships with their own fathers were differentially related to their current attachment styles, depending on their daughters' childhood sexual abuse status. The representation of past attachment relationships with peers had both main and protective effects on the mothers' trait anxiety symptoms. The relevance of attachment perspectives to adjustment among these mothers and intergenerational process in childhood sexual abuse are discussed, and implications for future research and clinical practices are identified.

The differential influence of absent and harsh fathers on juvenile delinquency.

PubMed

Simmons, Cortney; Steinberg, Laurence; Frick, Paul J; Cauffman, Elizabeth

2018-01-01

Researchers have identified father absence as a contributor to juvenile delinquency. Consequently, politicians and community leaders are making efforts to re-engage fathers. However, it is possible that the presence of fathers is not, in itself, a substantial protective factor and, in some cases, can even be more detrimental than father absence. Employing a diverse sample of male juvenile offenders in the U.S. (ages 13-17), the present study examined the differential effects of absent fathers and harsh fathers on delinquency. Results indicated that youth in the harsh-father group engaged in more offending behaviors and used more substances than youth in the absent-father group. This difference remained even after controlling for the mother-child relationship. Implications of these findings for future research and delinquency prevention programs are discussed. Copyright © 2017 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.

Geographic in wing morphology relate to colonization history in New World but not Old World populations of yellow dung flies.

PubMed

Schäfer, Martin A; Berger, David; Rohner, Patrick T; Kjaersgaard, Anders; Bauerfeind, Stephanie S; Guillaume, Frédéric; Fox, Charles W; Blanckenhorn, Wolf U

2018-06-17

Geographic clines offer insights about putative targets and agents of natural selection as well as tempo and mode of adaptation. However, demographic processes can lead to clines that are indistinguishable from adaptive divergence. Using the widespread yellow dung fly Scathophaga stercoraria (Diptera: Scathophagidae), we examine quantitative genetic differentiation (Q ST ) of wing shape across North America, Europe and Japan, and compare this differentiation with that of ten microsatellites (F ST ). Morphometric analyses of 28 populations reared at three temperatures revealed significant thermal plasticity, sexual dimorphism and geographic differentiation in wing shape. In North America morphological differentiation followed the decline in microsatellite variability along the presumed route of recent colonization from the southeast to the northwest. Across Europe, where S. stercoraria presumably existed for much longer time and where no molecular pattern of isolation by distance was evident, clinal variation was less pronounced despite significant morphological differentiation (Q ST >F ST ). Shape vector comparisons further indicate that thermal plasticity (hot-to-cold) does not mirror patterns of latitudinal divergence (south-to-north), as might have been expected under a scenario with temperature as the major agent of selection. Our findings illustrate the importance of detailed phylogeographic information when interpreting geographic clines of dispersal traits in an adaptive evolutionary framework. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

[Protective effect of arctigenin in GK rats combined with hypertension macroangiopathy].

PubMed

Feng, Qin; Sun, Bao-cun; Xia, Wen-kai

2015-03-01

To study the protective effect of Arctigenin in goto-kakizaki (GK) rats combined with hypertension macroangiopathy. Six-week-old GK rats were divided randomly according to blood glucose level into four groups: the model group and low, middle and high dose arctigenin groups (12.5, 25, 50 mg x kg(-1)), with Wistar rats as the normal group. All of GK rats were given high-glucose and high-fat diet. After 16 weeks, GK rats were orally administrated with 10 mg x kg(-1) x d(-1) N-Ω-nitro-L-arginine methyl ester for eight weeks. During the modeling, all of arctigenin groups were orally administrated with different dose of arctigenin twice a day; The model group and the normal group were given solvents. At the beginning, mid-term and end of the experiment, blood glucose was measured. At the end of the experiment, efforts were made to detect blood pressure, collect abdominal aortic blood after anesthesia, fix thoracic aorta after bloodletting to make paraffin sections, observe morphological characteristics and detect the expression of VEGF by immunohistochemistry. According to the results, the blood glucose rose in all GK rats, with no significant difference between the drug group and the model group. At the end of the experiment, the blood pressure significantly increased in GK rats, indicating that Arctigenin could notably reduce the blood pressure in GK rats in a dose-dependent manner. The blood routine test showed increases in both the total white blood cell count and differential blood count, MPV and PDW, abnormal blood platelet parameters and decrease in PLT in GK rats, suggesting that Arctigenin could remarkably reduce the total white blood cell count and differential blood count, MPV and PDW. The thoracic aortic morphological observation revealed obvious endangium lesions in GK rats, demonstrating that Arctigenin could ameliorate the lesion extent. VEGF immumohistochemical staining showed a higher VEGF expression in the model group but lower expression in Arctigenin groups. In conclusion, Arctigenin had a protective effect on aorta in GK rats. Its mechanism may be related to blood pressure lowering, anti-inflammation, improvement in blood platelet function and reduction of VEGF expression.

The predominant protective effect of tianeptine over other antidepressants in models of neuronal apoptosis: the effect blocked by inhibitors of MAPK/ERK1/2 and PI3-K/Akt pathways.

PubMed

Jantas, D; Krawczyk, S; Lason, W

2014-02-01

Tianeptine (Tian) possesses neuroprotective potential, however, little is known about the effect of this drug in models of neuronal apoptosis. In the present study, we aimed (1) to compare the neuroprotective capacities of some antidepressants (ADs) in the models of staurosporine (St)- and doxorubicin (Dox)-evoked cell death, activating the intracellular and the extracellular apoptotic pathway, respectively; (2) to identify the Tian-modulated steps underlying its neuroprotective action; (3) to test the effect of various ADs against Dox-evoked cell damage in glia cells. Primary neuronal and glia cell cultures and retinoic acid-differentiated human neuroblastoma SH-SY5Y (RA-SH-SY5Y) cells were co-treated with imipramine, fluoxetine, citalopram, reboxetine, mirtazapine or Tian and St or Dox. The data showed the predominant neuroprotective effect of Tian over other tested ADs against St- and Dox-induced cell damage in primary neurons and in RA-SH-SY5Y cells. This effect was shown to be caspase-3-independent but connected with attenuation of DNA fragmentation. Moreover, neuroprotection elicited by Tian was blocked by pharmacological inhibitors of MAPK/ERK1/2 and PI3-K/Akt signaling pathways as well by inhibitor of necroptosis, necrostatin-1. Interestingly, the protective effects of all tested ADs were demonstrated in primary glia cells against the Dox-evoked cell damage. The obtained data suggests the glial cells as a common target for protective action of various ADs whereas in relation to neuronal cells only Tian possesses such properties, at least against St- and Dox-induced cell damage. Moreover, this neuroprotective effect of Tian is caspase-3-independent and engages the regulation of survival pathways (MAPK/ERK1/2 and PI3-K/Akt).

Differential privacy based on importance weighting

PubMed Central

Ji, Zhanglong

2014-01-01

This paper analyzes a novel method for publishing data while still protecting privacy. The method is based on computing weights that make an existing dataset, for which there are no confidentiality issues, analogous to the dataset that must be kept private. The existing dataset may be genuine but public already, or it may be synthetic. The weights are importance sampling weights, but to protect privacy, they are regularized and have noise added. The weights allow statistical queries to be answered approximately while provably guaranteeing differential privacy. We derive an expression for the asymptotic variance of the approximate answers. Experiments show that the new mechanism performs well even when the privacy budget is small, and when the public and private datasets are drawn from different populations. PMID:24482559

Candida albicans morphology and dendritic cell subsets determine T helper cell differentiation

PubMed Central

Gerami-Nejad, Maryam; Kumamoto, Yosuke; Mohammed, Javed A.; Jarrett, Elizabeth; Drummond, Rebecca A.; Zurawski, Sandra M.; Zurawski, Gerard; Berman, Judith; Iwasaki, Akiko; Brown, Gordon D.; Kaplan, Daniel H.

2015-01-01

Summary Candida albicans is a dimorphic fungus responsible for chronic mucocutaneous and systemic infections. Mucocutaneous immunity to C. albicans requires T helper-17 (Th17) cell differentiation that is thought to depend on recognition of filamentous C. albicans. Systemic immunity is considered T cell independent. Using a murine skin infection model, we compared T helper cell responses to yeast and filamentous C. albicans, We found that only yeast induced Th17 cell responses through a mechanism that required Dectin-1 mediated expression of interleukin-6 (IL-6) by Langerhans cells. Filamentous forms induced Th1 without Th17 cell responses due to the absence of Dectin-1 ligation. Notably, Th17 cell responses provided protection against cutaneous infection while Th1 cell responses provided protection against systemic infection. Thus, C. albicans morphology drives distinct T helper cell responses that provide tissue specific protection. These findings provide insight into compartmentalization of Th responses, C. albicans pathogenesis and have critical implications for vaccine strategies. PMID:25680275

Effect of a 2.45-GHz radiofrequency electromagnetic field on neutrophil chemotaxis and phagocytosis in differentiated human HL-60 cells.

PubMed

Koyama, Shin; Narita, Eijiro; Suzuki, Yoshihisa; Taki, Masao; Shinohara, Naoki; Miyakoshi, Junji

2015-01-01

The potential public health risks of radiofrequency (RF) fields have been discussed at length, especially with the use of mobile phones spreading extensively throughout the world. In order to investigate the properties of RF fields, we examined the effect of 2.45-GHz RF fields at the specific absorption rate (SAR) of 2 and 10 W/kg for 4 and 24 h on neutrophil chemotaxis and phagocytosis in differentiated human HL-60 cells. Neutrophil chemotaxis was not affected by RF-field exposure, and subsequent phagocytosis was not affected either compared with that under sham exposure conditions. These studies demonstrated an initial immune response in the human body exposed to 2.45-GHz RF fields at the SAR of 2 W/kg, which is the maximum value recommended by the International Commission for Non-Ionizing Radiation Protection (ICNIRP) guidelines. The results of our experiments for RF-field exposure at an SAR under 10 W/kg showed very little or no effects on either chemotaxis or phagocytosis in neutrophil-like human HL-60 cells. © The Author 2014. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

Differential gene expression analysis of ‘Chili’ (Pyrus bretschneideri) fruit pericarp with two types of bagging treatments

PubMed Central

Wang, Yuling; Zhang, Xinfu; Wang, Ran; Bai, Yingxin; Liu, Chenglian; Yuan, Yongbing; Yang, Yingjie; Yang, Shaolan

2017-01-01

Preharvest bagging is a simple, grower-friendly and safe physical protection technique commonly applied to many fruits, and the application of different fruit bags can have various effects. To explore the molecular mechanisms underlying the fruit quality effects of different bagging treatments, digital gene expression (DGE) profiling of bagged and unbagged ‘Chili’ (Pyrus bretschneideri Rehd.) pear pericarp during development was performed. Relative to unbagged fruit, a total of 3022 and 769 differentially expressed genes (DEGs) were detected in the polyethylene (PE)-bagged and non-woven fabric-bagged fruit, respectively. DEGs annotated as photosynthesis-antenna proteins and photosynthesis metabolism pathway were upregulated in non-woven fabric-bagged fruit but downregulated in the PE-bagged fruit. Non-woven fabric bagging inhibited lignin synthesis in ‘Chili’ pear pericarp by downregulating DEGs involved in phenylpropanoid biosynthesis; consequently, the fruit lenticels in non-woven fabric-bagged fruit were smaller than those in the other treatments. The results indicate that the non-woven fabric bagging method has a positive effect on the appearance of ‘Chili’ pear fruit but neither of the two bagging treatments is conducive to the accumulation of soluble sugar. PMID:28280542

Effect of date seeds on oxidative damage and antioxidant status in vivo.

PubMed

Habib, Hosam M; Ibrahim, Wissam H

2011-07-01

Date seeds have been shown to contain high amounts of antioxidants. However, in vivo studies on date seeds are lacking. Therefore the purpose of this study was to determine the effect of date seeds on oxidative damage and antioxidant status in vivo. Male Wistar rats were fed a basal diet containing 0, 70 or 140 g kg(-1) date seeds for 30 days. All three diets were isonitrogenous and isocaloric. Indication of oxidative damage was assessed in the liver and serum, and antioxidant status was assessed in the liver. Serum biochemical parameters, including indicators of tissue cellular damage and complete blood count with differential, were also determined. The results showed that date seeds significantly (P<0.05) reduced liver and serum malondialdehyde (a lipid peroxidative damage product) and serum lactate dehydrogenase and creatine kinase. Liver antioxidants (vitamin E, vitamin C, glutathione, superoxide dismutase, glutathione peroxidase and catalase), complete blood count with differential and other serum biochemical parameters assessed were not significantly altered by date seeds. The results obtained suggest a protective effect of date seeds against in vivo oxidative damage, possibly through the action of their bioactive antioxidants. Copyright © 2011 Society of Chemical Industry.

Value-based differential pricing: efficient prices for drugs in a global context.

PubMed

Danzon, Patricia; Towse, Adrian; Mestre-Ferrandiz, Jorge

2015-03-01

This paper analyzes pharmaceutical pricing between and within countries to achieve second-best static and dynamic efficiency. We distinguish countries with and without universal insurance, because insurance undermines patients' price sensitivity, potentially leading to prices above second-best efficient levels. In countries with universal insurance, if each payer unilaterally sets an incremental cost-effectiveness ratio (ICER) threshold based on its citizens' willingness-to-pay for health; manufacturers price to that ICER threshold; and payers limit reimbursement to patients for whom a drug is cost-effective at that price and ICER, then the resulting price levels and use within each country and price differentials across countries are roughly consistent with second-best static and dynamic efficiency. These value-based prices are expected to differ cross-nationally with per capita income and be broadly consistent with Ramsey optimal prices. Countries without comprehensive insurance avoid its distorting effects on prices but also lack financial protection and affordability for the poor. Improving pricing efficiency in these self-pay countries includes improving regulation and consumer information about product quality and enabling firms to price discriminate within and between countries. © 2013 The Authors. Health Economics published by John Wiley & Sons Ltd.

Plasma sprayed manganese-cobalt spinel coatings: Process sensitivity on phase, electrical and protective performance

NASA Astrophysics Data System (ADS)

Han, Su Jung; Pala, Zdenek; Sampath, Sanjay

2016-02-01

Manganese cobalt spinel (Mn1.5Co1.5O4, MCO) coatings are prepared by the air plasma spray (APS) process to examine their efficacy in serving as protective coatings from Cr-poisoning of the cathode side in intermediate temperature-solid oxide fuel cells (IT-SOFCs). These complex oxides are susceptible to process induced stoichiometric and phase changes which affect their functional performance. To critically examine these effects, MCO coatings are produced with deliberate modifications to the spray process parameters to explore relationship among process conditions, microstructure and functional properties. The resultant interplay among particle thermal and kinetic energies are captured through process maps, which serve to characterize the parametric effects on properties. The results show significant changes to the chemistry and phase composition of the deposited material resulting from preferential evaporation of oxygen. Post deposition annealing recovers oxygen in the coatings and allows partial recovery of the spinel phase, which is confirmed through thermo-gravimetric analysis (TGA)/differential scanning calorimetry (DSC), X-ray Diffraction (XRD), and magnetic hysteresis measurements. In addition, coatings with high density after sintering show excellent electrical conductivity of 40 S cm-1 at 800 °C while simultaneously providing requisite protection characteristics against Cr-poisoning. This study provides a framework for optimal evaluation of MCO coatings in intermediate temperature SOFCs.

Controlling initial biodegradation of magnesium by a biocompatible strontium phosphate conversion coating.

PubMed

Chen, X B; Nisbet, D R; Li, R W; Smith, P N; Abbott, T B; Easton, M A; Zhang, D-H; Birbilis, N

2014-03-01

A simple strontium phosphate (SrP) conversion coating process was developed to protect magnesium (Mg) from the initial degradation post-implantation. The coating morphology, deposition rate and resultant phases are all dependent on the processing temperature, which determines the protective ability for Mg in minimum essential medium (MEM). Coatings produced at 80 °C are primarily made up of strontium apatite (SrAp) with a granular surface, a high degree of crystallinity and the highest protective ability, which arises from retarding anodic dissolution of Mg in MEM. Following 14 days' immersion in MEM, the SrAp coating maintained its integrity with only a small fraction of the surface corroded. The post-degradation effect of uncoated Mg and Mg coated at 40 and 80 °C on the proliferation and differentiation of human mesenchymal stem cells was also studied, revealing that the SrP coatings are biocompatible and permit proliferation to a level similar to that of pure Mg. The present study suggests that the SrP conversion coating is a promising option for controlling the early rapid degradation rate, and hence hydrogen gas evolution, of Mg implants without adverse effects on surrounding cells and tissues. Copyright © 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

State transitions and physicochemical aspects of cryoprotection and stabilization in freeze-drying of Lactobacillus rhamnosus GG (LGG).

PubMed

Pehkonen, K S; Roos, Y H; Miao, S; Ross, R P; Stanton, C

2008-06-01

The frozen and dehydrated state transitions of lactose and trehalose were determined and studied as factors affecting the stability of probiotic bacteria to understand physicochemical aspects of protection against freezing and dehydration of probiotic cultures. Lactobacillus rhamnosus GG was frozen (-22 or -43 degrees C), freeze-dried and stored under controlled water vapour pressure (0%, 11%, 23% and 33% relative vapour pressure) conditions. Lactose, trehalose and their mixture (1 : 1) were used as protective media. These systems were confirmed to exhibit relatively similar state transition and water plasticization behaviour in freeze-concentrated and dehydrated states as determined by differential scanning calorimetry. Ice formation and dehydrated materials were studied using cold-stage microscopy and scanning electron microscopy. Trehalose and lactose-trehalose gave the most effective protection of cell viability as observed from colony forming units after freezing, dehydration and storage. Enhanced cell viability was observed when the freezing temperature was -43 degrees C. State transitions of protective media affect ice formation and cell viability in freeze-drying and storage. Formation of a maximally freeze-concentrated matrix with entrapped microbial cells is essential in freezing prior to freeze-drying. Freeze-drying must retain a solid amorphous state of protectant matrices. Freeze-dried matrices contain cells entrapped in the protective matrices in the freezing process. The retention of viability during storage seems to be controlled by water plasticization of the protectant matrix and possibly interactions of water with the dehydrated cells. Highest cell viability was obtained in glassy protective media. This study shows that physicochemical properties of protective media affect the stability of dehydrated cultures. Trehalose and lactose may be used in combination, which is particularly important for the stabilization of probiotic bacteria in dairy systems.

Th1 differentiation drives the accumulation of intravascular, non-protective CD4 T cells during tuberculosis

PubMed Central

Sallin, Michelle A.; Sakai, Shunsuke; Kauffman, Keith D.; Young, Howard A.; Zhu, Jinfang; Barber, Daniel L.

2017-01-01

SUMMARY Recent data indicate that the differentiation state of Th1 cells determines their protective capacity against tuberculosis. Therefore, we examined the role of Th1 polarizing factors in the generation of protective and non-protective subsets of Mtb-specific Th1 cells. We find IL-12/23p40 promotes Th1 cell expansion and maturation beyond the CD73+CXCR3+T-betdim stage, and T-bet prevents deviation of Th1 cells into Th17 cells. Nevertheless, IL-12/23p40 and T-bet are also essential for the production of a prominent subset of intravascular CX3CR1+KLRG1+ Th1 cells that persists poorly and can neither migrate into the lung parenchyma nor control Mtb growth. Furthermore, T-bet suppresses development of CD69+CD103+ tissue resident phenotype effectors in lung. In contrast, Th1 cell-derived IFNγ inhibits the accumulation of intravascular CX3CR1+KLRG1+ Th1 cells. Thus, although IL-12 and T-bet are essential host survival factors, they simultaneously oppose lung CD4 T cell responses at several levels, demonstrating the dual nature of Th1 polarization in tuberculosis. PMID:28355562

Δ⁹-tetrahydrocannabinol (Δ⁹-THC) exerts a direct neuroprotective effect in a human cell culture model of Parkinson's disease.

PubMed

Carroll, C B; Zeissler, M-L; Hanemann, C O; Zajicek, J P

2012-10-01

Δ⁹-tetrahydrocannabinol (Δ⁹-THC) is neuroprotective in models of Parkinson's disease (PD). Although CB1 receptors are increased within the basal ganglia of PD patients and animal models, current evidence suggests a role for CB1 receptor-independent mechanisms. Here, we utilized a human neuronal cell culture PD model to further investigate the protective properties of Δ⁹-THC. Differentiated SH-SY5Y neuroblastoma cells were exposed to PD-relevant toxins: 1-methyl-4-phenylpyridinium (MPP+), lactacystin and paraquat. Changes in CB1 receptor level were determined by quantitative polymerase chain reaction and Western blotting. Cannabinoids and modulatory compounds were co-administered with toxins for 48 h and the effects on cell death, viability, apoptosis and oxidative stress assessed. We found CB1 receptor up-regulation in response to MPP+, lactacystin and paraquat and a protective effect of Δ⁹-THC against all three toxins. This neuroprotective effect was not reproduced by the CB1 receptor agonist WIN55,212-2 or blocked by the CB1 antagonist AM251. Furthermore, the antioxidants α-tocopherol and butylhydroxytoluene as well as the antioxidant cannabinoids, nabilone and cannabidiol were unable to elicit the same neuroprotection as Δ⁹-THC. However, the peroxisome proliferator-activated receptor-gamma (PPARγ) antagonist T0070907 dose-dependently blocked the neuroprotective, antioxidant and anti-apoptotic effects of Δ⁹-THC, while the PPARγ agonist pioglitazone resulted in protection from MPP+-induced neurotoxicity. Furthermore, Δ⁹-THC increased PPARγ expression in MPP+-treated SH-SY5Y cells, another indicator of PPARγ activation. We have demonstrated up-regulation of the CB1 receptor in direct response to neuronal injury in a human PD cell culture model, and a direct neuronal protective effect of Δ⁹-THC that may be mediated through PPARγ activation. © 2011 The Authors. Neuropathology and Applied Neurobiology © 2011 British Neuropathological Society.

Dietary long-chain omega-3 fatty acids of marine origin: a comparison of their protective effects on coronary heart disease and breast cancers.

PubMed

Judé, Sébastien; Roger, Sébastien; Martel, Eric; Besson, Pierre; Richard, Serge; Bougnoux, Philippe; Champeroux, Pascal; Le Guennec, Jean-Yves

2006-01-01

The relationship between high fish consumption and low mortality following coronary heart disease (CHD) and low incidence of breast cancer was first mentioned 3 decades ago. The fishes of interest are rich in omega-3 long-chain polyunsaturated fatty acids (omega-3 LC-PUFAs), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which could be the active nutrients. The current consensus about cardioprotection is that omega-3 LC-PUFAs would mainly exert antiarrhythmic effects. One of the proposed mechanisms is that circulating non-esterified LC-PUFAs partition into cardiac cells membrane phospholipids and exert a direct effect on ionic channels and/or modify intracellular calcium homeostasis. In another hypothesis, changes in the metabolism of phosphoinositides would be involved and lead to the differential activation of PKC isoforms. As compared to the mechanisms proposed for the cardioprotective effects of omega-3 LC-PUFAs, less is known about the molecular mechanisms involved in breast cancers prevention. Some proposed mechanisms such as the modulation of phosphoinositides metabolism and/or modulation of intracellular calcium homeostasis, are common to both pathologies. Other hypotheses involve the alteration of the cellular redox status induced by highly peroxidizable polyunsaturated fatty acids (FA), or the modulation of gene expression, both phenomena being tightly linked to apoptosis. In this review, we report and compare some proposed mechanisms for the involvement of omega-3 LC-PUFAs in both cardiac and breast cancer protection. Deliberately, we chose to discuss only the mechanisms, which are less described in other reviews such as ionic channels in cancer, calcium homeostasis, PKC activation or matrix metalloproteinases in both cancer and cardiac models. The leitmotiv along this review is that cardio- and cancero-protective effects use common pathways. Comparison of the cellular effects might therefore help to highlight the "protective" pathways.

Comparison of risk estimates using life-table methods.

PubMed

Sullivan, R E; Weng, P S

1987-08-01

Risk estimates promulgated by various radiation protection authorities in recent years have become increasingly more complex. Early "integral" estimates in the form of health effects per 0.01 person-Gy (per person-rad) or per 10(4) person-Gy (per 10(6) person-rad) have tended to be replaced by "differential" estimates which are age- and sex-dependent and specify both minimum induction (latency) and duration of risk expression (plateau) periods. These latter types of risk estimate must be used in conjunction with a life table in order to reduce them to integral form. In this paper, the life table has been used to effect a comparison of the organ and tissue risk estimates derived in several recent reports. In addition, a brief review of life-table methodology is presented and some features of the models used in deriving differential coefficients are discussed. While the great number of permutations possible with dose-response models, detailed risk estimates and proposed projection models precludes any unique result, the reduced integral coefficients are required to conform to the linear, absolute-risk model recommended for use with the integral risk estimates reviewed.

Oxidative and ER stress-dependent ASK1 activation in steatotic hepatocytes and Kupffer cells sensitizes mice fatty liver to ischemia/reperfusion injury.

PubMed

Imarisio, Chiara; Alchera, Elisa; Bangalore Revanna, Chandrashekar; Valente, Guido; Follenzi, Antonia; Trisolini, Elena; Boldorini, Renzo; Carini, Rita

2017-11-01

Steatosis intensifies hepatic ischemia/reperfusion (I/R) injury increasing hepatocyte damage and hepatic inflammation. This study evaluates if this process is associated to a differential response of steatotic hepatocytes (HP) and Kupffer cells (KC) to I/R injury and investigates the molecular mechanisms involved. Control or steatotic (treated with 50 μmol palmitic acid, PA) mouse HP or KC were exposed to hypoxia/reoxygenation (H/R). C57BL/6 mice fed 9 week with control or High Fat diet underwent to partial hepatic IR. PA increased H/R damage of HP and further activated the ASK1-JNK axis stimulated by ER stress during H/R. PA also induced the production of oxidant species (OS), and OS prevention nullified the capacity of PA to increase H/R damage and ASK1/JNK stimulation. ASK1 inhibition prevented JNK activation and entirely protected HP damage. In KC, PA directly activated ER stress, ASK1 and p38 MAPK and increased H/R damage. However, in contrast to HP, ASK1 inhibition further increased H/R damage by preventing p38 MAPK activation. In mice liver, steatosis induced the expression of activated ASK1 in only KC, whereas I/R exposure of steatotic liver activated ASK1 expression also in HP. "In vivo", ASK1 inhibition prevented ASK1, JNK and p38 MAPK activation and protected I/R damage and expression of inflammatory markers. Lipids-induced ASK1 stimulation differentially affects HP and KC by promoting cytotoxic or protective signals. ASK1 increases H/R damage of HP by stimulating JNK and protects KC activating p38MAPK. These data support the potentiality of the therapeutic employment of ASK1 inhibitors that can antagonize the damaging effects of I/R upon fatty liver surgery by the contextual reduction of HP death and of KC-mediated reactions. Copyright © 2017 Elsevier Inc. All rights reserved.

Gastrodin: an ancient Chinese herbal medicine as a source for anti-osteoporosis agents via reducing reactive oxygen species.

PubMed

Huang, Qiang; Shi, Jun; Gao, Bo; Zhang, Hong-Yang; Fan, Jing; Li, Xiao-Jie; Fan, Jin-Zhu; Han, Yue-Hu; Zhang, Jin-Kang; Yang, Liu; Luo, Zhuo-Jing; Liu, Jian

2015-04-01

Increased levels of reactive oxygen species (ROS) are a crucial pathogenic factor of osteoporosis. Gastrodin, isolated from the traditional Chinese herbal agent Gastrodia elata, is a potent antioxidant. We hypothesized that gastrodin demonstrates protective effects against osteoporosis by partially reducing reactive oxygen species in human bone marrow mesenchymal stem cells (hBMMSCs) and a macrophage cell line (RAW264.7 cells). We investigated gastrodin on osteogenic and adipogenic differentiation under oxidative stress in hBMMSCs. We also tested gastrodin on osteoclastic differentiation in RAW264.7 cells. Hydrogen peroxide (H2O2) was used to establish an oxidative cell injury model. Our results showed that gastrodin significantly promoted the proliferation of hBMMSCs, improved some osteogenic markers, reduced lipid generation and inhibited the mRNA expression of several adipogenic genes in hBMMSCs. Moreover, gastrodin reduced the number of osteoclasts, TRAP activity and the expression of osteoclast-specific genes in RAW264.7 cells. Gastrodin suppressed the production of reactive oxygen species in both hBMMSCs and RAW264.7 cells. In vivo, we established a murine ovariectomized (OVX) osteoporosis model. Our data revealed that gastrodin treatment reduced the activity of serum bone degradation markers, such as CTX-1 and TRAP. Importantly, it ameliorated the micro-architecture of trabecular bones. Gastrodin decreased osteoclast numbers in vivo by TRAP staining. To conclude, these results indicated that gastrodin shows protective effects against osteoporosis linking to a reduction in reactive oxygen species, suggesting that gastrodin may be useful in the prevention and treatment of osteoporosis. Copyright © 2014 Elsevier Inc. All rights reserved.

Two functional serotonin polymorphisms moderate the effect of food reinforcement on BMI

PubMed Central

Carr, Katelyn A.; Lin, Henry; Fletcher, Kelly D.; Sucheston, Lara; Singh, Prashant K.; Salis, Robbert; Erbe, Richard; Faith, Myles; Allison, David; Stice, Eric; Epstein, Leonard H.

2014-01-01

Food reinforcement, or the motivation to eat, has been associated with increased energy intake, greater body weight and prospective weight gain. Much of the previous research on the reinforcing value of food has focused on the role of dopamine, but it may be worthwhile to examine genetic polymorphisms in the serotonin and opioid systems as these neurotransmitters have been shown to be related to reinforcement processes and to influence energy intake. We examined the relationship among 44 candidate genetic polymorphisms in the dopamine, serotonin and opioid systems, and food reinforcement and body mass index (BMI) in a sample of 245 individuals. Polymorphisms in the Monoamine oxidase A (MAOA-LPR) and serotonin receptor 2A genes (rs6314) moderated the effect of food reinforcement on BMI, accounting for an additional 5-10% variance and revealed a potential role of the single nucleotide polymorphism, rs6314 in the serotonin 2A receptor as a differential susceptibility factor for obesity. Differential susceptibility describes a factor that can confer either risk or protection depending on a second variable, such that rs6314 is predictive of both high and low BMI based on the level of food reinforcement, while the diathesis stress or dual-gain model influences only one end of the outcome measure. The interaction with MAOA-LPR better fit the dual-risk or diathesis stress model, with the 3.5R/4R allele conferring protection for individuals low in food reinforcement. These results provide new insight into genes theoretically involved in obesity and support the hypothesis that genetics moderate the association between food reinforcement on BMI. PMID:23544600

Distinct endothelial phenotypes evoked by arterial waveforms derived from atherosclerosis-susceptible and -resistant regions of human vasculature

NASA Astrophysics Data System (ADS)

Dai, Guohao; Kaazempur-Mofrad, Mohammad R.; Natarajan, Sripriya; Zhang, Yuzhi; Vaughn, Saran; Blackman, Brett R.; Kamm, Roger D.; García-Cardeña, Guillermo; Gimbrone, Michael A., Jr.

2004-10-01

Atherosclerotic lesion localization to regions of disturbed flow within certain arterial geometries, in humans and experimental animals, suggests an important role for local hemodynamic forces in atherogenesis. To explore how endothelial cells (EC) acquire functional/dysfunctional phenotypes in response to vascular region-specific flow patterns, we have used an in vitro dynamic flow system to accurately reproduce arterial shear stress waveforms on cultured human EC and have examined the effects on EC gene expression by using a high-throughput transcriptional profiling approach. The flow patterns in the carotid artery bifurcations of several normal human subjects were characterized by using 3D flow analysis based on actual vascular geometries and blood flow profiles. Two prototypic arterial waveforms, "athero-prone" and "athero-protective," were defined as representative of the wall shear stresses in two distinct regions of the carotid artery (carotid sinus and distal internal carotid artery) that are typically "susceptible" or "resistant," respectively, to atherosclerotic lesion development. These two waveforms were applied to cultured EC, and cDNA microarrays were used to analyze the differential patterns of EC gene expression. In addition, the differential effects of athero-prone vs. athero-protective waveforms were further characterized on several parameters of EC structure and function, including actin cytoskeletal organization, expression and localization of junctional proteins, activation of the NF-B transcriptional pathway, and expression of proinflammatory cytokines and adhesion molecules. These global gene expression patterns and functional data reveal a distinct phenotypic modulation in response to the wall shear stresses present in atherosclerosis-susceptible vs. atherosclerosis-resistant human arterial geometries.

Genetic diversity, genetic structure and demographic history of Cycas simplicipinna (Cycadaceae) assessed by DNA sequences and SSR markers

PubMed Central

2014-01-01

Background Cycas simplicipinna (T. Smitinand) K. Hill. (Cycadaceae) is an endangered species in China. There were seven populations and 118 individuals that we could collect were genotyped in this study. Here, we assessed the genetic diversity, genetic structure and demographic history of this species. Results Analyses of data of DNA sequences (two maternally inherited intergenic spacers of chloroplast, cpDNA and one biparentally inherited internal transcribed spacer region ITS4-ITS5, nrDNA) and sixteen microsatellite loci (SSR) were conducted in the species. Of the 118 samples, 86 individuals from the seven populations were used for DNA sequencing and 115 individuals from six populations were used for the microsatellite study. We found high genetic diversity at the species level, low genetic diversity within each of the seven populations and high genetic differentiation among the populations. There was a clear genetic structure within populations of C. simplicipinna. A demographic history inferred from DNA sequencing data indicates that C. simplicipinna experienced a recent population contraction without retreating to a common refugium during the last glacial period. The results derived from SSR data also showed that C. simplicipinna underwent past effective population contraction, likely during the Pleistocene. Conclusions Some genetic features of C. simplicipinna such as having high genetic differentiation among the populations, a clear genetic structure and a recent population contraction could provide guidelines for protecting this endangered species from extinction. Furthermore, the genetic features with population dynamics of the species in our study would help provide insights and guidelines for protecting other endangered species effectively. PMID:25016306

Beetroot (Beta vulgaris) rescues mice from γ-ray irradiation by accelerating hematopoiesis and curtailing immunosuppression.

PubMed

Cho, Jinhee; Bing, So Jin; Kim, Areum; Lee, Nam Ho; Byeon, Sang-Hee; Kim, Gi-Ok; Jee, Youngheun

2017-12-01

Beetroot [Beta vulgaris Linné (Chenopodiaceae)], a vegetable usually consumed as a food or a medicinal plant in Europe, has been reported to have antioxidant and anti-inflammatory properties. Since the lymphohematopoietic system is the most sensitive tissue to ionizing radiation, protecting it from radiation damage is one of the best ways to decrease detrimental effects from radiation exposure. In this study, we evaluated the radio-protective effects of beetroot in hematopoietic stem cells (HSCs) and progenitor cells. Beetroot extract was administered at a dose of 400 mg/mouse per os (p.o.) three times into C57BL/6 mice and, at day 10 after γ-ray irradiation, diverse molecular presentations were measured and compared against non-irradiated and irradiated mice with PBS treatments. Survival of beetroot-fed and unfed irradiated animal was also compared. Beetroot not only stimulated cell proliferation, but also minimized DNA damage of splenocytes. Beetroot also repopulated S-phase cells and increased Ki-67 or c-Kit positive cells in bone marrow. Moreover, beetroot-treated mice showed notable boosting of differentiation of HSCs into burst-forming units-erythroid along with increased production of IL-3. Also, beetroot-treated mice displayed enhancement in the level of hematocrit and hemoglobin as well as the number of red blood cell in peripheral blood. Beetroot diet improved survival rate of lethally exposed mice with a dose reduction factor (DRF) of 1.1. These results suggest that beetroot has the potency to preserve bone marrow integrity and stimulate the differentiation of HSCs against ionizing radiation.

The protective effect of ursodeoxycholic acid in an in vitro model of the human fetal heart occurs via targeting cardiac fibroblasts.

PubMed

Schultz, Francisca; Hasan, Alveera; Alvarez-Laviada, Anita; Miragoli, Michele; Bhogal, Navneet; Wells, Sarah; Poulet, Claire; Chambers, Jenny; Williamson, Catherine; Gorelik, Julia

2016-01-01

Bile acids are elevated in the blood of women with intrahepatic cholestasis of pregnancy (ICP) and this may lead to fetal arrhythmia, fetal hypoxia and potentially fetal death in utero. The bile acid taurocholic acid (TC) causes abnormal calcium dynamics and contraction in neonatal rat cardiomyocytes. Ursodeoxycholic acid (UDCA), a drug clinically used to treat ICP, prevents adverse effects of TC. During development, the fetus is in a state of relative hypoxia. Although this is essential for the development of the heart and vasculature, resident fibroblasts can transiently differentiate into myofibroblasts and form gap junctions with cardiomyocytes in vitro, resulting in cardiomyocyte depolarization. We expanded on previously published work using an in vitro hypoxia model to investigate the differentiation of human fetal fibroblasts into myofibroblasts. Recent evidence shows that potassium channels are involved in maintaining the membrane potential of ventricular fibroblasts and that ATP-dependent potassium (KATP) channel subunits are expressed in cultured fibroblasts. KATP channels are a valuable target as they are thought to have a cardioprotective role during ischaemic and hypoxic conditions. We investigated whether UDCA could modulate fibroblast membrane potential. We established the isolation and culture of human fetal cardiomyocytes and fibroblasts to investigate the effect of hypoxia, TC and UDCA on human fetal cardiac cells. UDCA hyperpolarized myofibroblasts and prevented TC-induced depolarisation, possibly through the activation of KATP channels that are expressed in cultured fibroblasts. Also, similar to the rat model, UDCA can counteract TC-induced calcium abnormalities in human fetal cultures of cardiomyocytes and myofibroblasts. Under normoxic conditions, we found a higher number of myofibroblasts in cultures derived from human fetal hearts compared to cells isolated from neonatal rat hearts, indicating a possible increased number of myofibroblasts in human fetal hearts. Hypoxia further increased the number of human fetal and rat neonatal myofibroblasts. However, chronically administered UDCA reduced the number of myofibroblasts and prevented hypoxia-induced depolarisation. In conclusion, our results show that the protective effect of UDCA involves both the reduction of fibroblast differentiation into myofibroblasts, and hyperpolarisation of myofibroblasts, most likely through the stimulation of potassium channels, i.e. KATP channels. This could be important in validating UDCA as an antifibrotic and antiarrhythmic drug for treatment of failing hearts and fetal arrhythmia. Copyright © 2016. Published by Elsevier Ltd.

Ethnic Identity and Major Depression in Asian American Subgroups Nationwide: Differential Findings in Relation to Subcultural Contexts.

PubMed

Ai, Amy L; Nicdao, Ethel G; Appel, Hoa B; Lee, Daniel Hyung Jik

2015-12-01

Asian Americans (AA) are the fastest growing minority population in the United States. Leading AA scholars have highlighted the unmet service needs and the necessity to investigate subgroup variations in the mental health of AAs. This study addressed a research gap of whether racial and ethnic identity (REI) in three AA subgroups (Chinese, Filipino, and Vietnamese) consistently protects against major depressive disorder (MDD), counteracting the deleterious role of discrimination. Using the National Latino and Asian American Study (NLAAS), we explored the varying and incremental predictive values of REI, above and beyond the effects of known demographic and acculturation predictors, alongside other potentially protective factors. In three sets of two-step logistic regressions, REI had an inverse relationship with MDD in the Filipino subgroup only but a positive association in the Chinese subgroup. The damaging role of negative REI moderated the effect of discrimination. The longest stay in the United States and discrimination predicted a higher likelihood of a MDD diagnosis in the Filipino subgroup. Social support contributed to the lower odds of MDD in Chinese and Vietnamese subgroups, had lower odds of having MDD, and religious attendance may act as a protective factor in the Vietnamese subgroup. Our findings do not reinforce uniform protection of REI but lend partial support for two underlying rationales. Based on cultural psychologists' framework, inconsistent findings are interpreted within the sociocultural contexts of the 3 subgroups. © 2015 Wiley Periodicals, Inc.

Exploring the Therapeutic Mechanism of Desmodium styracifolium on Oxalate Crystal-Induced Kidney Injuries Using Comprehensive Approaches Based on Proteomics and Network Pharmacology.

PubMed

Hou, Jiebin; Chen, Wei; Lu, Hongtao; Zhao, Hongxia; Gao, Songyan; Liu, Wenrui; Dong, Xin; Guo, Zhiyong

2018-01-01

Purpose: As a Chinese medicinal herb, Desmodium styracifolium (Osb.) Merr (DS) has been applied clinically to alleviate crystal-induced kidney injuries, but its effective components and their specific mechanisms still need further exploration. This research first combined the methods of network pharmacology and proteomics to explore the therapeutic protein targets of DS on oxalate crystal-induced kidney injuries to provide a reference for relevant clinical use. Methods: Oxalate-induced kidney injury mouse, rat, and HK-2 cell models were established. Proteins differentially expressed between the oxalate and control groups were respectively screened using iTRAQ combined with MALDI-TOF-MS. The common differential proteins of the three models were further analyzed by molecular docking with DS compounds to acquire differential targets. The inverse docking targets of DS were predicted through the platform of PharmMapper. The protein-protein interaction (PPI) relationship between the inverse docking targets and the differential proteins was established by STRING. Potential targets were further validated by western blot based on a mouse model with DS treatment. The effects of constituent compounds, including luteolin, apigenin, and genistein, were investigated based on an oxalate-stimulated HK-2 cell model. Results: Thirty-six common differentially expressed proteins were identified by proteomic analysis. According to previous research, the 3D structures of 15 major constituents of DS were acquired. Nineteen differential targets, including cathepsin D (CTSD), were found using molecular docking, and the component-differential target network was established. Inverse-docking targets including p38 MAPK and CDK-2 were found, and the network of component-reverse docking target was established. Through PPI analysis, 17 inverse-docking targets were linked to differential proteins. The combined network of component-inverse docking target-differential proteins was then constructed. The expressions of CTSD, p-p38 MAPK, and p-CDK-2 were shown to be increased in the oxalate group and decreased in kidney tissue by the DS treatment. Luteolin, apigenin, and genistein could protect oxalate-stimulated tubular cells as active components of DS. Conclusion: The potential targets including the CTSD, p38 MAPK, and CDK2 of DS in oxalate-induced kidney injuries and the active components (luteolin, apigenin, and genistein) of DS were successfully identified in this study by combining proteomics analysis, network pharmacology prediction, and experimental validation.

TSG-6 Regulates Bone Remodeling through Inhibition of Osteoblastogenesis and Osteoclast Activation*S⃞

PubMed Central

Mahoney, David J.; Mikecz, Katalin; Ali, Tariq; Mabilleau, Guillaume; Benayahu, Dafna; Plaas, Anna; Milner, Caroline M.; Day, Anthony J.; Sabokbar, Afsaneh

2008-01-01

TSG-6 is an inflammation-induced protein that is produced at pathological sites, including arthritic joints. In animal models of arthritis, TSG-6 protects against joint damage; this has been attributed to its inhibitory effects on neutrophil migration and plasmin activity. Here we investigated whether TSG-6 can directly influence bone erosion. Our data reveal that TSG-6 inhibits RANKL-induced osteoclast differentiation/activation from human and murine precursor cells, where elevated dentine erosion by osteoclasts derived from TSG-6-/- mice is consistent with the very severe arthritis seen in these animals. However, the long bones from unchallenged TSG-6-/- mice were found to have higher trabecular mass than controls, suggesting that in the absence of inflammation TSG-6 has a role in bone homeostasis; we have detected expression of the TSG-6 protein in the bone marrow of unchallenged wild type mice. Furthermore, we have observed that TSG-6 can inhibit bone morphogenetic protein-2 (BMP-2)-mediated osteoblast differentiation. Interaction analysis revealed that TSG-6 binds directly to RANKL and to BMP-2 (as well as other osteogenic BMPs but not BMP-3) via composite surfaces involving its Link and CUB modules. Consistent with this, the full-length protein is required for maximal inhibition of osteoblast differentiation and osteoclast activation, although the isolated Link module retains significant activity in the latter case. We hypothesize that TSG-6 has dual roles in bone remodeling; one protective, where it inhibits RANKL-induced bone erosion in inflammatory diseases such as arthritis, and the other homeostatic, where its interactions with BMP-2 and RANKL help to balance mineralization by osteoblasts and bone resorption by osteoclasts. PMID:18586671

Understanding Coral's Short-term Adaptive Ability to Changing Environment

NASA Astrophysics Data System (ADS)

Tisthammer, K.; Richmond, R. H.

2016-02-01

Corals in Maunalua Bay, Hawaii are under chronic pressures from sedimentation and terrestrial runoffs containing multiple pollutants as a result of large scale urbanization that has taken place in the last 100 years. However, some individual corals thrive despite the prolonged exposure to these environmental stressors, which suggests that these individuals may have adapted to withstand such stressors. A recent survey showed that the lobe coral Porites lobata from the `high-stress' nearshore site had an elevated level of stress ixnduced proteins, compared to those from the `low-stress,' less polluted offshore site. To understand the genetic basis for the observed differential stress responses between the nearshore and offshore P. lobata populations, an analysis of the lineage-scale population genetic structure, as well as a reciprocal transplant experiment were conducted. The result of the genetic analysis revealed a clear genetic differentiation between P. lobata from the nearshore site and the offshore site. Following the 30- day reciprocal transplant experiment, protein expression profiles and other stress-related physiological characteristics were compared between the two populations. The experimental results suggest that the nearshore genotype can cope better with sedimentation/pollutants than the offshore genotype. This indicates that the observed genetic differentiation is due to selection for tolerance to these environmental stressors. Understanding the little-known, linage-scale genetic variation in corals offers a critical insight into their short-term adaptive ability, which is indispensable for protecting corals from impending environmental and climate change. The results of this study also offer a valuable tool for resource managers to make effective decisions on coral reef conservation, such as designing marine protected areas that incorporate and maintain such genetic diversity, and establishing acceptable pollution run-off levels.

Interrogation of transcriptomic changes associated with drug-induced hepatic sinusoidal dilatation in colorectal cancer.

PubMed

Jarzabek, Monika A; Proctor, William R; Vogt, Jennifer; Desai, Rupal; Dicker, Patrick; Cain, Gary; Raja, Rajiv; Brodbeck, Jens; Stevens, Dale; van der Stok, Eric P; Martens, John W M; Verhoef, Cornelis; Hegde, Priti S; Byrne, Annette T; Tarrant, Jacqueline M

2018-01-01

Drug-related sinusoidal dilatation (SD) is a common form of hepatotoxicity associated with oxaliplatin-based chemotherapy used prior to resection of colorectal liver metastases (CRLM). Recently, hepatic SD has also been associated with anti-delta like 4 (DLL4) cancer therapies targeting the NOTCH pathway. To investigate the hypothesis that NOTCH signaling plays an important role in drug-induced SD, gene expression changes were examined in livers from anti-DLL4 and oxaliplatin-induced SD in non-human primate (NHP) and patients, respectively. Putative mechanistic biomarkers of bevacizumab (bev)-mediated protection against oxaliplatin-induced SD were also investigated. RNA was extracted from whole liver sections or centrilobular regions by laser-capture microdissection (LCM) obtained from NHP administered anti-DLL4 fragment antigen-binding (F(ab')2 or patients with CRLM receiving oxaliplatin-based chemotherapy with or without bev. mRNA expression was quantified using high-throughput real-time quantitative PCR. Significance analysis was used to identify genes with differential expression patterns (false discovery rate (FDR) < 0.05). Eleven (CCL2, CCND1, EFNB2, ERG, ICAM1, IL16, LFNG, NOTCH1, NOTCH4, PRDX1, and TGFB1) and six (CDH5, EFNB2, HES1, IL16, MIK67, HES1 and VWF) candidate genes were differentially expressed in the liver of anti-DLL4- and oxaliplatin-induced SD, respectively. Addition of bev to oxaliplatin-based chemotherapy resulted in differential changes in hepatic CDH5, HEY1, IL16, JAG1, MMP9, NOTCH4 and TIMP1 expression. This work implicates NOTCH and IL16 pathways in the pathogenesis of drug-induced SD and further explains the hepato-protective effect of bev in oxaliplatin-induced SD observed in CRLM patients.

Effects of β-adrenergic receptor drugs on embryonic ventricular cell proliferation and differentiation and their impact on donor cell transplantation.

PubMed

Feridooni, Tiam; Hotchkiss, Adam; Baguma-Nibasheka, Mark; Zhang, Feixiong; Allen, Brittney; Chinni, Sarita; Pasumarthi, Kishore B S

2017-05-01

β-Adrenergic receptors (β-ARs) and catecholamines are present in rodents as early as embryonic day (E)10.5. However, it is not known whether β-AR signaling plays any role in the proliferation and differentiation of ventricular cells in the embryonic heart. Here, we characterized expression profiles of β-AR subtypes and established dose-response curves for the nonselective β-AR agonist isoproterenol (ISO) in the developing mouse ventricular cells. Furthermore, we investigated the effects of ISO on cell cycle activity and differentiation of cultured E11.5 ventricular cells. ISO treatment significantly reduced tritiated thymidine incorporation and cell proliferation rates in both cardiac progenitor cell and cardiomyocyte populations. The ISO-mediated effects on DNA synthesis could be abolished by cotreatment of E11.5 cultures with either metoprolol (a β 1 -AR antagonist) or ICI-118,551 (a β 2 -AR antagonist). In contrast, ISO-mediated effects on cell proliferation could be abolished only by metoprolol. Furthermore, ISO treatment significantly increased the percentage of differentiated cardiomyocytes compared with that in control cultures. Additional experiments revealed that β-AR stimulation leads to downregulation of Erk and Akt phosphorylation followed by significant decreases in cyclin D1 and cyclin-dependent kinase 4 levels in E11.5 ventricular cells. Consistent with in vitro results, we found that chronic stimulation of recipient mice with ISO after intracardiac cell transplantation significantly decreased graft size, whereas metoprolol protected grafts from the inhibitory effects of systemic catecholamines. Collectively, these results underscore the effects of β-AR signaling in cardiac development as well as graft expansion after cell transplantation. NEW & NOTEWORTHY β-Adrenergic receptor (β-AR) stimulation can decrease the proliferation of embryonic ventricular cells in vitro and reduce the graft size after intracardiac cell transplantation. In contrast, β 1 -AR antagonists can abrogate the antiproliferative effects mediated by β-AR stimulation and increase graft size. These results highlight potential interactions between adrenergic drugs and cell transplantation. Copyright © 2017 the American Physiological Society.

Young adults: beloved by food and drink marketers and forgotten by public health?

PubMed

Freeman, Becky; Kelly, Bridget; Vandevijvere, Stefanie; Baur, Louise

2016-12-01

Young adults are a highly desirable target population for energy-dense, nutrient-poor (EDNP) food and beverage marketing. But little research, resources, advocacy and policy action have been directed at this age group, despite the fact that young adults are gaining weight faster than previous generations and other population groups. Factors such as identity development and shifting interpersonal influences differentiate young adulthood from other life stages and influence the adoption of both healthy and unhealthy eating behaviours. EDNP food and beverage marketing campaigns use techniques to normalize brands within young adult culture, in particular through online social media. Young adults must be a priority population in future obesity prevention efforts. Stronger policies to protect young adults from EDNP food and beverage marketing may also increase the effectiveness of policies that are meant to protect younger children. Restrictions on EDNP food and beverage marketing should be extended to include Internet-based advertising and also aim to protect vulnerable young adults. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Effect of salt intake on beat-to-beat blood pressure nonlinear dynamics and entropy in salt-sensitive versus salt-protected rats.

PubMed

Fares, Souha A; Habib, Joseph R; Engoren, Milo C; Badr, Kamal F; Habib, Robert H

2016-06-01

Blood pressure exhibits substantial short- and long-term variability (BPV). We assessed the hypothesis that the complexity of beat-to-beat BPV will be differentially altered in salt-sensitive hypertensive Dahl rats (SS) versus rats protected from salt-induced hypertension (SSBN13) maintained on high-salt versus low-salt diet. Beat-to-beat systolic and diastolic BP series from nine SS and six SSBN13 rats (http://www.physionet.org) were analyzed following 9 weeks on low salt and repeated after 2 weeks on high salt. BP complexity was quantified by detrended fluctuation analysis (DFA), short- and long-range scaling exponents (αS and αL), sample entropy (SampEn), and traditional standard deviation (SD) and coefficient of variation (CV(%)). Mean systolic and diastolic BP increased on high-salt diet (P < 0.01) particularly for SS rats. SD and CV(%) were similar across groups irrespective of diet. Salt-sensitive and -protected rats exhibited similar complexity indices on low-salt diet. On high salt, (1) SS rats showed increased scaling exponents or smoother, systolic (P = 0.007 [αL]) and diastolic (P = 0.008 [αL]) BP series; (2) salt-protected rats showed lower SampEn (less complex) systolic and diastolic BP (P = 0.046); and (3) compared to protected SSBN13 rats, SS showed higher αL for systolic (P = 0.01) and diastolic (P = 0.005) BP Hypertensive SS rats are more susceptible to high salt with a greater rise in mean BP and reduced complexity. Comparable mean pressures in sensitive and protective rats when on low-salt diet coupled with similar BPV dynamics suggest a protective role of low-salt intake in hypertensive rats. This effect likely reflects better coupling of biologic oscillators. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Household-Level Expenditure on Protective Measures Against Mosquitoes on the Island of La Réunion, France

PubMed Central

Thuilliez, Josselin; Bellia, Claire; Dehecq, Jean-Sébastien; Reilhes, Olivier

2014-01-01

Background For decades La Réunion has experienced a number of epidemics that have resulted in efforts to control the density of Aedes species on this Island. This study was conducted to assess household-level expenditure on protective measures against mosquito nuisance on the Island of La Réunion in 2012. Methodology/Principal Findings Data was collected during a cross-sectional survey of 1024 households and used to determine the relationship between the use of chemically-based protective measures and subjective and objective indicators of the density of Aedes albopictus. The average household expenditure in July 2012 was USD 9.86 and the total household-level expenditure over a one-year period was extrapolated to USD 28.05million (range: USD 25.58 million to USD 30.76 million). Much of this money was spent on measures thought to be relatively ineffective against Aedes mosquitoes. Expenditure on protective measures was not influenced by the level of knowledge on mosquitoes or by the visual nuisance they generated at home, but rather by the perception of risk related to a future epidemic of chikungunya and socioeconomic factors. Most importantly, household spending on protective measures was found to be influenced by a measure of zone-level mosquito density (the Breteau index), but not by objective indicators of the presence of mosquitoes within or around the house. Conclusions/Significance Household-level expenditure on chemically-based protective measures is high when compared to the investment made by public entities to achieve vector control, and it is differentially influenced by subjective and objective measures of mosquito density. The current situation could be improved, firstly by ensuring that the public is well-informed about mosquitoes and the effectiveness of various protective measures, and secondly by implementing interventions that could either complement current vector-control strategies and improve their effectiveness on a country-level, or that would steer the population toward the appropriate behaviours. PMID:24392170

Discovery of a Positive Allosteric Modulator of the Thyrotropin Receptor: Potentiation of Thyrotropin-Mediated Preosteoblast Differentiation In Vitro.

PubMed

Neumann, Susanne; Eliseeva, Elena; Boutin, Alisa; Barnaeva, Elena; Ferrer, Marc; Southall, Noel; Kim, David; Hu, Xin; Morgan, Sarah J; Marugan, Juan J; Gershengorn, Marvin C

2018-01-01

Recently, we showed that TSH-enhanced differentiation of a human preosteoblast-like cell model involved a β -arrestin 1 ( β -Arr 1)-mediated pathway. To study this pathway in more detail, we sought to discover a small molecule ligand that was functionally selective toward human TSH receptor (TSHR) activation of β -Arr 1. High-throughput screening using a cell line stably expressing mutated TSHRs and mutated β -Arr 1 (DiscoverX1 cells) led to the discovery of agonists that stimulated translocation of β -Arr 1 to the TSHR, but did not activate G s -mediated signaling pathways, i.e., cAMP production. D3- β Arr (NCGC00379308) was selected. In DiscoverX1 cells, D3- β Arr stimulated β -Arr 1 translocation with a 5.1-fold greater efficacy than TSH and therefore potentiated the effect of TSH in stimulating β -Arr 1 translocation. In human U2OS-TSHR cells expressing wild-type TSHRs, which is a model of human preosteoblast-like cells, TSH upregulated the osteoblast-specific genes osteopontin (OPN) and alkaline phosphatase (ALPL). D3- β Arr alone had only a weak effect to upregulate these bone markers, but D3- β Arr potentiated TSH-induced upregulation of ALPL and OPN mRNA levels 1.6-fold and 5.5-fold, respectively, at the maximum dose of ligands. Furthermore, the positive allosteric modulator effect of D3- β Arr resulted in an increase of TSH-induced secretion of OPN protein. In summary, we have discovered the first small molecule positive allosteric modulator of TSHR. As D3- β Arr potentiates the effect of TSH to enhance differentiation of a human preosteoblast in an in vitro model, it will allow a novel experimental approach for probing the role of TSH-induced β -Arr 1 signaling in osteoblast differentiation. U.S. Government work not protected by U.S. copyright.

Phylogeography and genetic effects of habitat fragmentation on endemic Urophysa (Ranunculaceae) in Yungui Plateau and adjacent regions

PubMed Central

Li, Min-Jie; Tan, Jin-Bo; Price, Megan; Xiao, Qun-Ying; Zhou, Song-Dong; Yu, Yan; He, Xing-Jin

2017-01-01

Urophysa is a Chinese endemic genus with only two species (U. rockii and U. henryi) distributed in Yungui Plateau (Guizhou Province) and adjacent regions (i.e., Provinces of Hunan, Hubei, Chongqing and Sichuan). The aim of this study was to determine the genetic diversity and population differentiation within Urophysa and investigate the effect of the Yungui Plateau uplift and climate oscillations on evolution of Urophysa. In this study, micro-morphological characteristics, nine microsatellite loci (SSR), two nuclear loci (ITS and ETS) and two chloroplast fragments (psbA-trnH and trnL-trnF) were used to analyze the phylogenetic relationships and assess genetic and phylogeographical structure of Urophysa. Isolation by distance (IBD) was performed to research the effects of geographical isolation. We detected high genetic diversity at the species level but low genetic diversity within populations. Striking genetic differentiation (AMOVA) among populations and a significant phylogeographical structure (NST > GST, p < 0.01) were detected among U. henryi populations, along with significant effects of isolation by distance (IBD). Molecular clock estimation using calibration strategy and cpDNA substitution rate indicated that the divergence of U. henryi occurred during late Miocene to early Quaternary, when the orogeny of Yungui Plateau was violent. U. rockii originated at the early Quaternary and further differentiated at early Pleistocene. Our results suggested that habitat fragmentation played an important role in the genetic diversity and population differentiation of U. rockii and U. henryi. Heterogenous geomorphological configuration and complicated environment resulted from rapid uplift of the Yungui Plateau were inferred as important incentives for the modern phylogeograhpical pattern and species divergence of Urophysa. The geographical isolation, limited gene flow, specialized morphologies and the Pleistocene climatic oscillation greatly contributed to the allopatric divergence of U. rockii. Significant genetic drift and inbreeding were detected in these two species, in situ measures should be implemented to protect them. PMID:29053749

HIV-1 Gp120 clade B/C induces a GRP78 driven cytoprotective mechanism in astrocytoma

PubMed Central

López, Sheila N.; Rodríguez-Valentín, Madeline; Rivera, Mariela; Rodríguez, Maridaliz; Babu, Mohan; Cubano, Luis A.; Xiong, Huangui; Wang, Guangdi; Kucheryavykh, Lilia; Boukli, Nawal M.

2017-01-01

HIV-1 clades are known to be one of the key factors implicated in modulating HIV-associated neurocognitive disorders. HIV-1 B and C clades account for the majority of HIV-1 infections, clade B being the most neuropathogenic. The mechanisms behind HIV-mediated neuropathogenesis remain the subject of active research. We hypothesized that HIV-1 gp120 clade B and C proteins may exert differential proliferation, cell survival and NeuroAIDS effects in human astrocytoma cells via the Unfolded Protein Response, an endoplasmic reticulum- based cytoprotective mechanism. The differential effect of gp120 clade B and C was evaluated using for the first time a Tandem Mass Tag isobaric labeling quantitative proteomic approach. Flow cytometry analyses were performed for cell cycle and cell death identification. Among the proteins differentiated by HIV-1 gp120 proteins figure cytoskeleton, oxidative stress, UPR markers and numerous glycolytic metabolism enzymes. Our results demonstrate that HIV-1 gp120 B induced migration, proliferative and protective responses granted by the expression of GRP78, while HIV-1 gp120 C induced the expression of key inflammatory and pro-apoptotic markers. These novel findings put forward the first evidence that GRP78 is a key player in HIV-1 clade B and C neuropathogenic discrepancies and can be used as a novel target for immunotherapies. PMID:28978127

Effects of VEGF-ANG-1-PLA nano-sustained release microspheres on proliferation and differentiation of ADSCs.

PubMed

He, Yucang; Li, Zihao; Chen, Zhuojie; Yu, Xiaofang; Ji, Ziwan; Wang, Jingping; Qian, Yao; Li, Liqun

2018-05-10

The improvement of fat graft viability might depend on the presence of multipotent resident adipose derived stem cells (ADSCs) which is the important component of stromal vascular fraction (SVF). Vascular endothelial growth factor (VEGF) and angiogenin-1 (Ang-1) are responsible for neovascularization. However, their half-life is too short to produce a biological effect. We thus investigated whether VEGF-ANG-1-polylactic acid (PLA) microspheres could enhance the angiogenic properties of ADSCs. PLA microspheres containing VEGF and ANG-1 were prepared by in vitro ultrasonic emulsification and characterized according to their encapsulation efficiency (EE), drug-loading rate (DL), particle size and drug release. The systemic toxicity of empty loaded nanospheres (NPs) and the ability of these microspheres to promote the proliferation and differentiation of ADSCs were evaluated. The EE and DL were above 86% and 2.8%, respectively. The drug release was completed after 20 days. Systemic toxicity was verified in ADSCs that received the unloaded NPs. It was observed that ADSCs treated with VEGF-ANG-1-PLA microspheres had an increase in the proliferation and the number of CD31 positive cells. ADSCs proliferation and differentiation toward endothelial cells (ECs) could be enhanced by the addition of VEGF-ANG-1-PLA nano-sustained release microspheres. This article is protected by copyright. All rights reserved.

Analysis of the Anti-Cancer Effects of Cincau Extract (Premna oblongifolia Merr) and Other Types of Non-Digestible Fibre Using Faecal Fermentation Supernatants and Caco-2 Cells as a Model of the Human Colon.

PubMed

Nurdin, Samsu U; Le Leu, Richard K; Young, Graeme P; Stangoulis, James C R; Christophersen, Claus T; Abbott, Catherine A

2017-04-03

Green cincau ( Premna oblongifolia Merr) is an Indonesian food plant with a high dietary fibre content. Research has shown that dietary fibre mixtures may be more beneficial for colorectal cancer prevention than a single dietary fibre type. The aim of this study was to investigate the effects of green cincau extract on short chain fatty acid (SCFA) production in anaerobic batch cultures inoculated with human faecal slurries and to compare these to results obtained using different dietary fibre types (pectin, inulin, and cellulose), singly and in combination. Furthermore, fermentation supernatants (FSs) were evaluated in Caco-2 cells for their effect on cell viability, differentiation, and apoptosis. Cincau increased total SCFA concentration by increasing acetate and propionate, but not butyrate concentration. FSs from all dietary fibre sources, including cincau, reduced Caco-2 cell viability. However, the effects of all FSs on cell viability, cell differentiation, and apoptosis were not simply explainable by their butyrate content. In conclusion, products of fermentation of cincau extracts induced cell death, but further work is required to understand the mechanism of action. This study demonstrates for the first time that this Indonesian traditional source of dietary fibre may be protective against colorectal cancer.

Differential behaviour of epicardial adipose tissue-secretomes with high and low orosomucoid levels from patients with cardiovascular disease in H9C2 cells.

PubMed

Lage, Ricardo; Moscoso, Isabel; Fernández-Trasancos, Ángel; Cebro, María; Couselo, Marinela; Fandiño-Vaquero, Rubén; Bravo, Susana B; Sierra, Juan; González-Juanatey, José Ramón; Eiras, Sonia

2015-11-15

Epicardial adipose tissue releases orosomucoid (ORM), an acute phase protein with multiple modulatory and protective properties. We aimed to identify the effect of EAT-supernatants according to their ORM levels on H9C2 cells. H9C2 were cultured with EAT-secretomes or ORM protein itself on a Real-Time Cell Analyser. Secretome proteins identification was performed by LC-mass spectrometry according to their ORM levels. Two of them were validated by ELISA in EAT-supernatants from 42 patients. ORM effect on H9C2 and neonatal rat cardiomyocytes apoptosis under hypoxia with or without fatty acid treatment was determined by Annexin-V flow cytometry measurement. Caspase-3 expression levels were determined by western blot in H9C2. Our results showed a differential effect of EAT-secretomes according their ORM levels. Although additional secreted proteins can contribute to their beneficial effects, ORM reduced hypoxia-induced apoptosis through caspase-3 inhibition. Our data showed the cardioprotective role of ORM and suggest that its quantification on EAT secretomes might help us to find new secreted factors with a cardioprotective role. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Correlates of Social Support Among Latino Immigrants.

PubMed

Held, Mary L

2018-04-01

Latino immigrants encounter considerable stressors that pose risks to health and well-being during settlement in the USA. Social support serves as a protective factor that can help to buffer the negative effects of stress. Despite the importance of social support, we know little about how Latino immigrants differentially experience this protective factor. The current study analyzed data from 100 Latino immigrants residing in Tennessee. Hierarchical multiple regression analysis was employed to examine variation in self-reported social support by immigrant characteristics and immigration-related factors. Females, immigrants who are not married/cohabitating, and those who reported experiencing a greater number of discrete stressors in the USA each reported lower levels of social support. Implications for practice include an increased emphasis on assessing levels of social support and designing services to strengthen support for the most vulnerable immigrants. Future research should consider a longitudinal analysis and specific types of social support.

A step function model to evaluate the real monetary value of man-sievert with real GDP.

PubMed

Na, Seong H; Kim, Sun G

2009-01-01

For use in a cost-benefit analysis to establish optimum levels of radiation protection in Korea under the ALARA principle, we introduce a discrete step function model to evaluate man-sievert monetary value in the real economic value. The model formula, which is unique and country-specific, is composed of real GDP, the nominal risk coefficient for cancer and hereditary effects, the aversion factor against radiation exposure, and average life expectancy. Unlike previous researches on alpha-value assessment, we show different alpha values in the real term, differentiated with respect to the range of individual doses, which would be more realistic and informative for application to the radiation protection practices. GDP deflators of economy can reflect the society's situations. Finally, we suggest that the Korean model can be generalized simply to other countries without normalizing any country-specific factors.

Synthesis of 5'-O-DMT-2'-O-TBS Mononucleosides Using an Organic Catalyst.

PubMed

Lee, Sunggi; Blaisdell, Thomas P; Kasaplar, Pinar; Sun, Xixi; Tan, Kian L

2014-06-24

This unit describes a highly effective method to produce 5'-O-DMT-2'-O-TBS mononucleosides selectively using a small organic catalyst. This methodology avoids the tedious protection/deprotection strategy necessary to differentiate the 2'- and 3'-hydroxyl groups in a ribonucleoside. The catalyst was synthesized in two steps, starting from the condensation of valinol and cyclopentyl aldehyde, followed by anionic addition of N-methylimidazole. Ring closure of the amino alcohol with N,N-dimethylformamide dimethyl acetal in methanol furnishes the catalyst. All four 2'-O-TBS protected mono-nucleosides, U, A(Bz), G(Ib), and C(Ac), were produced in a single step using 10 to 20 mol% of the catalyst at room temperature with excellent yields and selectivity. Further transformation to phosphoramidite demonstrates the utility of this protocol in the preparation of monomers useful for automated synthesis of RNA. Copyright © 2014 John Wiley & Sons, Inc.

Incremental cost-effectiveness evaluation of vaccinating girls against cervical cancer pre- and post-sexual debut in Belgium.

PubMed

Demarteau, Nadia; Van Kriekinge, Georges; Simon, Philippe

2013-08-20

Vaccination against human papillomavirus (HPV) to prevent cervical cancer (CC) primarily targets young girls before sexual debut and is cost-effective. We assessed whether vaccination with the HPV-16/18 AS04-adjuvanted vaccine added to screening remains cost-effective in females after sexual debut compared to screening alone in Belgium. The role of protection against non-HPV-16/18 was also investigated. A published Markov cohort model was adapted to Belgium. The model replicated the natural history of HPV infection, the effects of screening, and vaccination. Vaccine efficacy (VE) included non-HPV-16/18 protection based on the PATRICIA clinical trial data. Pre- and post-HPV exposure VE were differentiated. Lifetime vaccine protection was assumed. Input data were obtained from literature review, national databases and a Delphi panel. Costing was from a healthcare payer perspective. Costs were discounted at 3% and effects at 1.5%. The incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained and the number of lesions prevented with vaccination from age 12 to 40 was evaluated. The specific effect of non-HPV-16/18 protection was investigated. Univariate sensitivity analysis was performed on key variables. The model estimated that vaccinating a cohort of 100,000 girls at age 12 would prevent 646 CC cases over a lifetime (102 non-HPV-16/18) with an ICER of €9171/QALY. Vaccinating at age 26 would prevent 340 CC cases (40 non-HPV-16/18) with an ICER of €17,348/QALY and vaccinating at age 40 would prevent 146 CC cases (17 non-HPV-16/18) with an ICER of €42,847/QALY. The ICER remained under the highly cost-effective threshold (1×GDP/capita) until age 33 years and under the cost-effective threshold (3×GDP/capita) beyond age 40. Extending HPV vaccination to females post-sexual debut could lead to a substantial reduction in CC-related burden and would be cost-effective in Belgium. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Gender difference in cytoprotection induced by estrogen on female and male bovine aortic endothelial cells.

PubMed

Si, M L; Al-Sharafi, B; Lai, C C; Khardori, R; Chang, C; Su, C Y

2001-08-01

Before menopause, women have a lower risk of cardiovascular diseases than men. Studies attribute this gender difference to estrogenic protection in the female cardiovascular system. We have demonstrated that 17beta-estradiol (E2) protects female bovine aortic endothelial cells against oxidative injury, probably through the induction of antioxidant enzyme activities. In this study, we examined whether E2 confers a differential protection on male and female cells. Bovine aortic endothelial cells from both genders were preconditioned for 24 h with E2 (1 nM to 10 microM), and their resistance to paraquat (1 mM, 3 h), a superoxide generator, was measured using an MTT assay. In contrast to the protection observed in female bovine aortic endothelial cells, there was no protective effect by E2 on male bovine aortic endothelial cells at physiologic concentrations. However, E2 at 1-10 microM attenuated paraquat's toxicity in both male and female cells, probably through its direct antioxidant activity. E2 at 1 nM increased in female, but not in male, cells the activities of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase, which was associated with decreased levels of reactive oxygen species during subsequent paraquat exposure. This suggests that antioxidant enzyme induction plays some role in E2-augmented oxidative resistance in female endothelial cells.

Blood-stage malaria of Plasmodium chabaudi induces differential Tlr expression in the liver of susceptible and vaccination-protected Balb/c mice.

PubMed

Al-Quraishy, Saleh; Dkhil, Mohamed A; Alomar, Suliman; Abdel-Baki, Abdel Azeem S; Delic, Denis; Wunderlich, Frank; Araúzo-Bravo, Marcos J

2016-05-01

Protective vaccination induces self-healing of otherwise lethal blood-stage infections of Plasmodium chabaudi malaria. Here, we investigate mRNA expression patterns of all 12 members of the Toll-like receptor (Tlr) gene family in the liver, a major effector organ against blood-stage malaria, during lethal and vaccination-induced self-healing infections of P. chabaudi in female Balb/c mice. Gene expression microarrays reveal that all 12 Tlr genes are constitutively expressed, though at varying levels, and specifically respond to infection. Protective vaccination does not affect constitutive expression of any of the 12 Tlr genes but leads to differential expression (p < 0.05) of seven Tlrs (1, 2, 4, 7, 8, 12, and 13) in response to malaria. Quantitative PCR substantiates differential expression at p < 0.01. There is an increased expression of Tlr2 by approximately five-fold on day 1 post-infection (p.i.) and Tlr1 by approximately threefold on day 4 p.i.. At peak parasitemia on day 8 p.i., none of the 12 Tlrs display any differential expression. After peak parasitemia, towards the end of the crisis phase on day 11 p.i., expression of Tlrs 1, 4, and 12 is increased by approximately four-, two-, and three-fold, respectively, and that of Tlr7 is decreased by approximately two-fold. Collectively, our data suggest that though all 12 members of the Tlr gene family are specifically responsive to malaria in the liver, not only Tlr2 at the early stage of infection but also the Tlrs 1, 4, 7, and 12 towards the end of crisis phase are critical for vaccination-induced resolution and survival of otherwise lethal blood-stage malaria.

Immunoglobulin with High-Titer In Vitro Cross-Neutralizing Hepatitis C Virus Antibodies Passively Protects Chimpanzees from Homologous, but Not Heterologous, Challenge

PubMed Central

Engle, Ronald E.; Faulk, Kristina; Wang, Richard Y.; Farci, Patrizia; Alter, Harvey J.; Purcell, Robert H.

2015-01-01

The importance of neutralizing antibodies (NAbs) in protection against hepatitis C virus (HCV) remains controversial. We infused a chimpanzee with H06 immunoglobulin from a genotype 1a HCV-infected patient and challenged with genotype strains efficiently neutralized by H06 in vitro. Genotype 1a NAbs afforded no protection against genotype 4a or 5a. Protection against homologous 1a lasted 18 weeks, but infection emerged when NAb titers waned. However, 6a infection was prevented. The differential in vivo neutralization patterns have implications for HCV vaccine development. PMID:26085160

Risk Assessment of Power System considering the CPS of Transformers

NASA Astrophysics Data System (ADS)

Zhou, Long; Peng, Zewu; Liu, Xindong; Li, Canbing; Chen, Can

2018-02-01

This paper constructs a risk assessment framework of power system for device-level information security, analyzes the typical protection configuration of power transformers, and takes transformer gas protection and differential protection as examples to put forward a method that analyzes the cyber security in electric power system, which targets transformer protection parameters. We estimate the risk of power system accounting for the cyber security of transformer through utilizing Monte Carlo method and two indexes, which are the loss of load probability and the expected demand not supplied. The proposed approach is tested with IEEE 9 bus system and IEEE 118 bus system.

Blink reflex recovery cycle to differentiate Progressive Supranuclear Palsy from Cortico-basal syndrome.

PubMed

Sciacca, Giorgia; Nicoletti, Alessandra; Mostile, Giovanni; Luca, Antonina; Raciti, Loredana; Dibilio, Valeria; Drago, Filippo; Salomone, Salvatore; Zappia, Mario

2018-05-13

Progressive Supranuclear Palsy (PSP) and Cortico-basal syndrome (CBS) may share similar clinical findings and peculiar tests to distinguish between the two disorders could be useful. We evaluated Blink Reflex (BR) and R2 Blink Reflex Recovery Cycle (R2BRRC), determining diagnostic sensitivity, specificity, positive and negative predictive value of R2BRRC in differentiating PSP from CBS patients. This was a prospective data collection study investigating BR and R2BRRC at interstimulus intervals (ISIs) of 100, 150, 200, 300, 400, 500, 750 ms in 12 PSP patients, 8 CBS patients, and 10 controls. Patients with PSP have earlier recruitment of R2BRRC as compared to patients with CBS (ISI 100: p=0.002; ISI 150: p<0.001; ISI 200: p<0.001; ISI 300: p=0.02) and controls (ISI 100: p<0.001; ISI 150: p<0.001; ISI 200: p<0.001; ISI 300: p=0.004). The presence of an early recovery of the R2 differentiated PSP from CBS with specificity and sensitivity of 87.5% and 91.7% respectively. R2BRRC curve might be considered a useful tool in differentiating PSP from CBS patients. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Targeting Vaccine-Induced Extrafollicular Pathway of B Cell Differentiation Improves Rabies Postexposure Prophylaxis

PubMed Central

Haley, Shannon L.; Tzvetkov, Evgeni P.; Meuwissen, Samantha; Plummer, Joseph R.

2017-01-01

ABSTRACT Vaccine-induced B cells differentiate along two pathways. The follicular pathway gives rise to germinal centers (GCs) that can take weeks to fully develop. The extrafollicular pathway gives rise to short-lived plasma cells (PCs) that can rapidly secrete protective antibodies within days of vaccination. Rabies virus (RABV) postexposure prophylaxis (PEP) requires rapid vaccine-induced humoral immunity for protection. Therefore, we hypothesized that targeting extrafollicular B cell responses for activation would improve the speed and magnitude of RABV PEP. To test this hypothesis, we constructed, recovered, and characterized a recombinant RABV-based vaccine expressing murine B cell activating factor (BAFF) (rRABV-mBAFF). BAFF is an ideal molecule to improve early pathways of B cell activation, as it links innate and adaptive immunity, promoting potent B cell responses. Indeed, rRABV-mBAFF induced a faster, higher antibody response in mice and enhanced survivorship in PEP settings compared to rRABV. Interestingly, rRABV-mBAFF and rRABV induced equivalent numbers of GC B cells, suggesting that rRABV-mBAFF augmented the extrafollicular B cell pathway. To confirm that rRABV-mBAFF modulated the extrafollicular pathway, we used a signaling lymphocytic activation molecule (SLAM)-associated protein (SAP)-deficient mouse model. In response to antigen, SAP-deficient mice form extrafollicular B cell responses but do not generate GCs. rRABV-mBAFF induced similar anti-RABV antibody responses in SAP-deficient and wild-type mice, demonstrating that BAFF modulated immunity through the extrafollicular and not the GC B cell pathway. Collectively, strategies that manipulate pathways of B cell activation may facilitate the development of a single-dose RABV vaccine that replaces current complicated and costly RABV PEP. IMPORTANCE Effective RABV PEP is currently resource- and cost-prohibitive in regions of the world where RABV is most prevalent. In order to diminish the requirements for rabies immunoglobulin (RIG) and multiple vaccinations for effective prevention of clinical rabies, a more rapidly protective vaccine is needed. This work presents a successful approach to rapidly generate antibody-secreting PCs in response to vaccination by targeting the extrafollicular B cell pathway. We demonstrate that the improved early antibody responses induced by rRABV-mBAFF confer improved protection against RABV in a PEP model. Significantly, activation of the early extrafollicular B cell pathway, such as that demonstrated here, could improve the efficacy of vaccines targeting other pathogens against which rapid protection would decrease morbidity and mortality. PMID:28148792

Targeting Vaccine-Induced Extrafollicular Pathway of B Cell Differentiation Improves Rabies Postexposure Prophylaxis.

PubMed

Haley, Shannon L; Tzvetkov, Evgeni P; Meuwissen, Samantha; Plummer, Joseph R; McGettigan, James P

2017-04-15

Vaccine-induced B cells differentiate along two pathways. The follicular pathway gives rise to germinal centers (GCs) that can take weeks to fully develop. The extrafollicular pathway gives rise to short-lived plasma cells (PCs) that can rapidly secrete protective antibodies within days of vaccination. Rabies virus (RABV) postexposure prophylaxis (PEP) requires rapid vaccine-induced humoral immunity for protection. Therefore, we hypothesized that targeting extrafollicular B cell responses for activation would improve the speed and magnitude of RABV PEP. To test this hypothesis, we constructed, recovered, and characterized a recombinant RABV-based vaccine expressing murine B cell activating factor (BAFF) (rRABV-mBAFF). BAFF is an ideal molecule to improve early pathways of B cell activation, as it links innate and adaptive immunity, promoting potent B cell responses. Indeed, rRABV-mBAFF induced a faster, higher antibody response in mice and enhanced survivorship in PEP settings compared to rRABV. Interestingly, rRABV-mBAFF and rRABV induced equivalent numbers of GC B cells, suggesting that rRABV-mBAFF augmented the extrafollicular B cell pathway. To confirm that rRABV-mBAFF modulated the extrafollicular pathway, we used a signaling lymphocytic activation molecule (SLAM)-associated protein (SAP)-deficient mouse model. In response to antigen, SAP-deficient mice form extrafollicular B cell responses but do not generate GCs. rRABV-mBAFF induced similar anti-RABV antibody responses in SAP-deficient and wild-type mice, demonstrating that BAFF modulated immunity through the extrafollicular and not the GC B cell pathway. Collectively, strategies that manipulate pathways of B cell activation may facilitate the development of a single-dose RABV vaccine that replaces current complicated and costly RABV PEP. IMPORTANCE Effective RABV PEP is currently resource- and cost-prohibitive in regions of the world where RABV is most prevalent. In order to diminish the requirements for rabies immunoglobulin (RIG) and multiple vaccinations for effective prevention of clinical rabies, a more rapidly protective vaccine is needed. This work presents a successful approach to rapidly generate antibody-secreting PCs in response to vaccination by targeting the extrafollicular B cell pathway. We demonstrate that the improved early antibody responses induced by rRABV-mBAFF confer improved protection against RABV in a PEP model. Significantly, activation of the early extrafollicular B cell pathway, such as that demonstrated here, could improve the efficacy of vaccines targeting other pathogens against which rapid protection would decrease morbidity and mortality. Copyright © 2017 American Society for Microbiology.

Safety Analysis LOX-30 Liquid Oxygen Generator.

DTIC Science & Technology

1978-05-22

Valve. Protects the LOX—30 plant against over—pressurization. Valve opens at approximately 100 psig. (3) Oil Pressure Switch . Protects compressor...29 psig. d. Cryogenerator. •0 (1) 011 Pressure Switch . Prevents cryogenerator damage due to inadequate lubrication. The switch initiates system shut...when helium pressure is less than 200 psig, will result in compressor shut—down within ten seconds. (2) Differential Pressure Switch (2 each). These

Effect of dihydrotestosterone on the expression of mucin 1 and the activity of Wnt signaling in mouse corneal epithelial cells.

PubMed

Qin, Li; Pei, Cheng; Kang, Qian-Yan; Liu, Zhao; Li, Li

2016-01-01

To explore the effects of the androgen dihydrotestosterone on the expression of mucin 1 (MUC1) and the activity of Wnt signaling in mouse corneal epithelial cells. Primary mouse corneal epithelial cells were isolated from the corneas of BALB/c mice. Quantitative real-time polymerase chain reaction, immunofluorescence and Western blot analysis were used to quantify the differential expression of selected genes. The androgen receptor was silenced by transfecting cells with androgen receptor shRNAs. TOP-Flash and FOP-flash reporter plasmids were used to measure β-catenin-driven transcription. Dihydrotestosterone treatment increased MUC1 expression and activated the Wnt signaling pathway and led to the translocation of β-catenin and upregulation of the Wnt downstream target gene TATA box binding protein and urokinase plasminogen activator. These effects were prevented by downregulating the androgen receptor. Androgens may protect against dry eye by regulating the expression of MUC1 which is stimulated by the activation of Wnt signaling via the androgen receptor. An understanding of the mechanisms associated with androgen-mediated protection against dry eye is an important step in developing new therapies for this disease.

Ovocalyxin-36 is an effector protein modulating the production of proinflammatory mediators.

PubMed

Kovacs-Nolan, Jennifer; Cordeiro, Cristianne; Young, Denise; Mine, Yoshinori; Hincke, Maxwell

2014-07-15

Sepsis is a systemic inflammatory response syndrome during infection. Therapeutic agents are essential to protect the host from sepsis. Ovocalyxin-36 (OCX-36) is a chicken eggshell membrane protein and shares protein sequence and gene organization homology with bactericidal permeability-increasing protein (BPI), lipopolysaccharide-binding protein (LBP) and palate, lung and nasal epithelium clone (PLUNC) proteins that play a major role in innate immune protection. We recently reported that OCX-36 binds to both lipopolysaccharide (LPS) and lipoteichoic acid (LTA) (Cordeiro et al., 2013, PLoS ONE 8, e84112), which is an important activity to neutralize endotoxins and non-endotoxin pyrogens during an inflammatory response. Here we investigated the immune modulating effects of OCX-36 and enzymatically digested OCX-36 (dOCX-36) in vitro and in a mouse model of endotoxemia. OCX-36 alone dose-dependently induced both TNF-α and nitric oxide (NO) production by RAW 264.7 macrophage cells, and this immunostimulatory effect was reduced by enzymatic digestion. In the presence of LPS, dOCX-36 was more effective than intact OCX-36 at reducing LPS-induced secretion of TNF-α from RAW 264.7 cells, but did not reduce NO production. In contrast, OCX-36 increased LPS-induced NO production, both in the presence and absence of FBS, PCR array analysis confirmed that OCX-36 and dOCX-36 differentially regulated genes involved in innate immunity, and dOCX-36 down-regulated the expression of genes involved in LPS signaling and inflammatory responses. In vivo, dOCX-36 was more effective at reducing LPS-induced inflammatory symptoms and inhibiting the local production of pro-inflammatory mediators in the small intestine. These results suggest that OCX-36 and OCX-36 derived peptides may differentially modulate innate immune responses, and support our hypothesis that OCX-36 derived peptides have potential therapeutic applications in sepsis. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

Effect of Condom Use on Per-act HSV-2 Transmission Risk in HIV-1, HSV-2-discordant Couples.

PubMed

Magaret, Amalia S; Mujugira, Andrew; Hughes, James P; Lingappa, Jairam; Bukusi, Elizabeth A; DeBruyn, Guy; Delany-Moretlwe, Sinead; Fife, Kenneth H; Gray, Glenda E; Kapiga, Saidi; Karita, Etienne; Mugo, Nelly R; Rees, Helen; Ronald, Allan; Vwalika, Bellington; Were, Edwin; Celum, Connie; Wald, Anna

2016-02-15

The efficacy of condoms for protection against transmission of herpes simplex virus type 2 (HSV-2) has been examined in a variety of populations with different effect measures. Often the efficacy has been assessed as change in hazard of transmission with consistent vs inconsistent use, independent of the number of acts. Condom efficacy has not previously measured on a per-act basis. We examined the per-act HSV-2 transmission rates with and without condom use among 911 African HSV-2 and human immunodeficiency virus type 1 (HIV-1) serodiscordant couples followed for an average of 18 months in an HIV prevention study. Infectivity models were used to associate the log10 probability of HSV-2 transmission over monthly risk periods with reported numbers of protected and unprotected sex acts. Condom efficacy was computed as the proportionate reduction in transmission risk for protected relative to unprotected sex acts. Transmission of HSV-2 occurred in 68 couples, including 17 with susceptible women and 51 with susceptible men. The highest rate of transmission was from men to women: 28.5 transmissions per 1000 unprotected sex acts. We found that condoms were differentially protective against HSV-2 transmission by sex; condom use reduced per-act risk of transmission from men to women by 96% (P < .001) and marginally from women to men by 65% (P = .060). Condoms are recommended as an effective preventive method for heterosexual transmission of HSV-2. © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Isothiocyanate from Moringa oleifera seeds mitigates hydrogen peroxide-induced cytotoxicity and preserved morphological features of human neuronal cells

PubMed Central

Shaari, Khozirah; Rosli, Rozita

2018-01-01

Reactive oxygen species are well known for induction of oxidative stress conditions through oxidation of vital biomarkers leading to cellular death via apoptosis and other process, thereby causing devastative effects on the host organs. This effect is believed to be linked with pathological alterations seen in several neurodegenerative disease conditions. Many phytochemical compounds proved to have robust antioxidant activities that deterred cells against cytotoxic stress environment, thus protect apoptotic cell death. In view of that we studied the potential of glucomoringin-isothiocyanate (GMG-ITC) or moringin to mitigate the process that lead to neurodegeneration in various ways. Neuroprotective effect of GMG-ITC was performed on retinoic acid (RA) induced differentiated neuroblastoma cells (SHSY5Y) via cell viability assay, flow cytometry analysis and fluorescence microscopy by means of acridine orange and propidium iodide double staining, to evaluate the anti-apoptotic activity and morphology conservation ability of the compound. Additionally, neurite surface integrity and ultrastructural analysis were carried out by means of scanning and transmission electron microscopy to assess the orientation of surface and internal features of the treated neuronal cells. GMG-ITC pre-treated neuron cells showed significant resistance to H2O2-induced apoptotic cell death, revealing high level of protection by the compound. Increase of intracellular oxidative stress induced by H2O2 was mitigated by GMG-ITC. Thus, pre-treatment with the compound conferred significant protection to cytoskeleton and cytoplasmic inclusion coupled with conservation of surface morphological features and general integrity of neuronal cells. Therefore, the collective findings in the presence study indicated the potentials of GMG-ITC to protect the integrity of neuron cells against induced oxidative-stress related cytotoxic processes, the hallmark of neurodegenerative diseases. PMID:29723199

Development of quercetin-phospholipid complex to improve the bioavailability and protection effects against carbon tetrachloride-induced hepatotoxicity in SD rats.

PubMed

Zhang, Kexia; Zhang, Meiyu; Liu, Ziying; Zhang, Yuanyuan; Gu, Liqiang; Hu, Gaosheng; Chen, Xiaohui; Jia, Jingming

2016-09-01

Quercetin (QT) is a natural flavonoid with various biological activities and pharmacological actions. However, the bioavailability of QT is relatively low due to its low solubility which severely limits its use. In this study, we intended to improve the bioavailability of QT by preparing quercetin-phospholipid complex (QT-PC) and investigate the protective effect of QT-PC against carbon tetrachloride (CCl4) induced acute liver damage in Sprague-Dawley (SD) rats. The physicochemical properties of QT-PC were characterized in terms of infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (XRPD) and water/n-octanol solubility. FTIR, DSC and XRPD data confirmed the formation of QT-PC. The water solubility of QT was improved significantly in the prepared complex, indicating its increased hydrophilicity. Oral bioavailability of QT and QT-PC was evaluated in SD rats, and the plasma QT was estimated by HPLC-MS. QT-PC exhibited higher Cmax (1.58±0.11 vs. 0.67±0.08μg/mL), increased AUC0-∞ (8.60±1.25 vs. 2.41±0.51mg/Lh) and t1/2z (7.76±1.09 vs. 4.81±0.87h) when compared to free QT. The greater absorption of QT-PC group suggested the improved bioavailability. Moreover, biochemical changes and histopathological observations revealed that QT-PC provided better protection to rat liver than free QT at the same dose. Thus, phospholipid complexation might be one of the suitable approaches to improve the oral bioavailability of QT and obtain better protective effects against CCl4 induced acute liver damage in SD rats than free QT at the same dose level. Copyright © 2016 Elsevier B.V. All rights reserved.

Chemical form of selenium differentially influences DNA repair pathways following exposure to lead nitrate.

PubMed

McKelvey, Shauna M; Horgan, Karina A; Murphy, Richard A

2015-01-01

Lead, an environmental toxin is known to induce a broad range of physiological and biochemical dysfunctions in humans through a number of mechanisms including the deactivation of antioxidants thus leading to generation of reactive oxygen species (ROS) and subsequent DNA damage. Selenium on the other hand has been proven to play an important role in the protection of cells from free radical damage and oxidative stress, though its effects are thought to be form and dose dependent. As the liver is the primary organ required for metabolite detoxification, HepG2 cells were chosen to assess the protective effects of various selenium compounds following exposure to the genotoxic agent lead nitrate. Initially DNA damage was quantified using a comet assay, gene expression patterns associated with DNA damage and signalling were also examined using PCR arrays and the biological pathways which were most significantly affected by selenium were identified. Interestingly, the organic type selenium compounds (selenium yeast and selenomethionine) conferred protection against lead induced DNA damage in HepG2 cells; this is evident by reduction in the quantity of DNA present in the comet tail of cells cultured in their presence with lead. This trend also followed through the gene expression changes noted in DNA damage pathways analysed. These results were in contrast with those of inorganic sodium selenite which promoted lead induced DNA damage evident in both the comet assay results and the gene expression analysis. Over all this study provided valuable insights into the effects which various selenium compounds had on the DNA damage and signalling pathway indicating the potential for using organic forms of selenium such as selenium enriched yeast to protect against DNA damaging agents. Copyright © 2014 Elsevier GmbH. All rights reserved.

Isothiocyanate from Moringa oleifera seeds mitigates hydrogen peroxide-induced cytotoxicity and preserved morphological features of human neuronal cells.

PubMed

Jaafaru, Mohammed Sani; Nordin, Norshariza; Shaari, Khozirah; Rosli, Rozita; Abdull Razis, Ahmad Faizal

2018-01-01

Reactive oxygen species are well known for induction of oxidative stress conditions through oxidation of vital biomarkers leading to cellular death via apoptosis and other process, thereby causing devastative effects on the host organs. This effect is believed to be linked with pathological alterations seen in several neurodegenerative disease conditions. Many phytochemical compounds proved to have robust antioxidant activities that deterred cells against cytotoxic stress environment, thus protect apoptotic cell death. In view of that we studied the potential of glucomoringin-isothiocyanate (GMG-ITC) or moringin to mitigate the process that lead to neurodegeneration in various ways. Neuroprotective effect of GMG-ITC was performed on retinoic acid (RA) induced differentiated neuroblastoma cells (SHSY5Y) via cell viability assay, flow cytometry analysis and fluorescence microscopy by means of acridine orange and propidium iodide double staining, to evaluate the anti-apoptotic activity and morphology conservation ability of the compound. Additionally, neurite surface integrity and ultrastructural analysis were carried out by means of scanning and transmission electron microscopy to assess the orientation of surface and internal features of the treated neuronal cells. GMG-ITC pre-treated neuron cells showed significant resistance to H2O2-induced apoptotic cell death, revealing high level of protection by the compound. Increase of intracellular oxidative stress induced by H2O2 was mitigated by GMG-ITC. Thus, pre-treatment with the compound conferred significant protection to cytoskeleton and cytoplasmic inclusion coupled with conservation of surface morphological features and general integrity of neuronal cells. Therefore, the collective findings in the presence study indicated the potentials of GMG-ITC to protect the integrity of neuron cells against induced oxidative-stress related cytotoxic processes, the hallmark of neurodegenerative diseases.

The Polyphenol Fisetin Protects Bone by Repressing NF-κB and MKP-1-Dependent Signaling Pathways in Osteoclasts

PubMed Central

Léotoing, Laurent; Wauquier, Fabien; Guicheux, Jérôme; Miot-Noirault, Elisabeth; Wittrant, Yohann; Coxam, Véronique

2013-01-01

Osteoporosis is a bone pathology leading to increase fractures risk and challenging quality of life. Since current treatments could exhibit deleterious side effects, the use of food compounds derived from plants represents a promising innovative alternative due to their potential therapeutic and preventive activities against human diseases. In this study, we investigated the ability of the polyphenol fisetin to counter osteoporosis and analyzed the cellular and molecular mechanisms involved. In vivo, fisetin consumption significantly prevented bone loss in estrogen deficiency and inflammation mice osteoporosis models. Indeed, bone mineral density, micro-architecture parameters and bone markers were positively modulated by fisetin. Consistent with in vivo results, we showed that fisetin represses RANKL-induced osteoclast differentiation and activity as demonstrated by an inhibition of multinucleated cells formation, TRAP activity and differentiation genes expression. The signaling pathways NF-κB, p38 MAPK, JNK and the key transcription factors c-Fos and NFATc1 expressions induced by RANKL, were negatively regulated by fisetin. We further showed that fisetin inhibits the constitutive proteasomal degradation of MKP-1, the phosphatase that deactivates p38 and JNK. Consistently, using shRNA stable cell lines, we demonstrated that impairment of MKP-1 decreases fisetin potency. Taken together, these results strongly support that fisetin should be further considered as a bone protective agent. PMID:23861901

An Antibody Blocking Activin Type II Receptors Induces Strong Skeletal Muscle Hypertrophy and Protects from Atrophy

PubMed Central

Minetti, Giulia C.; Sheppard, KellyAnn; Ibebunjo, Chikwendu; Feige, Jerome N.; Hartmann, Steffen; Brachat, Sophie; Rivet, Helene; Koelbing, Claudia; Morvan, Frederic; Hatakeyama, Shinji

2014-01-01

The myostatin/activin type II receptor (ActRII) pathway has been identified to be critical in regulating skeletal muscle size. Several other ligands, including GDF11 and the activins, signal through this pathway, suggesting that the ActRII receptors are major regulatory nodes in the regulation of muscle mass. We have developed a novel, human anti-ActRII antibody (bimagrumab, or BYM338) to prevent binding of ligands to the receptors and thus inhibit downstream signaling. BYM338 enhances differentiation of primary human skeletal myoblasts and counteracts the inhibition of differentiation induced by myostatin or activin A. BYM338 prevents myostatin- or activin A-induced atrophy through inhibition of Smad2/3 phosphorylation, thus sparing the myosin heavy chain from degradation. BYM338 dramatically increases skeletal muscle mass in mice, beyond sole inhibition of myostatin, detected by comparing the antibody with a myostatin inhibitor. A mouse version of the antibody induces enhanced muscle hypertrophy in myostatin mutant mice, further confirming a beneficial effect on muscle growth beyond myostatin inhibition alone through blockade of ActRII ligands. BYM338 protects muscles from glucocorticoid-induced atrophy and weakness via prevention of muscle and tetanic force losses. These data highlight the compelling therapeutic potential of BYM338 for the treatment of skeletal muscle atrophy and weakness in multiple settings. PMID:24298022

PLGA-based microcarriers induce mesenchymal stem cell chondrogenesis and stimulate cartilage repair in osteoarthritis.

PubMed

Morille, Marie; Toupet, Karine; Montero-Menei, Claudia N; Jorgensen, Christian; Noël, Danièle

2016-05-01

In the present study, we aimed at evaluating the ability of novel PLGA-P188-PLGA-based microspheres to induce the differentiation of mesenchymal stem/stromal cells (MSC) into chondrocytes. To this aim, we tested microspheres releasing TGFβ3 (PAM-T) in vitro and in situ, in a pathological osteoarthritic (OA) environment. We first evaluated the chondrogenic differentiation of human MSCs seeded onto PAM-T in vitro and confirmed the up-regulation of chondrogenic markers while the secretome of the cells was not changed by the 3D environment. We then injected human MSC seeded onto PAM-T in the knee joints of mice with collagenase-induced OA. After 6 weeks, histological analysis revealed that formation of a cartilage-like tissue occurred at the vicinity of PAM-T that was not observed when MSCs were seeded onto PAM. We also noticed that the endogenous articular cartilage was less degraded. The extent of cartilage protection was further analysed by confocal laser microscopy. When MSCs seeded onto PAM-T were injected early after OA induction, protection of cartilage against degradation was evidenced and this effect was associated to a higher survival of MSCs in presence of TGFβ3. This study points to the interest of using MSCs seeded onto PAM for cartilage repair and stimulation of endogenous cartilage regeneration. Copyright © 2016 Elsevier Ltd. All rights reserved.

Multiple Response System: Evaluation of Policy Change in North Carolina's Child Welfare System.

PubMed

Lawrence, C Nicole; Rosanbalm, Katie D; Dodge, Kenneth A

2011-11-01

Systemic challenges within child welfare have prompted many states to explore new strategies aimed at protecting children while meeting the needs of families, but doing so within the confines of shrinking budgets. Differential Response has emerged as a promising practice for low or moderate risk cases of child maltreatment. This mixed methods evaluation explored various aspects of North Carolina's differential response system, known as the Multiple Response System (MRS), including: child safety, timeliness of response and case decision, frontloading of services, case distribution, implementation of Child and Family Teams, collaboration with community-based service providers and Shared Parenting. Utilizing Child Protective Services (CPS) administrative data, researchers found that compared to matched control counties, MRS: had a positive impact on child safety evidenced by a decline in the rates of substantiations and re-assessments; temporarily disrupted timeliness of response in pilot counties but had no effect on time to case decision; and increased the number of upfront services provided to families during assessment. Qualitative data collected through focus groups with providers and phone interviews with families provided important information on key MRS strategies, highlighting aspects that families and social workers like as well as identifying areas for improvement. This information is useful for continuous quality improvement efforts, particularly related to the development of training and technical assistance programs at the state and local level.

Associations between Family Communication Patterns, Sibling Closeness, and Adoptive Status

PubMed Central

Samek, Diana R.; Rueter, Martha A.

2011-01-01

Previous research has demonstrated the protective effect of family and sibling closeness on child adjustment, but fewer studies have investigated how closeness is promoted within families. Guided by Family Communication Patterns Theory, we tested the association between family communication and sibling emotional and behavioral closeness, and whether adoptive status moderated this relationship. Participating families included 616 adoptive and non-adoptive families with two adolescent children. Hypotheses were tested using structural equation modeling. Sibling closeness was highest in families that emphasized both conversation and conformity and lowest in families that emphasized only conversation or neither conversation nor conformity. Emotional and behavioral closeness were differentially associated with adoption status, sibling age, and sibling gender. Few moderating effects of adoption status were found. Post hoc analyses showed moderating effects of sibling gender composition. PMID:21984844

Associations between Family Communication Patterns, Sibling Closeness, and Adoptive Status.

PubMed

Samek, Diana R; Rueter, Martha A

2011-10-01

Previous research has demonstrated the protective effect of family and sibling closeness on child adjustment, but fewer studies have investigated how closeness is promoted within families. Guided by Family Communication Patterns Theory, we tested the association between family communication and sibling emotional and behavioral closeness, and whether adoptive status moderated this relationship. Participating families included 616 adoptive and non-adoptive families with two adolescent children. Hypotheses were tested using structural equation modeling. Sibling closeness was highest in families that emphasized both conversation and conformity and lowest in families that emphasized only conversation or neither conversation nor conformity. Emotional and behavioral closeness were differentially associated with adoption status, sibling age, and sibling gender. Few moderating effects of adoption status were found. Post hoc analyses showed moderating effects of sibling gender composition.

Persistent Low-Level Replication of SIVΔnef Drives Maturation of Antibody and CD8 T Cell Responses to Induce Protective Immunity against Vaginal SIV Infection.

PubMed

Adnan, Sama; Reeves, R Keith; Gillis, Jacqueline; Wong, Fay E; Yu, Yi; Camp, Jeremy V; Li, Qingsheng; Connole, Michelle; Li, Yuan; Piatak, Michael; Lifson, Jeffrey D; Li, Wenjun; Keele, Brandon F; Kozlowski, Pamela A; Desrosiers, Ronald C; Haase, Ashley T; Johnson, R Paul

2016-12-01

Defining the correlates of immune protection conferred by SIVΔnef, the most effective vaccine against SIV challenge, could enable the design of a protective vaccine against HIV infection. Here we provide a comprehensive assessment of immune responses that protect against SIV infection through detailed analyses of cellular and humoral immune responses in the blood and tissues of rhesus macaques vaccinated with SIVΔnef and then vaginally challenged with wild-type SIV. Despite the presence of robust cellular immune responses, animals at 5 weeks after vaccination displayed only transient viral suppression of challenge virus, whereas all macaques challenged at weeks 20 and 40 post-SIVΔnef vaccination were protected, as defined by either apparent sterile protection or significant suppression of viremia in infected animals. Multiple parameters of CD8 T cell function temporally correlated with maturation of protection, including polyfunctionality, phenotypic differentiation, and redistribution to gut and lymphoid tissues. Importantly, we also demonstrate the induction of a tissue-resident memory population of SIV-specific CD8 T cells in the vaginal mucosa, which was dependent on ongoing low-level antigenic stimulation. Moreover, we show that vaginal and serum antibody titers inversely correlated with post-challenge peak viral load, and we correlate the accumulation and affinity maturation of the antibody response to the duration of the vaccination period as well as to the SIVΔnef antigenic load. In conclusion, maturation of SIVΔnef-induced CD8 T cell and antibody responses, both propelled by viral persistence in the gut mucosa and secondary lymphoid tissues, results in protective immune responses that are able to interrupt viral transmission at mucosal portals of entry as well as potential sites of viral dissemination.

Lipid-core nanocapsules as a nanomedicine for parenteral administration of tretinoin: development and in vitro antitumor activity on human myeloid leukaemia cells.

PubMed

Ourique, A F; Azoubel, S; Ferreira, C V; Silva, C B; Marchiori, M C L; Pohlmann, A R; Guterres, S S; Beck, R C R

2010-06-01

Tretinoin-loaded conventional nanocapsules have showed a significant protection of this drug against UVC radiation. However, this formulation presents a limited stability on storage. We hypothesized that the association of tretinoin to lipid-core nanocapsules could increase the physicochemical stability of such formulations, focusing on the development of a reliable nanomedicine for parenteral administration. However, this advantage should still be accompanied by the known photoprotective effect of conventional polymeric nanocapsules against the exposure of tretinoin to UV radiation. Results showed that tretinoin-loaded lipid-core nanocapsules improved the physicochemical stability of formulations under storage, without changing their ability to protect tretinoin either against UVA or UVC radiation. In addition, the effect of nanoencapsulation on the antiproliferative and differentiation properties of tretinoin was studied on human myeloid leukemia cells (HL60 cells) showing that tretinoin-loaded lipid-core nanocapsules presents a longer antitumor efficiency compared to the free tretinoin. These results allow us to propose the current formulation (tretinoin-loaded lipid-core nanocapsules) as a promising parenteral nanomedicine for the treatment of acute promyelocytic leukaemia.

Human Chorionic Gonadotropin and Breast Cancer

PubMed Central

Schüler-Toprak, Susanne; Treeck, Oliver; Ortmann, Olaf

2017-01-01

Breast cancer is well known as a malignancy being strongly influenced by female steroids. Pregnancy is a protective factor against breast cancer. Human chorionic gonadotropin (HCG) is a candidate hormone which could mediate this antitumoral effect of pregnancy. For this review article, all original research articles on the role of HCG in breast cancer were considered, which are listed in PubMed database and were written in English. The role of HCG in breast cancer seems to be a paradox. Placental heterodimeric HCG acts as a protective agent by imprinting a permanent genomic signature of the mammary gland determining a refractory condition to malignant transformation which is characterized by cellular differentiation, apoptosis and growth inhibition. On the other hand, ectopic expression of β-HCG in various cancer entities is associated with poor prognosis due to its tumor-promoting function. Placental HCG and ectopically expressed β-HCG exert opposite effects on breast tumorigenesis. Therefore, mimicking pregnancy by treatment with HCG is suggested as a strategy for breast cancer prevention, whereas targeting β-HCG expressing tumor cells seems to be an option for breast cancer therapy. PMID:28754015

Stressful life events and depressive symptoms in a post-war context: which informal support makes a difference?

PubMed

Jawad, May H; Sibai, Abla M; Chaaya, Monique

2009-03-01

Gerontological literature utilizes the life stress paradigm to understand the impact of stress on psychological well-being, as well as the protective role that social resources play in buffering those effects; however these relationships are not well understood within various historical and social contexts. Utilizing a sample of 490 community-residing older adults in post-civil war Lebanon, this study investigates the moderating role of various social support factors in the stress-depression relationship. Contrary to expectations, results suggest that older Lebanese are more susceptible to the effects of health-decline and serious accident events than other types of stressors such as losses in the family and financial problems. Furthermore, findings provide evidence for a differential protective role for the respondent's spouse and children for only certain stressful events. The discussion highlights the role of family as a stress buffer in a shifting physical, social and political environmental context. Results from this study add to the discourse by emphasizing the importance of understanding the saliency of the stressor as well as source of support provided.

Parent-Child Communication and Marijuana Initiation: Evidence Using Discrete-Time Survival Analysis

PubMed Central

Nonnemaker, James M.; Silber-Ashley, Olivia; Farrelly, Matthew C.; Dench, Daniel

2012-01-01

This study supplements existing literature on the relationship between parent-child communication and adolescent drug use by exploring whether parental and/or adolescent recall of specific drug-related conversations differentially impact youth's likelihood of initiating marijuana use. Using discrete-time survival analysis, we estimated the hazard of marijuana initiation using a logit model to obtain an estimate of the relative risk of initiation. Our results suggest that parent-child communication about drug use is either not protective (no effect) or—in the case of youth reports of communication—potentially harmful (leading to increased likelihood of marijuana initiation). PMID:22958867

Available data support protection of the Southwestern Willow Flycatcher under the Endangered Species Act

USGS Publications Warehouse

Theimer, Tad C.; Smith, Aaron D.; Mahoney, Sean M.; Ironside, Kirsten E.

2016-01-01

Zink (2015) argued there was no evidence for genetic, morphological, or ecological differentiation between the federally endangered Southwestern Willow Flycatcher (Empidonax traillii extimus) and other Willow Flycatcher subspecies. Using the same data, we show there is a step-cline in both the frequency of a mtDNA haplotype and in plumage variation roughly concordant with the currently recognized boundary between E. t. extimus and E. t adastus, the subspecies with which it shares the longest common boundary. The geographical pattern of plumage variation is also concordant with previous song analyses differentiating those 2 subspecies and identified birds in one low-latitude, high-elevation site in Arizona as the northern subspecies. We also demonstrate that the ecological niche modeling approach used by Zink yields the same result whether applied to the 2 flycatcher subspecies or to 2 unrelated species, E. t. extimus and Yellow Warbler (Setophaga petechia). As a result, any interpretation of those results as evidence for lack of ecological niche differentiation among Willow Flycatcher subspecies would also indicate no differentiation among recognized species and would therefore be an inappropriate standard for delineating subspecies. We agree that many analytical techniques now available to examine genetic, morphological, and ecological differentiation would improve our understanding of the distinctness (or lack thereof) of Willow Flycatcher subspecies, but we argue that currently available evidence supports protection of the Southwestern Willow Flycatcher under the Endangered Species Act.

Protective effects of L-selenomethionine on space radiation induced changes in gene expression.

PubMed

Stewart, J; Ko, Y-H; Kennedy, A R

2007-06-01

Ionizing radiation can produce adverse biological effects in astronauts during space travel. Of particular concern are the types of radiation from highly energetic, heavy, charged particles known as HZE particles. The aims of our studies are to characterize HZE particle radiation induced biological effects and evaluate the effects of L-selenomethionine (SeM) on these adverse biological effects. In this study, microarray technology was used to measure HZE radiation induced changes in gene expression, as well as to evaluate modulation of these changes by SeM. Human thyroid epithelial cells (HTori-3) were irradiated (1 GeV/n iron ions) in the presence or in the absence of 5 microM SeM. At 6 h post-irradiation, all cells were harvested for RNA isolation. Gene Chip U133Av2 from Affymetrix was used for the analysis of gene expression, and ANOVA and EASE were used for a determination of the genes and biological processes whose differential expression is statistically significant. Results of this microarray study indicate that exposure to small doses of radiation from HZE particles, 10 and 20 cGy from iron ions, induces statistically significant differential expression of 196 and 610 genes, respectively. In the presence of SeM, differential expression of 77 out of 196 genes (exposure to 10 cGy) and 336 out of 610 genes (exposure to 20 cGy) is abolished. In the presence or in the absence of SeM, radiation from HZE particles induces differential expression of genes whose products have roles in the induction of G1/S arrest during the mitotic cell cycle, as well as heat shock proteins. Some of the genes, whose expressions were affected by radiation from HZE particles and were unchanged in irradiated cells treated with SeM, have been shown to have altered expression levels in cancer cells. The conclusions of this report are that radiation from HZE particles can induce differential expression of many genes, some of which are known to play roles in the same processes that have been shown to be activated in cells exposed to radiation from photons (like cell cycle arrest in G1/S), and that supplementation with SeM abolishes HZE particle-induced differential expression of many genes. Understanding the roles that these genes play in the radiation-induced transformation of cells may help to decipher the origins of radiation-induced cancer.

Potential Role of Rebamipide in Osteoclast Differentiation and Mandibular Condylar Cartilage Homeostasis.

PubMed

Izawa, Takashi; Hutami, Islamy Rahma; Tanaka, Eiji

2018-04-20

Temporomandibular joint osteoarthritis (TMJ-OA) is a degenerative disease that involves changes in subchondral bone and progressive degradation of cartilage. Currently, rebamipide, a gastroprotective drug, is administered to protect gastric mucosa and accelerate ulcer healing. Recent studies have shown that rebamipide also attenuates cartilage degeneration by suppressing oxidative damage and inducing homeostasis of the extracellular matrix of articular chondrocytes. Regarding the latter, reduced expression of cathepsin K, NFATc1, c-Src, and integrin β3, and increased expression of nuclear factor-kappa B, have been found to be mediated by the transcription factor, receptor activator of nuclear factor kappa-B ligand (RANKL). Treatment with rebamipide was also found to activate, mitogen-activated protein kinases such as p38, ERK, and JNK to reduce osteoclast differentiation. Taken together, these results strongly indicate that rebamipide mediates inhibitory effects on cartilage degradation and osteoclastogenesis in TMJ-OA. Here, we highlight recent evidence regarding the potential for rebamipide to affect osteoclast differentiation and TMJ-OA pathogenesis. We also discuss the potential role of rebamipide to serve as a new strategy for the treatment of TMJ-OA. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Detection of Ozone and Nitric Oxide in Decomposition Products of Air-Insulated Switchgear Using Ultraviolet Differential Optical Absorption Spectroscopy (UV-DOAS).

PubMed

Li, Yalong; Zhang, Xiaoxing; Li, Xin; Cui, Zhaolun; Xiao, Hai

2018-01-01

Air-insulated switchgear cabinets play a role in the protection and control of the modern power grid, and partial discharge (PD) switchgear is a long-term process in the non-normal operation of one of the situations; thus, condition monitoring of the switchgear is important. The air-insulated switchgear during PD enables the decomposition of air components, namely, O 3 and NO. A set of experimental platforms was designed on the basis of the principle of ultraviolet differential optical absorption spectroscopy (UV-DOAS) to detect O 3 and NO concentrations in air-insulated switchgear. Differential absorption algorithm and wavelet transform were used to extract effective absorption spectra; a linear relationship between O 3 and NO concentrations and absorption spectrum data were established. O 3 detection linearity was up to 0.9992 and the detection limit was at 3.76 ppm. NO detection linearity was up to 0.9990 and the detection limit was at 0.64 ppm. Results indicate that detection platform is suitable for detecting trace O 3 and NO gases produced by PD of the air-insulated switchgear.

Clozapine protects PC-12 cells from death due to oxidative stress induced by hydrogen peroxide via a cell-type specific mechanism involving inhibition of extracellular signal-regulated kinase phosphorylation.

PubMed

Magliaro, Brian C; Saldanha, Colin J

2009-08-04

Recent evidence suggests that some atypical antipsychotic drugs may protect against oxidative stress and consequent neurodegeneration by mechanisms that remain unclear. Using the neuron-like rat pheochromocytoma (PC-12) cell line, Clozapine and N-desmethylclozapine were tested for their ability to protect against cell death due to oxidative stress induced by hydrogen peroxide (H(2)O(2)). These drugs demonstrated significant protection of PC-12 cells, as measured by both the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrasodium bromide (MTT) and Alamar Blue cell viability assays. However, neither viability assay detected a protective effect of Clozapine on human embryonic kidney (HEK293), rat primary cortical neurons, or human neuroblastoma (SH-SY5Y) exposed to H(2)O(2) treatment. The mechanism of protection involves a PC-12 cell-specific differential response to H(2)O(2) treatment vs. the other cell lines. Pre-treatment with 250 microM or 125 microM diethyldithiocarbamate (DETC), a superoxide dismutase (SOD) inhibitor, unexpectedly showed protection of the PC-12 cells from H(2)O(2) treatment. Western blots revealed that Clozapine, N-desmethylclozapine, and DETC reduce the phosphorylation of extracellular signal-regulated kinase (ERK) that is caused by H(2)O(2) exposure in PC-12 cells. In both HEK293 and SH-SY5Y cells, H(2)O(2) exposure did not increase ERK phosphorylation over control, demonstrating a different response to H(2)O(2) vs. PC-12 cells, and explaining why Clozapine could not protect these cells. Also, U0126, a specific MEK inhibitor, was able to protect PC-12 cells from H(2)O(2) exposure, showing that inhibiting ERK phosphorylation is sufficient to provide protection. Cumulatively, these results indicate that Clozapine, N-desmethylclozapine, DETC, and U0126 protect PC-12 cells by blocking the cell-type specific H(2)O(2) induced increase in ERK phosphorylation.

Fibroblast-induced switching to the mesenchymal-like phenotype and PI3K/mTOR signaling protects melanoma cells from BRAF inhibitors

PubMed Central

Seip, Kotryna; Nygaard, Vigdis; Haugen, Mads H.; Engesæter, Birgit Ø.; Mælandsmo, Gunhild M.; Prasmickaite, Lina

2016-01-01

The knowledge on how tumor-associated stroma influences efficacy of anti-cancer therapy just started to emerge. Here we show that lung fibroblasts reduce melanoma sensitivity to the BRAF inhibitor (BRAFi) vemurafenib only if the two cell types are in close proximity. In the presence of fibroblasts, the adjacent melanoma cells acquire de-differentiated mesenchymal-like phenotype. Upon treatment with BRAFi, such melanoma cells maintain high levels of phospho ribosomal protein S6 (pS6), i.e. active mTOR signaling, which is suppressed in the BRAFi sensitive cells without stromal contacts. Inhibitors of PI3K/mTOR in combination with BRAFi eradicate pS6high cell subpopulations and potentiate anti-cancer effects in melanoma protected by the fibroblasts. mTOR and BRAF co-inhibition also delayed the development of early-stage lung metastases in vivo. In conclusion, we demonstrate that upon influence from fibroblasts, melanoma cells undergo a phenotype switch to the mesenchymal state, which can support PI3K/mTOR signaling. The lost sensitivity to BRAFi in such cells can be overcome by co-targeting PI3K/mTOR. This knowledge could be explored for designing BRAFi combination therapies aiming to eliminate both stroma-protected and non-protected counterparts of metastases. PMID:26918352

Maternal prenatal psychological distress and preschool cognitive functioning: The protective role of positive parental engagement

PubMed Central

Schechter, Julia C.; Brennan, Patricia A.; Smith, Alicia K.; Stowe, Zachary N.; Newport, D. Jeffrey; Johnson, Katrina C.

2016-01-01

Considerable animal research and available human studies suggest that psychological distress experienced by mothers during gestation is associated with later neurodevelopmental deficits in offspring; however, little research has examined potential protective factors that might mitigate this risk. The current study examined the impact of maternal prenatal psychological distress during pregnancy on cognitive outcomes in preschoolers (ages 2.5-5 years) and positive parenting as a potential protective factor. Mother-child dyads (N=162, mean child age=44 months, 49% female) were recruited from a longitudinal cohort of women who had previously participated in a study of maternal mood disorders during pregnancy. Maternal prenatal distress was assessed with multiple measures collected throughout pregnancy. During a follow-up visit, mothers were interviewed about their psychological symptoms since the birth of the child, parenting behaviors were recorded during a parent-child interaction, and children's cognitive abilities were measured using the Differential Ability Scales, 2nd Edition. Maternal prenatal distress significantly predicted lower general cognitive abilities; however, this relationship was strongest for children whose mothers exhibited low levels of positive engagement and not significant when mothers exhibited high levels of positive engagement. Results suggest that positive parental engagement can protect against the detrimental effects of maternal prenatal distress on preschoolers cognitive abilities. PMID:27150387

Maternal Prenatal Psychological Distress and Preschool Cognitive Functioning: the Protective Role of Positive Parental Engagement.

PubMed

Schechter, Julia C; Brennan, Patricia A; Smith, Alicia K; Stowe, Zachary N; Newport, D Jeffrey; Johnson, Katrina C

2017-02-01

Considerable animal research and available human studies suggest that psychological distress experienced by mothers during gestation is associated with later neurodevelopmental deficits in offspring; however, little research has examined potential protective factors that might mitigate this risk. The current study examined the impact of maternal prenatal psychological distress during pregnancy on cognitive outcomes in preschoolers (ages 2.5-5 years) and positive parenting as a potential protective factor. Mother-child dyads (N = 162, mean child age = 44 months, 49 % female) were recruited from a longitudinal cohort of women who had previously participated in a study of maternal mood disorders during pregnancy. Maternal prenatal distress was assessed with multiple measures collected throughout pregnancy. During a follow-up visit, mothers were interviewed about their psychological symptoms since the birth of the child, parenting behaviors were recorded during a parent-child interaction, and children's cognitive abilities were measured using the Differential Ability Scales, 2nd Edition. Maternal prenatal distress significantly predicted lower general cognitive abilities; however, this relationship was strongest for children whose mothers exhibited low levels of positive engagement and not significant when mothers exhibited high levels of positive engagement. Results suggest that positive parental engagement can protect against the detrimental effects of maternal prenatal distress on preschoolers' cognitive abilities.

Normal and cancer mammary stem cells evade interferon-induced constraint through the miR-199a-LCOR Axis

PubMed Central

Celià-Terrassa, Toni; Liu, Daniel; Choudhury, Abrar; Hang, Xiang; Wei, Yong; Zamalloa, Jose; Alfaro-Aco, Raymundo; Chakrabarti, Rumela; Jiang, Yi-Zhou; Koh, Bong Ihn; Smith, Heath; DeCoste, Christina; Li, Jun-Jing; Shao, Zhi-Ming; Kang, Yibin

2017-01-01

Tumor-initiating cells (TICs), or cancer stem cells (CSC), possess stem cell-like properties observed in normal adult tissue stem cells. Normal and cancerous stem cells may therefore share regulatory mechanisms for maintaining self-renewing capacity and resisting differentiation elicited by cell-intrinsic or microenvironmental cues. Here, we show that miR-199a promotes stem cell properties in mammary stem cells (MaSCs) and breast CSCs by directly repressing nuclear receptor corepressor LCOR, which primes interferon (IFN) responses. Elevated miR-199a expression in stem cell-enriched populations protects normal and malignant stem-like cells from differentiation and senescence induced by IFNs that are produced by epithelial and immune cells in the mammary gland. Importantly, the miR-199a-LCOR-IFN axis is activated in poorly differentiated ER− breast tumors, functionally promotes tumor initiation and metastasis, and is associated with poor clinical outcome. Our study therefore reveals a common mechanism shared by normal and malignant stem cells to protect them from suppressive immune cytokine signaling. PMID:28530657

Preserved DNA Damage Checkpoint Pathway Protects against Complications in Long-Standing Type 1 Diabetes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bhatt, Shweta; Gupta, Manoj K.; Khamaisi, Mogher

The mechanisms underlying the development of complications in type 1 diabetes (T1D) are poorly understood. Disease modeling of induced pluripotent stem cells (iPSCs) from patients with longstanding T1D (disease duration ≥ 50 years) with severe (Medalist +C) or absent to mild complications (Medalist -C) revealed impaired growth, reprogramming, and differentiation in Medalist +C. Genomics and proteomics analyses suggested differential regulation of DNA damage checkpoint proteins favoring protection from cellular apoptosis in Medalist -C. In silico analyses showed altered expression patterns of DNA damage checkpoint factors among the Medalist groups to be targets of miR200, whose expression was significantly elevated inmore » Medalist +C serum. Notably, neurons differentiated from Medalist +C iPSCs exhibited enhanced susceptibility to genotoxic stress that worsened upon miR200 overexpression. Furthermore, knockdown of miR200 in Medalist +C fibroblasts and iPSCs rescued checkpoint protein expression and reduced DNA damage. Lastly, we propose miR200-regulated DNA damage checkpoint pathway as a potential therapeutic target for treating complications of diabetes.« less

Preserved DNA Damage Checkpoint Pathway Protects against Complications in Long-Standing Type 1 Diabetes

DOE PAGES

Bhatt, Shweta; Gupta, Manoj K.; Khamaisi, Mogher; ...

2015-08-04

The mechanisms underlying the development of complications in type 1 diabetes (T1D) are poorly understood. Disease modeling of induced pluripotent stem cells (iPSCs) from patients with longstanding T1D (disease duration ≥ 50 years) with severe (Medalist +C) or absent to mild complications (Medalist -C) revealed impaired growth, reprogramming, and differentiation in Medalist +C. Genomics and proteomics analyses suggested differential regulation of DNA damage checkpoint proteins favoring protection from cellular apoptosis in Medalist -C. In silico analyses showed altered expression patterns of DNA damage checkpoint factors among the Medalist groups to be targets of miR200, whose expression was significantly elevated inmore » Medalist +C serum. Notably, neurons differentiated from Medalist +C iPSCs exhibited enhanced susceptibility to genotoxic stress that worsened upon miR200 overexpression. Furthermore, knockdown of miR200 in Medalist +C fibroblasts and iPSCs rescued checkpoint protein expression and reduced DNA damage. Lastly, we propose miR200-regulated DNA damage checkpoint pathway as a potential therapeutic target for treating complications of diabetes.« less

Multiple mechanisms involved in diabetes protection by lipopolysaccharide in non-obese diabetic mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Jun; Department of Pharmacology, College of Medicine, Wuhan University of Science and Technology, Wuhan; Cao, Hui

Toll-like receptor 4 (TLR4) activation has been proposed to be important for islet cell inflammation and eventually β cell loss in the course of type 1 diabetes (T1D) development. However, according to the “hygiene hypothesis”, bacterial endotoxin lipopolysaccharide (LPS), an agonist on TLR4, inhibits T1D progression. Here we investigated possible mechanisms for the protective effect of LPS on T1D development in non-obese diabetic (NOD) mice. We found that LPS administration to NOD mice during the prediabetic state neither prevented nor reversed insulitis, but delayed the onset and decreased the incidence of diabetes, and that a multiple-injection protocol is more effectivemore » than a single LPS intervention. Further, LPS administration suppressed spleen T lymphocyte proliferation, increased the generation of CD4{sup +}CD25{sup +}Foxp3{sup +} regulatory T cells (Tregs), reduced the synthesis of strong Th1 proinflammatory cytokines, and downregulated TLR4 and its downstream MyD88-dependent signaling pathway. Most importantly, multiple injections of LPS induced a potential tolerogenic dendritic cell (DC) subset with low TLR4 expression without influencing the DC phenotype. Explanting DCs from repeated LPS-treated NOD mice into NOD/SCID diabetic mice conferred sustained protective effects against the progression of diabetes in the recipients. Overall, these results suggest that multiple mechanisms are involved in the protective effects of LPS against the development of diabetes in NOD diabetic mice. These include Treg induction, down-regulation of TLR4 and its downstream MyD88-dependent signaling pathway, and the emergence of a potential tolerogenic DC subset. - Highlights: • Administration of lipopolysaccharide (LPS) prevented type 1 diabetes in NOD mice. • Downregulating TLR4 level and MyD88-dependent pathway contributed to protection of LPS. • LPS administration also hampered DC maturation and promoted Treg differentiation.« less

17Beta-estradiol protects against oxidative stress-induced cell death through the glutathione/glutaredoxin-dependent redox regulation of Akt in myocardiac H9c2 cells.

PubMed

Urata, Yoshishige; Ihara, Yoshito; Murata, Hiroaki; Goto, Shinji; Koji, Takehiko; Yodoi, Junji; Inoue, Satoshi; Kondo, Takahito

2006-05-12

The GSH/glutaredoxin (GRX) system is involved in the redox regulation of certain enzyme activities, and this system protects cells from H2O2-induced apoptosis by regulating the redox state of Akt (Murata, H., Ihara, Y., Nakamura, H., Yodoi, J., Sumikawa, K., and Kondo, T. (2003) J. Biol. Chem. 278, 50226-50233). Estrogens, such as 17beta-estradiol (E2), play an important role in development, growth, and differentiation and appear to have protective effects on oxidative stress mediated by estrogen receptor alpha (ERalpha). However, the role of the ERbeta-mediated pathway in this cytoprotection and the involvement of E2 in the redox regulation are not well understood. In the present study, we demonstrated that E2 protected cardiac H9c2 cells, expressing ERbeta from H2O2-induced apoptosis concomitant with an increase in the activity of Akt. E2 induced the expression of glutaredoxin (GRX) as well as gamma-glutamylcysteine synthetase, a rate-limiting enzyme for the synthesis of GSH. Inhibitors for both gamma-glutamylcysteine synthetase and GRX and ICI182,780, a specific inhibitor of ERs, abolished the protective effect of E2 on cell survival as well as the activity of Akt, suggesting that ERbeta is involved in the cytoprotection and redox regulation by E2. Transcription of the GRX gene was enhanced by E2. The promoter activity of GRX was up-regulated by an ERbeta-dependent element. These results suggest that the GRX/GSH system is involved in the cytoprotective and genomic effects of E2 on the redox state of Akt, a pathway that is mediated, at least in part, by ERbeta. This mechanism may also play an antiapoptotic role in cancer cells during carcinogenesis or chemotherapy.

Nitric Oxide Modulates TGF-β–Directive Signals To Suppress Foxp3+ Regulatory T Cell Differentiation and Potentiate Th1 Development

PubMed Central

Lee, Seung-Woo; Choi, Heonsik; Eun, So-Young; Fukuyama, Satoshi; Croft, Michael

2011-01-01

TGF-β can induce Foxp3+ inducible regulatory T cells (Treg) and also synergize with IL-6 and IL-4 to induce Th17 and Th9 cells. We now report that NO modulates TGF-β activity away from Treg but toward the Th1 lineage. NO potentiated Th1 differentiation in the presence of TGF-β in both IL-12–independent and –dependent fashions by augmenting IFN-γ–activated STAT-1 and T-bet. Differentiation into Treg, Th1, and Th17 lineages could be modulated by NO competing with other cofactors, such as IL-6 and retinoic acid. NO antagonized IL-6 to block TGF-β–directed Th17 differentiation, and together with IL-6, NO suppressed Treg development induced by TGF-β and retinoic acid. Furthermore, we show that physiologically produced NO from TNF and inducible NO synthase-producing dendritic cells can contribute to Th1 development predominating over Treg development through a synergistic activity induced when these cells cocluster with conventional dendritic cells presenting Ag to naive Th cells. This illustrates that NO is another cofactor allowing TGF-β to participate in development of multiple Th lineages and suggests a new mechanism by which NO, which is associated with protection against intracellular pathogens, might maintain effective Th1 immunity. PMID:21555530

Etude de l'effet du gonflement par les solvants sur les proprietes du caoutchouc butyle

NASA Astrophysics Data System (ADS)

Nohile, Cedrick

Polymers and in particular elastomers are widely used for personal protective equipment against chemical and biological hazards. Among them, butyl rubber is one of the most effective elastomers against chemicals. However, if this rubber has a very good resistance to a wide range of them, it is sensitive to non polar solvents. These solvents will easily swell the material and may dramatically affect its properties. This situation may involve a large risk for. butyl rubber protective equipment users. It is thus essential to improve the understanding of the effect of solvents on the properties of butyl rubber. The research that was carried out had two objectives: to identify the parameters controlling the resistance of butyl rubber to solvents and to study the effect of swelling on the properties of butyl rubber. The results show that the resistance of butyl rubber to solvents appears to be controlled by three main parameters: the chemical class of the solvent, its saturation vapor pressure and its molar volume. In addition, swelling affects butyl rubber mechanical properties in a permanent way. The effects can be attributed to the extraction of plasticizers by the solvent and to the degradation of the physico-chemical structure of the polymer network. This chemical degradation was linked to a phenomenon of differential swelling which seems to be controlled by the solvent flow inside the material. These results question some general beliefs within the field of protection against chemical risks. They also open new perspectives for the development of predictive tools relative to the behavior of butyl rubber in the presence of solvents

Prostate cancer: The main risk and protective factors-Epigenetic modifications.

PubMed

Adjakly, Mawussi; Ngollo, Marjolaine; Dagdemir, Aslihan; Judes, Gaëlle; Pajon, Amaury; Karsli-Ceppioglu, Seher; Penault-Llorca, Frédérique; Boiteux, Jean-Paul; Bignon, Yves-Jean; Guy, Laurent; Bernard-Gallon, Dominique

2015-02-01

With 13 million new cases worldwide every year, prostate cancer is as a very real public health concern. Prostate cancer is common in over-50s men and the sixth-leading cause of cancer-related death in men worldwide. Like all cancers, prostate cancer is multifactorial - there are non-modifiable risk factors like heredity, ethnicity and geographic location, but also modifiable risk factors such as diet. Diet-cancer linkages have risen to prominence in the last few years, with accruing epidemiological data pointing to between-population incidence differentials in numerous cancers. Indeed, there are correlations between fat-rich diet and risk of hormone-dependent cancers like prostate cancer and breast cancer. Diet is a risk factor for prostate cancer, but certain micronutrients in specific diets are considered protective factors against prostate cancer. Examples include tomato lycopene, green tea epigallocatechin gallate, and soy phytoestrogens. These micronutrients are thought to exert cancer-protective effects via anti-oxidant pathways and inhibition of cell proliferation. Here, we focus in on the effects of phytoestrogens, and chiefly genistein and daidzein, which are the best-researched to date. Soy phytoestrogens are nonsteroid molecules whose structural similarity lends them the ability to mimic the effects of 17ß-estradiol. On top of anti-oxidant effects, there is evidence that soy phytoestrogens can modulate the epigenetic modifications found in prostate cancer. We also studied the impact of phytoestrogens on epigenetic modifications in prostate cancer, with special focus on DNA methylation, miRNA-mediated regulation and histone modifications. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

A Biologically-Based Computational Approach to Drug Repurposing for Anthrax Infection.

PubMed

Bai, Jane P F; Sakellaropoulos, Theodore; Alexopoulos, Leonidas G

2017-03-10

Developing drugs to treat the toxic effects of lethal toxin (LT) and edema toxin (ET) produced by B. anthracis is of global interest . We utilized a computational approach to score 474 drugs/compounds for their ability to reverse the toxic effects of anthrax toxins. For each toxin or drug/compound, we constructed an activity network by using its differentially expressed genes, molecular targets, and protein interactions. Gene expression profiles of drugs were obtained from the Connectivity Map and those of anthrax toxins in human alveolar macrophages were obtained from the Gene Expression Omnibus. Drug rankings were based on the ability of a drug/compound's mode of action in the form of a signaling network to reverse the effects of anthrax toxins; literature reports were used to verify the top 10 and bottom 10 drugs/compounds identified. Simvastatin and bepridil with reported in vitro potency for protecting cells from LT and ET toxicities were computationally ranked fourth and eighth. The other top 10 drugs were fenofibrate, dihydroergotamine, cotinine, amantadine, mephenytoin, sotalol, ifosfamide, and mefloquine; literature mining revealed their potential protective effects from LT and ET toxicities. These drugs are worthy of investigation for their therapeutic benefits and might be used in combination with antibiotics for treating B. anthracis infection.

A Biologically-Based Computational Approach to Drug Repurposing for Anthrax Infection

PubMed Central

Bai, Jane P. F.; Sakellaropoulos, Theodore; Alexopoulos, Leonidas G.

2017-01-01

Developing drugs to treat the toxic effects of lethal toxin (LT) and edema toxin (ET) produced by B. anthracis is of global interest. We utilized a computational approach to score 474 drugs/compounds for their ability to reverse the toxic effects of anthrax toxins. For each toxin or drug/compound, we constructed an activity network by using its differentially expressed genes, molecular targets, and protein interactions. Gene expression profiles of drugs were obtained from the Connectivity Map and those of anthrax toxins in human alveolar macrophages were obtained from the Gene Expression Omnibus. Drug rankings were based on the ability of a drug/compound’s mode of action in the form of a signaling network to reverse the effects of anthrax toxins; literature reports were used to verify the top 10 and bottom 10 drugs/compounds identified. Simvastatin and bepridil with reported in vitro potency for protecting cells from LT and ET toxicities were computationally ranked fourth and eighth. The other top 10 drugs were fenofibrate, dihydroergotamine, cotinine, amantadine, mephenytoin, sotalol, ifosfamide, and mefloquine; literature mining revealed their potential protective effects from LT and ET toxicities. These drugs are worthy of investigation for their therapeutic benefits and might be used in combination with antibiotics for treating B. anthracis infection. PMID:28287432

In vitro differentiation of neural cells from human adipose tissue derived stromal cells.

PubMed

Dave, Shruti D; Patel, Chetan N; Vanikar, Aruna V; Trivedi, Hargovind L

2018-01-01

Stem cells, including neural stem cells (NSCs), are endowed with self-renewal capability and hence hold great opportunity for the institution of replacement/protective therapy. We propose a method for in vitro generation of stromal cells from human adipose tissue and their differentiation into neural cells. Ten grams of donor adipose tissue was surgically resected from the abdominal wall of the human donor after the participants' informed consents. The resected adipose tissue was minced and incubated for 1 hour in the presence of an enzyme (collagenase-type I) at 37 0 C followed by its centrifugation. After centrifugation, the supernatant and pellets were separated and cultured in a medium for proliferation at 37 0 C with 5% CO2 for 9-10 days in separate tissue culture dishes for generation of mesenchymal stromal cells (MSC). At the end of the culture, MSC were harvested and analyzed. The harvested MSC were subjected for further culture for their differentiation into neural cells for 5-7 days using differentiation medium mainly comprising of neurobasal medium. At the end of the procedure, culture cells were isolated and studied for expression of transcriptional factor proteins: orthodenticle homolog-2 (OTX-2), beta-III-tubulin (β3-Tubulin), glial-fibrillary acid protein (GFAP) and synaptophysin-β2. In total, 50 neural cells-lines were generated. In vitro generated MSC differentiated neural cells' mean quantum was 5.4 ± 6.9 ml with the mean cell count being, 5.27 ± 2.65 × 10 3/ μl. All of them showed the presence of OTX-2, β3-Tubulin, GFAP, synaptophysin-β2. Neural cells can be differentiated in vitro from MSC safely and effectively. In vitro generated neural cells represent a potential therapy for recovery from spinal cord injuries and neurodegenerative disease.

The cancer paradigms of mammalian regeneration: can mammals regenerate as amphibians?

PubMed

Sarig, Rachel; Tzahor, Eldad

2017-04-01

Regeneration in mammals is restricted to distinct tissues and occurs mainly by expansion and maturation of resident stem cells. During regeneration, even subtle mutations in the proliferating cells may cause a detrimental effect by eliciting abnormal differentiation or malignant transformation. Indeed, cancer in mammals has been shown to arise through deregulation of stem cells maturation, which often leads to a differentiation block and cell transformation. In contrast, lower organisms such as amphibians retain a remarkable regenerative capacity in various organs, which occurs via de- and re-differentiation of mature cells. Interestingly, regenerating amphibian cells are highly resistant to oncogenic transformation. Therapeutic approaches to improve mammalian regeneration mainly include stem-cell transplantations; but, these have proved unsuccessful in non-regenerating organs such as the heart. A recently developed approach is to induce de-differentiation of mature cardiomyocytes using factors that trigger their re-entry into the cell cycle. This novel approach raises numerous questions regarding the balance between transformation and regeneration induced by de-differentiation of mature mammalian somatic cells. Can this balance be controlled artificially? Do de-differentiated cells acquire the protection mechanisms seen in regenerating cells of lower organisms? Is this model unique to the cardiac tissue, which rarely develops tumors? This review describes regeneration processes in both mammals and lower organisms and, particularly, the ability of regenerating cells to avoid transformation. By comparing the characteristics of mammalian embryonic and somatic cells, we discuss therapeutic strategies of using various cell populations for regeneration. Finally, we describe a novel cardiac regeneration approach and its implications for regenerative medicine. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Effect of alpha-lipoic acid on relieving ammonia stress and hepatic proteomic analyses of broilers.

PubMed

Lu, M; Bai, J; Xu, B; Sun, Q Y; Wei, F X; Tang, X F; Zhang, H F; Li, J; Wang, G L; Yin, Q Q; Li, S Y

2017-01-01

Ammonia in poultry houses not only affects worker health but also induces a variety of poultry diseases. Alpha-lipoic acid (LA) is an effective antioxidant that protects cells against oxidative injury during various toxic and pathological processes. This study was designed to evaluate the mitigating effects of LA supplementation on ammonia stress and hepatic proteome changes in broilers. Male broilers (22 d old) were allocated to 3 groups: (1) a control group without ammonia stress (CTRL); (2) exposure to 70 ppm ammonia (AM); and (3) exposure to 70 ppm ammonia and dietary administration of 300 mg/kg LA (AM+LA). Ammonia exposure significantly decreased broiler growth performance and plasma glutathione peroxidase activity (P < 0.05), and increased plasma malondialdehyde content and glutamic-pyruvic transaminase activity (P < 0.05). These negative effects were eliminated by LA supplementation. Comparative proteomic analyses revealed 291 differentially expressed proteins in the AM group compared to the CTRL and AM+LA groups. A total of 30 proteins were differentially expressed between the AM/CTRL and (AM+LA)/AM groups. The addition of LA restored 24 of these proteins to control levels; these proteins were mainly related to transcription regulation, detoxification, protein translation and degradation, and immune and stress responses. The differentially expressed proteins included the high mobility group box (HMGB) and glutathione S-transferase (GST), which is closely related to immune response and oxidative stress, and collagens, which are implicated in liver injury. The addition of LA to broiler diet may reduce ammonia toxicity by maintaining the antioxidant system, xenobiotic metabolism, and metabolic pathways. © 2016 Poultry Science Association Inc.

Vildagliptin Stimulates Endothelial Cell Network Formation and Ischemia-induced Revascularization via an Endothelial Nitric-oxide Synthase-dependent Mechanism*

PubMed Central

Ishii, Masakazu; Shibata, Rei; Kondo, Kazuhisa; Kambara, Takahiro; Shimizu, Yuuki; Tanigawa, Tohru; Bando, Yasuko K.; Nishimura, Masahiro; Ouchi, Noriyuki; Murohara, Toyoaki

2014-01-01

Dipeptidyl peptidase-4 inhibitors are known to lower glucose levels and are also beneficial in the management of cardiovascular disease. Here, we investigated whether a dipeptidyl peptidase-4 inhibitor, vildagliptin, modulates endothelial cell network formation and revascularization processes in vitro and in vivo. Treatment with vildagliptin enhanced blood flow recovery and capillary density in the ischemic limbs of wild-type mice, with accompanying increases in phosphorylation of Akt and endothelial nitric-oxide synthase (eNOS). In contrast to wild-type mice, treatment with vildagliptin did not improve blood flow in ischemic muscles of eNOS-deficient mice. Treatment with vildagliptin increased the levels of glucagon-like peptide-1 (GLP-1) and adiponectin, which have protective effects on the vasculature. Both vildagliptin and GLP-1 increased the differentiation of cultured human umbilical vein endothelial cells (HUVECs) into vascular-like structures, although vildagliptin was less effective than GLP-1. GLP-1 and vildagliptin also stimulated the phosphorylation of Akt and eNOS in HUVECs. Pretreatment with a PI3 kinase or NOS inhibitor blocked the stimulatory effects of both vildagliptin and GLP-1 on HUVEC differentiation. Furthermore, treatment with vildagliptin only partially increased the limb flow of ischemic muscle in adiponectin-deficient mice in vivo. GLP-1, but not vildagliptin, significantly increased adiponectin expression in differentiated 3T3-L1 adipocytes in vitro. These data indicate that vildagliptin promotes endothelial cell function via eNOS signaling, an effect that may be mediated by both GLP-1-dependent and GLP-1-independent mechanisms. The beneficial activity of GLP-1 for revascularization may also be partially mediated by its ability to increase adiponectin production. PMID:25100725

Vildagliptin stimulates endothelial cell network formation and ischemia-induced revascularization via an endothelial nitric-oxide synthase-dependent mechanism.

PubMed

Ishii, Masakazu; Shibata, Rei; Kondo, Kazuhisa; Kambara, Takahiro; Shimizu, Yuuki; Tanigawa, Tohru; Bando, Yasuko K; Nishimura, Masahiro; Ouchi, Noriyuki; Murohara, Toyoaki

2014-09-26

Dipeptidyl peptidase-4 inhibitors are known to lower glucose levels and are also beneficial in the management of cardiovascular disease. Here, we investigated whether a dipeptidyl peptidase-4 inhibitor, vildagliptin, modulates endothelial cell network formation and revascularization processes in vitro and in vivo. Treatment with vildagliptin enhanced blood flow recovery and capillary density in the ischemic limbs of wild-type mice, with accompanying increases in phosphorylation of Akt and endothelial nitric-oxide synthase (eNOS). In contrast to wild-type mice, treatment with vildagliptin did not improve blood flow in ischemic muscles of eNOS-deficient mice. Treatment with vildagliptin increased the levels of glucagon-like peptide-1 (GLP-1) and adiponectin, which have protective effects on the vasculature. Both vildagliptin and GLP-1 increased the differentiation of cultured human umbilical vein endothelial cells (HUVECs) into vascular-like structures, although vildagliptin was less effective than GLP-1. GLP-1 and vildagliptin also stimulated the phosphorylation of Akt and eNOS in HUVECs. Pretreatment with a PI3 kinase or NOS inhibitor blocked the stimulatory effects of both vildagliptin and GLP-1 on HUVEC differentiation. Furthermore, treatment with vildagliptin only partially increased the limb flow of ischemic muscle in adiponectin-deficient mice in vivo. GLP-1, but not vildagliptin, significantly increased adiponectin expression in differentiated 3T3-L1 adipocytes in vitro. These data indicate that vildagliptin promotes endothelial cell function via eNOS signaling, an effect that may be mediated by both GLP-1-dependent and GLP-1-independent mechanisms. The beneficial activity of GLP-1 for revascularization may also be partially mediated by its ability to increase adiponectin production. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Activation of GPR55 increases neural stem cell proliferation and promotes early adult hippocampal neurogenesis.

PubMed

Hill, Jeremy D; Zuluaga-Ramirez, Viviana; Gajghate, Sachin; Winfield, Malika; Persidsky, Yuri

2018-06-11

The cannabinoid system exerts functional regulation of neural stem cell (NSC) proliferation and adult neurogenesis, yet not all effects of cannabinoid-like compounds seen can be attributed to the cannabinoid 1 receptor (CB 1 R) or cannabinoid 2 receptor (CB 2 R). The recently de-orphaned GPR55 has been shown to be activated by numerous cannabinoid ligands suggesting that GPR55 is a third cannabinoid receptor. Here we examined the role of GPR55 activation in NSC proliferation and early adult neurogenesis. The effects of GPR55 agonists (LPI, O-1602, ML184) on human NSC proliferation in vitro were assessed by flow cytometry. hNSC differentiation was determined by flow cytometry, qPCR, and immunohistochemistry. Immature neuron formation in the hippocampus of C57BL/6 and GPR55 -/- mice was evaluated by immunohistochemistry. Activation of GPR55 significantly increased proliferation rates of hNSCs in vitro. These effects were attenuated by ML193, a selective GPR55 antagonist. ML184 significantly promoted neuronal differentiation in vitro while ML193 reduced differentiation rates as compared to vehicle treatment. Continuous administration into the hippocampus of O-1602 via cannula connected to osmotic pump resulted in increased Ki67+ cells within the dentate gyrus. O-1602 increased immature neuron generation as assessed by DCX+ and BrdU+ cells as compared to vehicle treated animals. GPR55 -/- animals displayed reduced rates of proliferation and neurogenesis within the hippocampus while O-1602 had no effect as compared to vehicle controls. Together, these findings suggest GPR55 activation as a novel target and strategy to regulate NSC proliferation and adult neurogenesis. This article is protected by copyright. All rights reserved.

Protein expression profiling identifies molecular targets of quercetin as a major dietary flavonoid in human colon cancer cells.

PubMed

Wenzel, Uwe; Herzog, Angelika; Kuntz, Sabine; Daniel, Hannelore

2004-07-01

A high dietary intake of plant foods is thought to contribute to the prevention of colorectal cancers in humans and flavonoids as part of such a diet are considered to contribute to those protective effects. Quercetin is a major dietary flavonoid consumed with a diet rich in onions, tea, and apples. We used HT-29 human colon cancer cells and investigated the effects of quercetin on proliferation, apoptosis, and differentiation as processes shown to be disregulated during cancer development. To identify the cellular targets of quercetin action, two-dimensional gel electrophoresis was performed and proteins altered in expression level after quercetin exposure of cells were identified by mass spectrometry of peptide fragments generated by tryptic digestion. Quercetin inhibited the proliferation of HT-29 cells with an IC(50)-value of 81.2 +/- 6.6 microM. Cell differentiation based on surface expression of alkaline phosphatase was enhanced 4-fold and the activity of the pro-apoptotic effector caspase-3 increased 3-fold. Those effects were associated with the regulation of heat-shock proteins and annexins shown to both play a crucial role in the process of apoptosis. Cytoskeletal caspase substrates were found as regulated as well and various proteins involved in intermediary metabolism and in gene regulation showed altered steady-state expression levels upon quercetin treatment of cells. In conclusion, quercetin alters the levels of a variety of proteins involved in growth, differentiation, and apoptosis of colon cancer cells. Their identification as molecular targets of quercetin may explain the anti-cancer activities of this flavonoid.

Thiazide diuretics directly induce osteoblast differentiation and mineralized nodule formation by targeting a NaCl cotransporter in bone

PubMed Central

Dvorak, Melita M; De Joussineau, Cyrille; Carter, D Howard; Pisitkun, Trairak; Knepper, Mark A; Gamba, Gerardo; Kemp, Paul J; Riccardi, Daniela

2008-01-01

Thiazide diuretics are used, worldwide, as the first-choice drug for patients with uncomplicated hypertension. In addition to their anti-hypertensive actions, they increase bone mineral density and reduce the prevalence of fractures, indicating that thiazides may have a role in the management of postmenopausal osteoporosis. Traditionally, the bone-protective effects of thiazides have been attributed to an increase in renal calcium reabsorption, secondary to the inhibition of the sodium chloride cotransporter, NCC, expressed in the kidney distal tubule. Whether thiazides exert a direct osteoanabolic effect independently of their renal action is controversial. Here we demonstrate that freshly frozen sections of human and rat bone express NCC, principally in bone-forming cells, the osteoblasts. In primary and established culture models of osteoblasts, fetal rat calvarial (FRC) and human MG63 cells, NCC protein is virtually absent in proliferating cells while its expression is dramatically increased during differentiation. Thiazides directly stimulate the production of osteoblast markers, runt-related transcription factor 2 (runx2) and osteopontin, in the absence of a proliferative effect. Using overexpression/knockdown studies in FRC cells, we show that thiazides, but not loop diuretics, increase mineralized nodule formation acting on NCC. Overall, our study demonstrates that thiazides stimulate osteoblast differentiation and bone mineral formation independently of their renal actions. In addition to their use as part of a therapeutic treatment plan for elderly, hypertensive individuals, our discovery opens up the possibility that bone-specific drug targeting by thiazides may be developed for the prevention and treatment of osteoporosis in the patient population as a whole. PMID:17656470

Understanding MIH: definition, epidemiology, differential diagnosis and new treatment guidelines.

PubMed

Mast, P; Rodrigueztapia, M T; Daeniker, L; Krejci, I

2013-09-01

Molar-Incisor Hypomineralisation (MIH) is a congenital disease which increases in prevalence. It affects permanent first molars and, often to a lesser degree, permanent incisors with variable severity. The aetiology is unknown, but different hypotheses have been advanced. Differential diagnosis is mandatory not to confound MIH with other diseases. Treatment consists in a minimally invasive approach by reinforcing and protecting the existing dental structure. In more severe cases, restorative treatment may be indicated.

Antigen Availability Shapes T Cell Differentiation and Function during Tuberculosis.

PubMed

Moguche, Albanus O; Musvosvi, Munyaradzi; Penn-Nicholson, Adam; Plumlee, Courtney R; Mearns, Helen; Geldenhuys, Hennie; Smit, Erica; Abrahams, Deborah; Rozot, Virginie; Dintwe, One; Hoff, Søren T; Kromann, Ingrid; Ruhwald, Morten; Bang, Peter; Larson, Ryan P; Shafiani, Shahin; Ma, Shuyi; Sherman, David R; Sette, Alessandro; Lindestam Arlehamn, Cecilia S; McKinney, Denise M; Maecker, Holden; Hanekom, Willem A; Hatherill, Mark; Andersen, Peter; Scriba, Thomas J; Urdahl, Kevin B

2017-06-14

CD4 T cells are critical for protective immunity against Mycobacterium tuberculosis (Mtb), the cause of tuberculosis (TB). Yet to date, TB vaccine candidates that boost antigen-specific CD4 T cells have conferred little or no protection. Here we examined CD4 T cell responses to two leading TB vaccine antigens, ESAT-6 and Ag85B, in Mtb-infected mice and in vaccinated humans with and without underlying Mtb infection. In both species, Mtb infection drove ESAT-6-specific T cells to be more differentiated than Ag85B-specific T cells. The ability of each T cell population to control Mtb in the lungs of mice was restricted for opposite reasons: Ag85B-specific T cells were limited by reduced antigen expression during persistent infection, whereas ESAT-6-specific T cells became functionally exhausted due to chronic antigenic stimulation. Our findings suggest that different vaccination strategies will be required to optimize protection mediated by T cells recognizing antigens expressed at distinct stages of Mtb infection. Copyright © 2017 Elsevier Inc. All rights reserved.

An approach for access differentiation design in medical distributed applications built on databases.

PubMed

Shoukourian, S K; Vasilyan, A M; Avagyan, A A; Shukurian, A K

1999-01-01

A formalized "top to bottom" design approach was described in [1] for distributed applications built on databases, which were considered as a medium between virtual and real user environments for a specific medical application. Merging different components within a unified distributed application posits new essential problems for software. Particularly protection tools, which are sufficient separately, become deficient during the integration due to specific additional links and relationships not considered formerly. E.g., it is impossible to protect a shared object in the virtual operating room using only DBMS protection tools, if the object is stored as a record in DB tables. The solution of the problem should be found only within the more general application framework. Appropriate tools are absent or unavailable. The present paper suggests a detailed outline of a design and testing toolset for access differentiation systems (ADS) in distributed medical applications which use databases. The appropriate formal model as well as tools for its mapping to a DMBS are suggested. Remote users connected via global networks are considered too.

46 CFR 252.34 - Protection and indemnity insurance.

Code of Federal Regulations, 2011 CFR

2011-10-01

.... The adjustment of the wage percentage differential shall not be used for Japan, where operators incur minimal costs for deductible absorptions, rather than no costs. For Japan, the insurance related costs...

Aroclor1254 interferes with estrogen receptor-mediated neuroprotection against beta-amyloid toxicity in cholinergic SN56 cells.

PubMed

Bang, Yeojin; Lim, Juhee; Kim, Sa Suk; Jeong, Hyung Min; Jung, Ki-Kyung; Kang, Il-Hyun; Lee, Kwang-Youl; Choi, Hyun Jin

2011-10-01

Because estrogen plays important neurotrophic and neuroprotective roles in the brain by activating estrogen receptors (ERs), disruption of normal estrogen signaling can leave neurons vulnerable to a variety of insults, including β-amyloid peptide (Aβ). Aroclor1254 (A1254) belongs to the endocrine-disrupting chemical (EDC) polychlorinated biphenyls and has anti-estrogenic properties. In the present study, we evaluated the effect of A1254 on the protective activity of estrogen against Aβ toxicity in differentiated cholinergic SN56 cells. Aged Aβ25-35 causes apoptotic cell death in differentiated SN56 cells, and the cytotoxic evidences are effectively rescued by estrogen. We found that A1254 abolishes the neuroprotective activity of estrogen against Aβ toxicity, and attenuates the suppressive effect of estrogen on Aβ-induced tau phosphorylation and JNK activation. The effects of A1254 on the neuroprotective effects of estrogen in Aβ toxicity are very similar to the effects of the estrogen receptor antagonist ICI182,780. Thus, exposure to EDCs that have anti-estrogenic activity might interfere with normal estrogen-activated neuroprotective signaling events and leave neurons more vulnerable to dangerous stimuli. Our present results provide new understanding of the mechanisms contributing to the harmful effects of EDCs on the function and viability of neurons, and the possible relevance of EDCs in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease. Copyright © 2011 Elsevier B.V. All rights reserved.

Fibrin Glue Improves the Therapeutic Effect of MSCs by Sustaining Survival and Paracrine Function

PubMed Central

Kim, Inok; Lee, Sung Koo; Yoon, Jung In; Kim, Da Eun

2013-01-01

Fibrin glue has been widely investigated as a cell delivery vehicle for improving the therapeutic effects of mesenchymal stem cells (MSCs). Implanted MSCs produce their therapeutic effects by secreting paracrine factors and by replacing damaged tissues after differentiation. While the influence of fibrin glue on the differentiation potential of MSCs has been well documented, its effect on paracrine function of MSCs is largely unknown. Herein we investigated the influence of fibrin glue on the paracrine effects of MSCs. MSCs were isolated from human adipose tissue. The effects of fibrin glue on survival, migration, secretion of growth factors, and immune suppression of MSCs were investigated in vitro. MSCs in fibrin glue survived and secreted growth factors such as the vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) over 14 days. VEGF and immune modulators, including the transforming growth factor (TGF)-β1 and prostaglandin E2, secreted from MSCs in fibrin glue significantly increased under inflammatory conditions. Thus, MSCs in fibrin glue effectively suppressed immune reactions. In addition, fibrin glue protected the MSCs from oxidative stress and prevented human dermal fibroblast death induced by exposure to extreme stress. In contrast, MSCs within fibrin glue hardly migrated. These results suggest that fibrin glue may sustain survival of implanted MSCs and their paracrine function. Our results provide a mechanistic data to allow further development of MSCs with fibrin glue as a clinical treatment. PMID:23701237

Prostacyclin Suppresses Twist Expression in the Presence of Indomethacin in Bone Marrow-Derived Mesenchymal Stromal Cells

PubMed Central

Kemper, Oliver; Herten, Monika; Fischer, Johannes; Haversath, Marcel; Beck, Sascha; Classen, Tim; Warwas, Sebastian; Tassemeier, Tjark; Landgraeber, Stefan; Lensing-Höhn, Sabine; Krauspe, Rüdiger; Jäger, Marcus

2014-01-01

Background Iloprost, a stable prostacyclin I2 analogue, seems to have an osteoblast-protective potential, whereas indomethacin suppresses new bone formation. The aim of this study was to investigate human bone marrow stromal cell (BMSC) proliferation and differentiation towards the osteoblastic lineage by administration of indomethacin and/or iloprost. Material/Methods Human bone marrow cells were obtained from 3 different donors (A=26 yrs/m; B=25 yrs/f, C=35 yrs/m) via vacuum aspiration of the iliac crest followed by density gradient centrifugation and flow cytometry with defined antigens (CD105+/73+/45−/14−). The cells were seeded and incubated as follows: without additives (Group 0; donor A/B/C), with 10−7 M iloprost only (Group 0+ilo; A/B), with indomethacin only in concentrations of 10−6 M (Group 1, A), 10−5 M (Group 2, B), 10−4 M (Group 3, A/B), and together with 10−7 M iloprost (Groups 4–6, A/B/C). On Day 10 and 28, UV/Vis spectrometric and immunocytochemical assays (4 samples per group and donor) were performed to investigate cell proliferation (cell count measurement) and differentiation towards the osteoblastic lineage (CD34−, CD45−, CD105+, type 1 collagen (Col1), osteocalcin (OC), alkaline phosphatase (ALP), Runx2, Twist, specific ALP-activity). Results Indomethacin alone suppressed BMSC differentiation towards the osteoblastic lineage by downregulation of Runx2, Col1, and ALP. In combination with indomethacin, iloprost increased cell proliferation and differentiation and it completely suppressed Twist expression at Day 10 and 28. Iloprost alone did not promote cell proliferation, but moderately enhanced Runx2 and Twist expression. However, the proliferative effects and the specific ALP-activity varied donor-dependently. Conclusions Iloprost partially antagonized the suppressing effects of indomethacin on BMSC differentiation towards the osteoblast lineage. It enhanced the expression of Runx2 and, only in the presence of indomethacin, it completely suppressed Twist. Thus, in the treatment of avascular osteonecrosis or painful bone marrow edema, the undesirable effects of indomethacin might be counterbalanced by iloprost. PMID:25382306

Tissue Specific Expression Of Sprouty1 In Mice Protects Against High Fat Diet Induced Fat Accumulation, Bone Loss, And Metabolic Dysfunction

PubMed Central

Urs, Sumithra; Henderson, Terry; Le, Phuong; Rosen, Clifford J.; Liaw, Lucy

2012-01-01

We recently characterized Sprouty1 (Spry1), a growth factor signaling inhibitor as a regulator of marrow progenitor cells promoting osteoblast differentiation at the expense of adipocytes. Adipose tissue specific Spry1 expression in mice resulted in increased bone mass and reduced body fat while conditional knockout of Spry1 had the opposite effect with decreased bone and increased body fat. Because Spry1 suppresses normal fat development, we tested the hypothesis that Spry1 expression prevents high fat diet-induced obesity, bone loss, and associated lipid abnormalities and demonstrate that Spry1 has a long-term protective effect on mice fed a high caloric diet. We studied diet-induced obesity in mice with fatty acid binding promoter (aP2)-driven expression or conditional knockout of Spry1 in adipocytes. Phenotyping was performed by whole body dual-energy X-ray absorptiometry, microCT, histology and blood analysis. In conditional Spry1 null mice, high fat diet increased body fat by 40%, impaired glucose regulation, and led to liver steatosis. However, over-expression of Spry1 led to 35% lower body fat, reduced bone loss, and normal metabolic function compared to single transgenics. This protective phenotype was associated with decreased circulating insulin (70%) and leptin (54%) compared to controls on a high fat diet. Additionally, Spry1 expression decreased adipose tissue inflammation by 45%. We show that conditional Spry1 expression in adipose tissue protects against high fat diet-induced obesity and associated bone loss. PMID:22142492

Tissue-specific expression of Sprouty1 in mice protects against high-fat diet-induced fat accumulation, bone loss and metabolic dysfunction.

PubMed

Urs, Sumithra; Henderson, Terry; Le, Phuong; Rosen, Clifford J; Liaw, Lucy

2012-09-28

We recently characterised Sprouty1 (Spry1), a growth factor signalling inhibitor as a regulator of marrow progenitor cells promoting osteoblast differentiation at the expense of adipocytes. Adipose tissue-specific Spry1 expression in mice resulted in increased bone mass and reduced body fat, while conditional knockout of Spry1 had the opposite effect with decreased bone mass and increased body fat. Because Spry1 suppresses normal fat development, we tested the hypothesis that Spry1 expression prevents high-fat diet-induced obesity, bone loss and associated lipid abnormalities, and demonstrate that Spry1 has a long-term protective effect on mice fed a high-energy diet. We studied diet-induced obesity in mice with fatty acid binding promoter-driven expression or conditional knockout of Spry1 in adipocytes. Phenotyping was performed by whole-body dual-energy X-ray absorptiometry, microCT, histology and blood analysis. In conditional Spry1-null mice, a high-fat diet increased body fat by 40 %, impaired glucose regulation and led to liver steatosis. However, overexpression of Spry1 led to 35 % (P < 0·05) lower body fat, reduced bone loss and normal metabolic function compared with single transgenics. This protective phenotype was associated with decreased circulating insulin (70 %) and leptin (54 %; P < 0·005) compared with controls on a high-fat diet. Additionally, Spry1 expression decreased adipose tissue inflammation by 45 %. We show that conditional Spry1 expression in adipose tissue protects against high-fat diet-induced obesity and associated bone loss.

Chondrogenic Differentiation Increases Antidonor Immune Response to Allogeneic Mesenchymal Stem Cell Transplantation

PubMed Central

Ryan, Aideen E; Lohan, Paul; O'Flynn, Lisa; Treacy, Oliver; Chen, Xizhe; Coleman, Cynthia; Shaw, Georgina; Murphy, Mary; Barry, Frank; Griffin, Matthew D; Ritter, Thomas

2014-01-01

Allogeneic mesenchymal stem cells (allo-MSCs) have potent regenerative and immunosuppressive potential and are being investigated as a therapy for osteoarthritis; however, little is known about the immunological changes that occur in allo-MSCs after ex vivo induced or in vivo differentiation. Three-dimensional chondrogenic differentiation was induced in an alginate matrix, which served to immobilize and potentially protect MSCs at the site of implantation. We show that allogeneic differentiated MSCs lost the ability to inhibit T-cell proliferation in vitro, in association with reduced nitric oxide and prostaglandin E2 secretion. Differentiation altered immunogenicity as evidenced by induced proliferation of allogeneic T cells and increased susceptibility to cytotoxic lysis by allo-specific T cells. Undifferentiated or differentiated allo-MSCs were implanted subcutaneously, with and without alginate encapsulation. Increased CD3+ and CD68+ infiltration was evident in differentiated and splenocyte encapsulated implants only. Without encapsulation, increased local memory T-cell responses were detectable in recipients of undifferentiated and differentiated MSCs; however, only differentiated MSCs induced systemic memory T-cell responses. In recipients of encapsulated allogeneic cells, only differentiated allo-MSCs induced memory T-cell responses locally and systemically. Systemic alloimmune responses to differentiated MSCs indicate immunogenicity regardless of alginate encapsulation and may require immunosuppressive therapy for therapeutic use. PMID:24184966

Has the mammary gland a protective mechanism against overexposure to triiodothyronine during the peripartum period? The prolactin pulse down-regulates mammary type I deiodinase responsiveness to norepinephrine.

PubMed

Anguiano, B; Rojas-Huidobro, R; Delgado, G; Aceves, C

2004-11-01

Peripartum is a crucial period for mammary gland final differentiation and the onset of lactation. Although the 'trigger' for lactogenesis depends on several hormones, a key factor is the peripartum prolactin (PRL) pulse whose deletion results in a failure to initiate milk production. Other hormones having a critical role during this period but exerting a contrary effect are the thyronines. A transitory hypothyroidism occurs at peripartum in serum and several other extrathyroidal tissues, whereas the induction of hyperthyroidism during late pregnancy is associated with the absence of lactation after delivery. We analyzed the mammary gland during pregnancy and lactation for: (a) the type and amount of thyroid receptors (TRs), (b) the local triiodothyronine (T3) generation catalyzed by type I deiodinase (Dio1), (c) the Dio1 response to norepinephrine (NE) and (d) the effect on Dio1 and TRs of blocking the PRL pulse at peripartum. Our data showed that during pregnancy the mammary gland contains Dio1 in low amounts associated with the highest expression of TRalpha1; whereas during lactation the gland shows high levels of both Dio1 and TRalpha1. However, at peripartum, both TRs and Dio1 decrease, and Dio1 becomes refractory to NE. This refractoriness disappears when the PRL pulse is blocked by the dopamine agonist bromocriptine. This blockade is also accompanied by a significant decrease in cyclin D1 expression. Our data suggested that the peripartum PRL pulse is part of a protective mechanism against precocious differentiation and/or premature involution of the alveolar epithelium due to T3 overexposure.

Two functional serotonin polymorphisms moderate the effect of food reinforcement on BMI.

PubMed

Carr, Katelyn A; Lin, Henry; Fletcher, Kelly D; Sucheston, Lara; Singh, Prashant K; Salis, Robbert J; Erbe, Richard W; Faith, Myles S; Allison, David B; Stice, Eric; Epstein, Leonard H

2013-06-01

Food reinforcement, or the motivation to eat, has been associated with increased energy intake, greater body weight, and prospective weight gain. Much of the previous research on the reinforcing value of food has focused on the role of dopamine, but it may be worthwhile to examine genetic polymorphisms in the serotonin and opioid systems as these neurotransmitters have been shown to be related to reinforcement processes and to influence energy intake. We examined the relationship among 44 candidate genetic polymorphisms in the dopamine, serotonin, and opioid systems, as well as food reinforcement and body mass index (BMI) in a sample of 245 individuals. Polymorphisms in the monoamine oxidase A (MAOA-LPR) and serotonin receptor 2A genes (rs6314) moderated the effect of food reinforcement on BMI, accounting for an additional 5-10% variance and revealed a potential role of the single nucleotide polymorphism, rs6314, in the serotonin 2A receptor as a differential susceptibility factor for obesity. Differential susceptibility describes a factor that can confer either risk or protection depending on a second variable, such that rs6314 is predictive of both high and low BMI based on the level of food reinforcement, while the diathesis stress or dual-gain model only influences one end of the outcome measure. The interaction with MAOA-LPR better fits the diathesis stress model, with the 3.5R/4R allele conferring protection for individuals low in food reinforcement. These results provide new insight into genes theoretically involved in obesity, and support the hypothesis that genetics moderate the association between food reinforcement and BMI. PsycINFO Database Record (c) 2013 APA, all rights reserved.

TNF-alpha-induced apoptosis is prevented by erythropoietin treatment on SH-SY5Y cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pregi, Nicolas; Wenker, Shirley; Vittori, Daniela

2009-02-01

The growth factor erythropoietin (Epo) has shown neuronal protective action in addition to its well known proerythroid activity. Furthermore, Epo has dealt with cellular inflammation by inhibiting the expression of several proinflammatory cytokines, such as IL-1 and TNF-{alpha}. The action of TNF can have both apoptotic and antiapoptotic consequences due to altered balance between different cell signalling pathways. This work has focused on the apoptotic effects of this cytokine and the potential protective action of Epo. The model we used was neuroblastoma SH-SY5Y cells cultured in the presence of 25 ng/ml TNF-{alpha} or pretreated with 25 U/ml Epo for 12more » h before the addition of TNF-{alpha}. Apoptosis was evaluated by differential cell count after Hoechst staining, analysis of DNA ladder pattern, and measurement of caspase activity. Despite its ability to induce NF-{kappa}B nuclear translocation, TNF-{alpha} induced cell death, which was found to be associated to upregulation of TNF Receptor 1 expression. On the other hand, cells activated by Epo became resistant to cell death. Prevention of death receptor upregulation and caspase activation may explain this antiapoptotic effect of Epo, which may be also favoured by the induction of a higher expression of protective factors, such as Bcl-2 and NF-{kappa}B, through mechanisms involving Jak/STAT and PI3K signalling pathways.« less

Social communication competence and functional adaptation in a general population of children: preliminary evidence for sex-by-verbal IQ differential risk.

PubMed

Skuse, David H; Mandy, William; Steer, Colin; Miller, Laura L; Goodman, Robert; Lawrence, Kate; Emond, Alan; Golding, Jean

2009-02-01

The proportion of schoolchildren with mild social communicative deficits far exceeds the number diagnosed with an autistic spectrum disorder (ASD). We aimed to ascertain both the population distribution of such deficits and their association with functional adaptation and cognitive ability in middle childhood. The parent-report Social and Communication Disorders Checklist was administered to participants (n = 8,094) in the Avon Longitudinal Study of Parents and Children. We correlated impairment severity with independent clinical diagnoses of ASD, cognitive abilities, and teacher-rated maladaptive behavior. Social and Communication Disorders Checklist scores were continuously distributed in the general population; boys had mean scores 30% higher than girls. Social communicative deficits were associated with functional impairment at school, especially in domains of hyperactivity and conduct disorders. A sex-by-verbal IQ interaction effect occurred: verbal IQ was protective against social communication impairments across the range of abilities in female subjects only. In male subjects, this protective effect did not exist for those with above-average verbal IQ. Social communicative deficits are of prognostic significance, in terms of behavioral adjustment at school, for boys and girls. Their high general population prevalence emphasizes the importance of measuring such traits among clinically referred children who do not meet diagnostic ASD criteria. Above-average verbal IQ seems to confer protection against social communication impairments in female subjects but not in male subjects.

Valuing Equal Protection in Aviation Security Screening.

PubMed

Nguyen, Kenneth D; Rosoff, Heather; John, Richard S

2017-12-01

The growing number of anti-terrorism policies has elevated public concerns about discrimination. Within the context of airport security screening, the current study examines how American travelers value the principle of equal protection by quantifying the "equity premium" that they are willing to sacrifice to avoid screening procedures that result in differential treatments. In addition, we applied the notion of procedural justice to explore the effect of alternative selective screening procedures on the value of equal protection. Two-hundred and twenty-two respondents were randomly assigned to one of three selective screening procedures: (1) randomly, (2) using behavioral indicators, or (3) based on demographic characteristics. They were asked to choose between airlines using either an equal or a discriminatory screening procedure. While the former requires all passengers to be screened in the same manner, the latter mandates all passengers undergo a quick primary screening and, in addition, some passengers are selected for a secondary screening based on a predetermined selection criterion. Equity premiums were quantified in terms of monetary cost, wait time, convenience, and safety compromise. Results show that equity premiums varied greatly across respondents, with many indicating little willingness to sacrifice to avoid inequitable screening, and a smaller minority willing to sacrifice anything to avoid the discriminatory screening. The selective screening manipulation was effective in that equity premiums were greater under selection by demographic characteristics compared to the other two procedures. © 2017 Society for Risk Analysis.

Generation of protective T cell-independent antiviral antibody responses in SCID mice reconstituted with follicular or marginal zone B cells.

PubMed

Guay, Heath M; Mishra, Rabinarayan; Garcea, Robert L; Welsh, Raymond M; Szomolanyi-Tsuda, Eva

2009-07-01

B cells generated in the bone marrow of adult mice enter the periphery as transitional B cells and subsequently differentiate into one of two phenotypically and functionally distinct subsets, marginal zone (MZ) or follicular (Fo) B cells. Recent reports indicate, however, that in response to environmental cues, such as lymphopenia, mature Fo B cells can change to display phenotypic markers characteristic of MZ B cells. Previously, we found that splenic B cells transferred to SCID mice responded to polyoma virus (PyV) infection with T cell-independent (TI) IgM and IgG secretion, reducing the viral load and protecting mice from the lethal effect of the infection. The contribution of MZ and Fo B cell subsets to this antiviral TI-2 response, however, has not been addressed. In this study, we show that both sort-purified MZ and Fo B cells generate protective TI Ab responses to PyV infection when transferred into SCID mice. Moreover, the transferred Fo B cells in the spleens of the PyV-infected SCID mice change phenotype, with many of them displaying MZ B cell characteristics. These findings demonstrate the plasticity of the B cell subsets in virus-infected hosts and show for the first time that B cells derived exclusively from Fo B cells can effectively function in antiviral TI-2 responses.

Specific TRPC6 Channel Activation, a Novel Approach to Stimulate Keratinocyte Differentiation*S⃞

PubMed Central

Müller, Margarethe; Essin, Kirill; Hill, Kerstin; Beschmann, Heike; Rubant, Simone; Schempp, Christoph M.; Gollasch, Maik; Boehncke, W. Henning; Harteneck, Christian; Müller, Walter E.; Leuner, Kristina

2008-01-01

The protective epithelial barrier in our skin undergoes constant regulation, whereby the balance between differentiation and proliferation of keratinocytes plays a major role. Impaired keratinocyte differentiation and proliferation are key elements in the pathophysiology of several important dermatological diseases, including atopic dermatitis and psoriasis. Ca2+ influx plays an essential role in this process presumably mediated by different transient receptor potential (TRP) channels. However, investigating their individual role was hampered by the lack of specific stimulators or inhibitors. Because we have recently identified hyperforin as a specific TRPC6 activator, we investigated the contribution of TRPC6 to keratinocyte differentiation and proliferation. Like the endogenous differentiation stimulus high extracellular Ca2+ concentration ([Ca2+]o), hyperforin triggers differentiation in HaCaT cells and in primary cultures of human keratinocytes by inducing Ca2+ influx via TRPC6 channels and additional inhibition of proliferation. Knocking down TRPC6 channels prevents the induction of Ca2+- and hyperforin-induced differentiation. Importantly, TRPC6 activation is sufficient to induce keratinocyte differentiation similar to the physiological stimulus [Ca2+]o. Therefore, TRPC6 activation by hyperforin may represent a new innovative therapeutic strategy in skin disorders characterized by altered keratinocyte differentiation. PMID:18818211

Differential antimutagenicity of WR-1065 added after irradiation in L5178Y cell lines

NASA Technical Reports Server (NTRS)

Evans, H. H.; Horng, M. F.; Ricanati, M.; McCoy, E. C.

1999-01-01

The purpose of this study was to determine the antimutagenicity of WR-1065 added after irradiation of cells of cell lines differing in their ability to rejoin radiation-induced DNA double-strand breaks (DSBs). The postirradiation antimutagenicity of WR-1065 at the thymidine kinase locus was demonstrated for L5178Y (LY)-S1 cells that are deficient in repair of DNA DSBs. Less postirradiation antimutagenicity of WR-1065 was observed in LY-R16 and LY-SR1 cells, which are relatively efficient in DSB repair. Postirradiation treatment with WR-1065 had only a small stimulatory effect on DSB rejoining. A 3-h incubation of irradiated LY cells with WR-1065 caused slight changes in the distribution of cells in the phases of the cell cycle that differed between LY-S1 and LY-SR1 cells. Both LY-S1 and LY-SR1 cells were protected against the cytotoxic and mutagenic effects of radiation when WR-1065 was present 30 min before and during the irradiation. We conclude that the differential postirradiation effects of WR-1065 in the LY-S1 and LY-SR1 cells are not caused by differences in cellular uptake of the radioprotector or in its radical scavenging activity. Possible mechanisms for the postirradiation antimutagenicity of WR-1065 are discussed.

Oncolytic HSV virotherapy in murine sarcomas differentially triggers an antitumor T-cell response in the absence of virus permissivity

PubMed Central

Leddon, Jennifer L; Chen, Chun-Yu; Currier, Mark A; Wang, Pin-Yi; Jung, Francesca A; Denton, Nicholas L; Cripe, Kevin M; Haworth, Kellie B; Arnold, Michael A; Gross, Amy C; Eubank, Timothy D; Goins, William F; Glorioso, Joseph C; Cohen, Justus B; Grandi, Paola; Hildeman, David A; Cripe, Timothy P

2015-01-01

Multiple studies have indicated that in addition to direct oncolysis, virotherapy promotes an antitumor cytotoxic T cell response important for efficacy. To study this phenomenon further, we tested three syngeneic murine sarcoma models that displayed varied degrees of permissiveness to oncolytic herpes simplex virus replication and cytotoxicity in vitro, with the most permissive being comparable to some human sarcoma tumor lines. The in vivo antitumor effect ranged from no or modest response to complete tumor regression and protection from tumor rechallenge. The in vitro permissiveness to viral oncolysis was not predictive of the in vivo antitumor effect, as all three tumors showed intact interferon signaling and minimal permissiveness to virus in vivo. Tumor shrinkage was T-cell mediated with a tumor-specific antigen response required for maximal antitumor activity. Further analysis of the innate and adaptive immune microenvironment revealed potential correlates of susceptibility and resistance, including favorable and unfavorable cytokine profiles, differential composition of intratumoral myeloid cells, and baseline differences in tumor cell immunogenicity and tumor-infiltrating T-cell subsets. It is likely that a more complete understanding of the interplay between the immunologic immune microenvironment and virus infection will be necessary to fully leverage the antitumor effects of this therapeutic platform. PMID:27119100

IVIg Promote Cross-Tolerance against Inflammatory Stimuli In Vitro and In Vivo.

PubMed

Domínguez-Soto, Ángeles; Simón-Fuentes, Miriam; de Las Casas-Engel, Mateo; Cuevas, Víctor D; López-Bravo, María; Domínguez-Andrés, Jorge; Saz-Leal, Paula; Sancho, David; Ardavín, Carlos; Ochoa-Grullón, Juliana; Sánchez-Ramón, Silvia; Vega, Miguel A; Corbí, Angel L

2018-05-09

IVIg is an approved therapy for immunodeficiency and for several autoimmune and inflammatory diseases. However, the molecular basis for the IVIg anti-inflammatory activity remains to be fully explained and cannot be extrapolated from studies on animal models of disease. We now report that IVIg impairs the generation of human monocyte-derived anti-inflammatory macrophages by inducing JNK activation and activin A production and limits proinflammatory macrophage differentiation by inhibiting GM-CSF-driven STAT5 activation. In vivo, IVIg provokes a rapid increase in peripheral blood activin A, CCL2, and IL-6 levels, an effect that can be recapitulated in vitro on human monocytes. On differentiating monocytes, IVIg promotes the acquisition of altered transcriptional and cytokine profiles, reduces TLR expression and signaling, and upregulates negative regulators of TLR-initiated intracellular signaling. In line with these effects, in vivo IVIg infusion induces a state tolerant toward subsequent stimuli that results in reduced inflammatory cytokine production after LPS challenge in human peripheral blood and significant protection from LPS-induced death in mice. Therefore, IVIg conditions human macrophages toward the acquisition of a state of cross-tolerance against inflammatory stimuli, an effect that correlates with the net anti-inflammatory action of IVIg in vivo. Copyright © 2018 by The American Association of Immunologists, Inc.

DNA methylation dynamics during in vivo differentiation of blood and skin stem cells

PubMed Central

Bock, Christoph; Beerman, Isabel; Lien, Wen-Hui; Smith, Zachary D.; Gu, Hongcang; Boyle, Patrick; Gnirke, Andreas; Fuchs, Elaine; Rossi, Derrick J.; Meissner, Alexander

2012-01-01

DNA methylation is a mechanism of epigenetic regulation that is common to all vertebrates. Functional studies underscore its relevance for tissue homeostasis, but the global dynamics of DNA methylation during in vivo differentiation remain underexplored. Here we report high-resolution DNA methylation maps of adult stem cell differentiation in mouse, focusing on 19 purified cell populations of the blood and skin lineages. DNA methylation changes were locus-specific and relatively modest in magnitude. They frequently overlapped with lineage-associated transcription factors and their binding sites, suggesting that DNA methylation may protect cells from aberrant transcription factor activation. DNA methylation and gene expression provided complementary information, and combining the two enabled us to infer the cellular differentiation hierarchy of the blood lineage directly from genomic data. In summary, these results demonstrate that in vivo differentiation of adult stem cells is associated with small but informative changes in the genomic distribution of DNA methylation. PMID:22841485

Development of novel cationic chitosan-and anionic alginate–coated poly(d,l-lactide-co-glycolide) nanoparticles for controlled release and light protection of resveratrol

PubMed Central

Sanna, Vanna; Roggio, Anna Maria; Siliani, Silvia; Piccinini, Massimo; Marceddu, Salvatore; Mariani, Alberto; Sechi, Mario

2012-01-01

Background Resveratrol, like other natural polyphenols, is an extremely photosensitive compound with low chemical stability, which limits the therapeutic application of its beneficial effects. The development of innovative formulation strategies, able to overcome physicochemical and pharmacokinetic limitations of this compound, may be achieved via suitable carriers able to associate controlled release and protection. In this context, nanotechnology is proving to be a powerful strategy. In this study, we developed novel cationic chitosan (CS)- and anionic alginate (Alg)-coated poly(d,l-lactide-co-glycolide) nanoparticles (NPs) loaded with the bioactive polyphenolic trans-(E)-resveratrol (RSV) for biomedical applications. Methods NPs were prepared by the nanoprecipitation method and characterized in terms of morphology, size and zeta potential, encapsulation efficiency, Raman spectroscopy, swelling properties, differential scanning calorimetry, and in vitro release studies. The protective effect of the nanosystems under the light-stressed RSV and long-term stability were investigated. Results NPs turned out to be spherical in shape, with size ranging from 135 to about 580 nm, depending on the composition and the amount of polyelectrolytes, while the encapsulation efficiencies increased from 8% of uncoated poly(d,l-lactide-co-glycolide) (PLGA) to 23% and 32% of Alg- and CS-coated PLGA NPs, respectively. All nanocarriers are characterized by a biphasic release pattern, and more effective controlled release rates are obtained for NPs formulated with higher polyelectrolyte concentrations. Stability studies revealed that encapsulation provides significant protection against light-exposure degradation, by reducing the trans–cis photoisomerization reaction. Moreover, the nanosystems are able to prevent the degradation of trans isoform and the leakage of RSV from the carrier for a period of 6 months. Conclusion Our findings indicated that the newly developed CS- and Alg-coated PLGA NPs are suitable to be used for the delivery of bioactive RSV. The encapsulation of RSV into optimized polymeric NPs provides improved drug loading, effective controlled release, and protection against light-exposure degradation, thus opening new perspectives for the delivery of bioactive related phytochemicals to be used for (nano)chemoprevention/chemotherapy. PMID:23093904

FC-99 ameliorates sepsis-induced liver dysfunction by modulating monocyte/macrophage differentiation via Let-7a related monocytes apoptosis.

PubMed

Zhao, Yarong; Zhu, Haiyan; Wang, Haining; Ding, Liang; Xu, Lizhi; Chen, Dai; Shen, Sunan; Hou, Yayi; Dou, Huan

2018-03-13

The liver is a vital target for sepsis-related injury, leading to inflammatory pathogenesis, multiple organ dysfunction and high mortality rates. Monocyte-derived macrophage transformations are key events in hepatic inflammation. N 1 -[(4-methoxy)methyl]-4-methyl-1,2-benzenediamine (FC-99) previously displayed therapeutic potential on experimental sepsis. However, the underlying mechanism of this protective effect is still not clear. FC-99 treatment attenuated the liver dysfunction in septic mice that was accompanied with reduced numbers of pro-inflammatory Ly6C hi monocytes in the peripheral blood and CD11b + F4/80 lo monocyte-derived macrophages in the liver. These effects were attributed to the FC-99-induced apoptosis of CD11b + cells. In PMA-differentiated THP-1 cells, FC-99 repressed the expression of CD11b, CD14 and caspase3 and resulted in a high proportion of Annexin V + cells. Moreover, let-7a-5p expression was abrogated upon CLP stimulation in vivo , whereas it was restored by FC-99 treatment. TargetScan analysis and luciferase assays indicated that the anti-apoptotic protein BCL-XL was targeted by let-7a-5p. BCL-XL was inhibited by FC-99 in order to induce monocyte apoptosis, leading to the impaired monocyte-to-macrophage differentiation. Murine acute liver failure was generated by caecal ligation puncture surgery after FC-99 administration; Blood samples and liver tissues were collected to determine the monocyte/macrophage subsets and the induction of apoptosis. Human acute monocytic leukemia cell line (THP-1) cells were pretreated with FC-99 followed by phorbol-12-myristate-13-acetate (PMA) stimulation, in order to induce monocyte-to-macrophage differentiation. The target of FC-99 and the mechanistic analyses were conducted by microarrays, qRT-PCR validation, TargetScan algorithms and a luciferase report assay. FC-99 exhibits potential therapeutic effects on CLP-induced liver dysfunction by restoring let-7a-5p levels.

The mysterious human epidermal cell cycle, or an oncogene-induced differentiation checkpoint

PubMed Central

Gandarillas, Alberto

2012-01-01

Fifteen years ago, we reported that proto-oncogene MYC promoted differentiation of human epidermal stem cells, a finding that was surprising to the MYC and the skin research communities. MYC was one of the first human oncogenes identified, and it had been strongly associated with proliferation. However, it was later shown that MYC could induce apoptosis under low survival conditions. Currently, the notion that MYC promotes epidermal differentiation is widely accepted, but the cell cycle mechanisms that elicit this function remain unresolved. We have recently reported that keratinocytes respond to cell cycle deregulation and DNA damage by triggering terminal differentiation. This mechanism might constitute a homeostatic protection face to cell cycle insults. Here, I discuss recent and not-so-recent evidence suggesting the existence of a largely unexplored oncogene-induced differentiation response (OID) analogous to oncogene-induced apoptosis (OIA) or senescence (OIS). In addition, I propose a model for the role of the cell cycle in skin homeostasis maintenance and for the dual role of MYC in differentiation. PMID:23114621

Comparison of two real-time RT-PCR assays for differentiation of C-strain vaccinated from classical swine fever infected pigs and wild boars.

PubMed

Widén, F; Everett, H; Blome, S; Fernandez Pinero, J; Uttenthal, A; Cortey, M; von Rosen, T; Tignon, M; Liu, L

2014-10-01

Classical swine fever is one of the most important infectious diseases for the pig industry worldwide due to its economic impact. Vaccination is an effective means to control disease, however within the EU its regular use is banned owing to the inability to differentiate infected and vaccinated animals, the so called DIVA principle. This inability complicates monitoring of disease and stops international trade thereby limiting use of the vaccine in many regions. The C-strain vaccine is safe to use and gives good protection. It is licensed for emergency vaccination in the EU in event of an outbreak. Two genetic assays that can distinguish between wild type virus and C-strain vaccines have recently been developed. Here the results from a comparison of these two real-time RT-PCR assays in an interlaboratory exercise are presented. Both assays showed similar performance. Copyright © 2014 Elsevier Ltd. All rights reserved.

Heat Shock Protein Augmentation of Angelica gigas Nakai Root Hot Water Extract on Adipogenic Differentiation in Murine 3T3-L1 Preadipocytes

PubMed Central

Lumbera, Wenchie Marie L.; dela Cruz, Joseph; Yang, Seung-Hak; Hwang, Seong Gu

2016-01-01

There is a high association of heat shock on the alteration of energy and lipid metabolism. The alterations associated with thermal stress are composed of gene expression changes and adaptation through biochemical responses. Previous study showed that Angelica gigas Nakai (AGN) root extract promoted adipogenic differentiation in murine 3T3-L1 preadipocytes under the normal temperature condition. However, its effect in heat shocked 3T3-L1 cells has not been established. In this study, we investigated the effect of AGN root hot water extract in the adipogenic differentiation of murine 3T3-L1 preadipocytes following heat shock and its possible mechanism of action. Thermal stress procedure was executed within the same stage of preadipocyte confluence (G0) through incubation at 42°C for one hour and then allowed to recover at normal incubation temperature of 37°C for another hour before AGN treatment for both cell viability assay and Oil Red O. Cell viability assay showed that AGN was able to dose dependently (0 to 400 μg/mL) increase cell proliferation under normal incubation temperature and also was able to prevent cytotoxicity due to heat shock accompanied by cell proliferation. Confluent preadipocytes were subjected into heat shock procedure, recovery and then AGN treatment prior to stimulation with the differentiation solution. Heat shocked preadipocytes exhibited reduced differentiation as supported by decreased amount of lipid accumulation in Oil Red O staining and triglyceride measurement. However, those heat shocked preadipocytes that then were given AGN extract showed a dose dependent increase in lipid accumulation as shown by both evaluation procedures. In line with these results, real-time polymerase chain reaction (RT-PCR) and Western blot analysis showed that AGN increased adipogenic differentiation by upregulating heat shock protection related genes and proteins together with the adipogenic markers. These findings imply the potential of AGN in heat shock amelioration among 3T3-L1 preadipocytes through heat shock factor and proteins augmentation and enhanced adipogenic marker expression. PMID:26950875

Heat Shock Protein Augmentation of Angelica gigas Nakai Root Hot Water Extract on Adipogenic Differentiation in Murine 3T3-L1 Preadipocytes.

PubMed

Lumbera, Wenchie Marie L; Dela Cruz, Joseph; Yang, Seung-Hak; Hwang, Seong Gu

2016-03-01

There is a high association of heat shock on the alteration of energy and lipid metabolism. The alterations associated with thermal stress are composed of gene expression changes and adaptation through biochemical responses. Previous study showed that Angelica gigas Nakai (AGN) root extract promoted adipogenic differentiation in murine 3T3-L1 preadipocytes under the normal temperature condition. However, its effect in heat shocked 3T3-L1 cells has not been established. In this study, we investigated the effect of AGN root hot water extract in the adipogenic differentiation of murine 3T3-L1 preadipocytes following heat shock and its possible mechanism of action. Thermal stress procedure was executed within the same stage of preadipocyte confluence (G0) through incubation at 42°C for one hour and then allowed to recover at normal incubation temperature of 37°C for another hour before AGN treatment for both cell viability assay and Oil Red O. Cell viability assay showed that AGN was able to dose dependently (0 to 400 μg/mL) increase cell proliferation under normal incubation temperature and also was able to prevent cytotoxicity due to heat shock accompanied by cell proliferation. Confluent preadipocytes were subjected into heat shock procedure, recovery and then AGN treatment prior to stimulation with the differentiation solution. Heat shocked preadipocytes exhibited reduced differentiation as supported by decreased amount of lipid accumulation in Oil Red O staining and triglyceride measurement. However, those heat shocked preadipocytes that then were given AGN extract showed a dose dependent increase in lipid accumulation as shown by both evaluation procedures. In line with these results, real-time polymerase chain reaction (RT-PCR) and Western blot analysis showed that AGN increased adipogenic differentiation by upregulating heat shock protection related genes and proteins together with the adipogenic markers. These findings imply the potential of AGN in heat shock amelioration among 3T3-L1 preadipocytes through heat shock factor and proteins augmentation and enhanced adipogenic marker expression.

7-(4-Hydroxyphenyl)-1-phenyl-4E-hepten-3-one, a Diarylheptanoid from Alpinia officinarum, Protects Neurons against Amyloid-β Induced Toxicity.

PubMed

Huang, Xiaojie; Tang, Genyun; Liao, Yumei; Zhuang, Xiaoji; Dong, Xiao; Liu, Hui; Huang, Xiao-Jun; Ye, Wen-Cai; Wang, Ying; Shi, Lei

2016-12-01

Amyloid-β (Aβ) is one of the major causative agents of Alzheimer's disease (AD), the most common neurodegenerative disorder characterized by progressive cognitive impairment. While effective drugs for AD are currently limited, identifying anti-Aβ compounds from natural products has been shown as a promising strategy which may lead to breakthroughs for new drug candidate discovery. We have previously reported that 7-(4-hydroxyphenyl)-1-phenyl-4E-hepten-3-one (AO-1), a diarylheptanoid extracted from the plant Alpinia officinarum, has strong effects on neuronal differentiation and neurite outgrowth in vitro and in vivo. The present study further uncovers that AO-1 exerts neuroprotective effects against the neurotoxicity caused by Aβ. Under the damage of Aβ oligomers, the major pathological forms of Aβ, dendrites of neurons become atrophic and simplified, but such impairments were substantially alleviated by AO-1 treatment. Moreover, AO-1 reduced apoptotic levels and oxidative stress triggered by Aβ. Further analysis showed that the anti-caspase and dendrite protective effects of AO-1 were dependent on activation of phosphatidylinositol 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) pathways. These findings collectively identify AO-1 as a beneficial compound to ameliorate the deleterious effects of Aβ on dendrite integrity and cell survival, and may provide new insights on drug discovery of AD.

Stromal cell derived factor-1alpha protects stem cell derived insulin-producing cells from glucotoxicity under high glucose conditions in-vitro and ameliorates drug induced diabetes in rats

PubMed Central

2013-01-01

Background Diabetes mellitus is affecting more than 300 million people worldwide. Current treatment strategies cannot prevent secondary complications. Stem cells due to their regenerative power have long been the attractive target for the cell-based therapies. Mesenchymal stem cells (MSCs) possess the ability to differentiate into several cell types and to escape immune recognition in vitro. MSCs can be differentiated into insulin-producing cells (IPCs) and could be an exciting therapy for diabetes but problems like poor engraftment and survivability need to be confronted. It was hypothesized that stromal cell derived factor- 1alpha (SDF-1alpha) will enhance therapeutic potential of stem cell derived IPCs by increasing their survival and proliferation rate. Methods Novel culture conditions were developed to differentiate bone marrow derived mesenchymal stem cells (BMSCs) into IPCs by using endocrine differentiation inducers and growth factors via a three stage protocol. In order to enhance their therapeutic potential, we preconditioned IPCs with SDF-1alpha. Results Our results showed that SDF-1alpha increases survival and proliferation of IPCs and protects them from glucotoxicity under high glucose conditions in vitro. SDF-1alpha also enhances the glucose responsive insulin secretion in IPCs in vitro. SDF-1alpha preconditioning reverses hyperglycemia and increase serum insulin in drug induced diabetic rats. Conclusions The differentiation of BMSCs into IPCs and enhancement of their therapeutic potential by SDF-1alpha preconditioning may contribute to cell based therapies for diabetes. PMID:23648189

Bergamot essential oil differentially modulates intracellular Ca2+ levels in vascular endothelial and smooth muscle cells: a new finding seen with fura-2.

PubMed

You, Ji H; Kang, Purum; Min, Sun Seek; Seol, Geun Hee

2013-04-01

In this study, we compared the effect of the essential oil of Citrus bergamia Risso [bergamot, bergamot essential oil (BEO)] on the intracellular Ca levels in vascular endothelial (EA) and mouse vascular smooth muscle (MOVAS) cells, using the fura-2 fluorescence technique. BEO caused an initial transient increase in intracellular Ca concentration ([Ca]i) in EA cells, followed by a decrease, whereas it induced a sustained increase in [Ca]i in MOVAS cells. Linalyl acetate (LA) as a major component of BEO-induced [Ca]i mobilization was similar to BEO in EA cells. The increase of [Ca]i by LA was higher in EA cells than in MOVAS cells. [Ca]i rise induced by extracellular Ca application was significantly blocked by BEO or LA in EA cells but not in MOVAS cells, suggesting that BEO and LA block Ca influx in EA cells. The present results suggest that BEO and LA differentially modulate intracellular Ca levels in vascular endothelial and smooth muscle cells. In addition, blockade of Ca influx by BEO and LA in EA cells may explain the protective effects of BEO on endothelial dysfunction associated with cardiovascular disease.

Comparative proteomic analysis reveals the positive effect of exogenous spermidine on photosynthesis and salinity tolerance in cucumber seedlings.

PubMed

Sang, Ting; Shan, Xi; Li, Bin; Shu, Sheng; Sun, Jin; Guo, Shirong

2016-08-01

Our results based on proteomics data and physiological alterations proposed the putative mechanism of exogenous Spd enhanced salinity tolerance in cucumber seedlings. Current studies showed that exogenous spermidine (Spd) could alleviate harmful effects of salinity. It is important to increase our understanding of the beneficial physiological responses of exogenous Spd treatment, and to determine the molecular responses underlying these responses. Here, we combined a physiological analysis with iTRAQ-based comparative proteomics of cucumber (Cucumis sativus L.) leaves, treated with 0.1 mM exogenous Spd, 75 mM NaCl and/or exogenous Spd. A total of 221 differentially expressed proteins were found and involved in 30 metabolic pathways, such as photosynthesis, carbohydrate metabolism, amino acid metabolism, stress response, signal transduction and antioxidant. Based on functional classification of the differentially expressed proteins and the physiological responses, we found cucumber seedlings treated with Spd under salt stress had higher photosynthesis efficiency, upregulated tetrapyrrole synthesis, stronger ROS scavenging ability and more protein biosynthesis activity than NaCl treatment, suggesting that these pathways may promote salt tolerance under high salinity. This study provided insights into how exogenous Spd protects photosynthesis and enhances salt tolerance in cucumber seedlings.

CFHR1-Modified Neural Stem Cells Ameliorated Brain Injury in a Mouse Model of Neuromyelitis Optica Spectrum Disorders.

PubMed

Shi, Kaibin; Wang, Zhen; Liu, Yuanchu; Gong, Ye; Fu, Ying; Li, Shaowu; Wood, Kristofer; Hao, Junwei; Zhang, Guang-Xian; Shi, Fu-Dong; Yan, Yaping

2016-11-01

A major hurdle for effective stem cell therapy is ongoing inflammation in the target organ. Reconditioning the lesion microenvironment may be an effective way to promote stem cell therapy. In this study, we showed that engineered neural stem cells (NSCs) with complement factor H-related protein 1, a complement inhibitor protein, can attenuate inflammatory infiltration and immune-mediated damage of astrocytes, an important pathogenic progress in patients with neuromyelitis optica spectrum disorders. Furthermore, we demonstrated that transplantation of the complement factor H-related protein 1-modified NSCs effectively blocked the complement activation cascade and inhibited formation of the membrane attack complex, thus contributing to the protection of endogenous and transplanted NSC-differentiated astrocytes. Therefore, manipulation of the lesion microenvironment contributes to a more effective cell replacement therapeutic strategy for autoimmune diseases of the CNS. Copyright © 2016 by The American Association of Immunologists, Inc.

Protective Effect of Cactus Cladode Extracts on Peroxisomal Functions in Microglial BV-2 Cells Activated by Different Lipopolysaccharides.

PubMed

Saih, Fatima-Ezzahra; Andreoletti, Pierre; Mandard, Stéphane; Latruffe, Norbert; El Kebbaj, M'Hammed Saïd; Lizard, Gérard; Nasser, Boubker; Cherkaoui-Malki, Mustapha

2017-01-07

In this study, we aimed to evaluate the antioxidant and anti-inflammatory properties of Opuntia ficus-indica cactus cladode extracts in microglia BV-2 cells. Inflammation associated with microglia activation in neuronal injury can be achieved by LPS exposure. Using four different structurally and biologically well-characterized LPS serotypes, we revealed a structure-related differential effect of LPS on fatty acid β-oxidation and antioxidant enzymes in peroxisomes: Escherichia coli -LPS decreased ACOX1 activity while Salmonella minnesota -LPS reduced only catalase activity. Different cactus cladode extracts showed an antioxidant effect through microglial catalase activity activation and an anti-inflammatory effect by reducing nitric oxide (NO) LPS-dependent production. These results suggest that cactus extracts may possess a neuroprotective activity through the induction of peroxisomal antioxidant activity and the inhibition of NO production by activated microglial cells.

Influence of HLA-C Expression Level on HIV Control

PubMed Central

Apps, Richard; Qi, Ying; Carlson, Jonathan M.; Chen, Haoyan; Gao, Xiaojiang; Thomas, Rasmi; Yuki, Yuko; Del Prete, Greg Q.; Goulder, Philip; Brumme, Zabrina L.; Brumme, Chanson J.; John, Mina; Mallal, Simon; Nelson, George; Bosch, Ronald; Heckerman, David; Stein, Judy L.; Soderberg, Kelly A.; Moody, M. Anthony; Denny, Thomas N.; Zeng, Xue; Fang, Jingyuan; Moffett, Ashley; Lifson, Jeffrey D.; Goedert, James J.; Buchbinder, Susan; Kirk, Gregory D.; Fellay, Jacques; McLaren, Paul; Deeks, Steven G.; Pereyra, Florencia; Walker, Bruce; Michael, Nelson L.; Weintrob, Amy; Wolinsky, Steven; Liao, Wilson; Carrington, Mary

2013-01-01

A variant upstream of human leukocyte antigen C (HLA-C) shows the most significant genome-wide effect on HIV control in European Americans and is also associated with the level of HLA-C expression. We characterized the differential cell surface expression levels of all common HLA-C allotypes and tested directly for effects of HLA-C expression on outcomes of HIV infection in 5243 individuals. Increasing HLA-C expression was associated with protection against multiple outcomes independently of individual HLA allelic effects in both African and European Americans, regardless of their distinct HLA-C frequencies and linkage relationships with HLA-B and HLA-A. Higher HLA-C expression was correlated with increased likelihood of cytotoxic T lymphocyte responses and frequency of viral escape mutation. In contrast, high HLA-C expression had a deleterious effect in Crohn’s disease, suggesting a broader influence of HLA expression levels in human disease. PMID:23559252