bluuebunny/crossref_metadata_2025 huggingface dataset:
Achieving Healthy School Siting and Planning Policies: Understanding Shared Concerns of Environmental Planners, Public Health Professionals, and Educators
Authors: Cohen Alison
Published: April 2010

Policy decisions regarding the quality of the physical school environment—both, school siting and school facility planning policies—are often considered through the lens of environmental planning, public health, or education policy, but rarely through all three. Environmental planners consider environmental justice issues on a local level and/or consider the regional impact of a school. Public health professionals focus on toxic exposures and populations particularly vulnerable to negative health outcomes. Educators and education policymakers emphasize investing in human capital of both students and staff. By understanding these respective angles and combining these efforts around the common goals of achieving adequacy and excellence, we can work toward a regulatory system for school facilities that recognizes children as a uniquely vulnerable population and seeks to create healthier school environments in which children can learn and adults can work.
Surveillance of Nail Gun Injuries by Journeymen Carpenters Provides Important Insight into Experiences of Apprentices
Authors: Lipscomb Hester , Nolan James , Patterson Dennis , Dement John M.
Published: April 2010

Experienced journeymen conducted detailed surveillance interviews with injured apprentice carpenters ( n = 413). Nail gun injuries commonly occurred due to inadvertent discharge, ricocheting or projectile nails, and penetration of the wood surface. Framing nailers with contact trip triggers were most often involved; these triggers allow nail discharge anytime the trigger and nose piece are both depressed including following recoil of the tool after firing. Injured workers made concrete and practical suggestions for prevention. Scenarios were identified where changes in work practice, safer triggers, and thoughtful training could prevent injuries. Most injuries were not reported through workers' compensation; this was often due to perceived lack of injury severity, but also involved subtle as well as overt pressures on apprentices not to report. These case-based analyses are consistent with reports that many injuries from nail guns could be prevented with existing safer trigger mechanisms and training. Efforts should also focus on improved injury reporting.
PCBs in School—Persistent Chemicals, Persistent Problems
Authors: Herrick Robert F.
Published: April 2010

The issue of polychlorinated biphenyls (PCB) exposures resulting from occupancy of PCB-contaminated buildings is not new, but the contribution of building materials to that contamination is largely unrecognized. A rapidly emerging base of evidence shows that PCBs can be widely found in caulking and paint in masonry buildings constructed or renovated from about 1950 to the late 1970s. These materials can cause extensive PCB contamination of the building interiors and surrounding soil, and people who teach, live, or attend school in these buildings can have elevated serum PCB levels. The potential risk associated with this source of PCB exposure is not known; however, it is worth noting that the specific PCB congeners found at high levels in the building environments, and in biological samples from the occupants, include some that are suspected of being potent neurotoxins. The U.S. Environmental Protection Agency (EPA) is moving to address this issue in schools; however, the costs of remediating contaminated buildings will pose a formidable obstacle to most school districts.
Negotiating Indoor Air—Case Report on Negotiation of Teachers' Union, School Board on Air Contaminants
Authors: Gibson Sarah , Levenstein Charles
Published: April 2010

School districts increasingly understand the need for an indoor air quality plan, but may have difficulty in producing a plan that all necessary parties will accept. This article provides a case study of how one Massachusetts school district, after experiencing environmental problems in an elementary school, worked with parents and unions to develop a comprehensive indoor air quality plan.
“Serving Two Masters”—An Interview with School Teacher and Union Organizer Debra Askwith
Authors: Scammell Madeleine Kangsen , Rodrigues Ema
Published: April 2010

Debra Askwith is a teacher, union member, and environmental health and safety activist in the public schools of Springfield, Massachusetts. In the following interview, she talks about her experiences organizing around the right to public information as a teacher and aunion member. Working with the assistance of lawyers, she has learned to maneuver in the hierarchy of city and school administrators as well as the city's department of education, finding allies and meeting resistance in a variety of places. She has worked on asbestos, mold, indoor air quality, infectious disease, and civil rights to protect all students and workers.
Physico-mechanical properties of rubber seed shell carbon: Filled natural rubber compounds
Authors: Ekebafe L.O. , Imanah J.E. , Okieimen F.E.
Published: April 2010

Samples of rubber seed shells were carbonized at varying temperatures (100, 200, 300, 400, 500, 600, 700, 800?C) for three hours each and sieved through 150?m screen. The portion of the rubber seed shell carbon that passed through the screen was characterized in terms of loss on ignition, surface area, moisture content, pH, bulk density, and metal content and used in compounding natural rubber. The characterization shows that the pH, conductivity, loss on ignition and the surface area increases as the heating temperature increases, unlike the bulk density which decreases. The compound mixes were cured using efficient vulcanization system. Cure characteristics and physico-mechanical properties of the vulcanisates were measured as a function of filler loading along with that of N330 carbon-black filled natural rubber vulcanisate. The results of the cure characteristics showed that the cure times, scorch times and the torque gradually increased, with increasing filler content for rubber seed shell carbon-filled natural rubber, with filler obtained at carbonizing temperature of 600?C tending to show optimum cure indices. The physico-mechanical properties of the vulcanisates increase with filler loading. The reinforcing potential of the carbonized rubber seed shell carbon was found to increase markedly for the filler obtained at the temperature range 500-600?C and then decrease with further increase in temperature.
Sitagliptin (MK0431) Inhibition of Dipeptidyl Peptidase IV Decreases Nonobese Diabetic Mouse CD4+ T-Cell Migration Through Incretin-Dependent and -Independent Pathways
Authors: Kim Su-Jin , Nian Cuilan , McIntosh Christopher H.S.
Published: April 2010

OBJECTIVE

Treatment of NOD mice with the dipeptidyl peptidase-IV (DPP-IV) inhibitor sitagliptin preserved islet transplants through a pathway involving modulation of splenic CD4+ T-cell migration. In the current study, effects of sitagliptin on migration of additional subsets of CD4+ T-cells were examined and underlying molecular mechanisms were further defined.

RESEARCH DESIGN AND METHODS

Effects of sitagliptin on migration of NOD mouse splenic, thymic, and lymph node CD4+ T-cells were determined. Signaling modules involved in DPP-IV-, Sitagliptin- and incretin-mediated modulation of CD4+ T-cell migration were studied using Western blot and Rac1 and nuclear factor-κB (NF-κB) activity assays.

RESULTS

Migration of splenic and lymph node CD4+ T-cells of diabetic NOD mice was reduced by sitagliptin treatment. In vitro treatment of splenic, but not thymic or lymph node CD4+ T-cells, from nondiabetic NOD mice with soluble (s) DPP-IV increased migration. Sitagliptin abolished sDPP-IV effects on splenic CD4+ T-cell migration, whereas incretins decreased migration of lymph node, but not splenic, CD4+ T-cells. Splenic CD4+ T-cells demonstrating increased in vitro migration in response to sDPP-IV and lymph node CD4+ T-cells that were nonresponsive to incretins selectively infiltrated islets of NOD mice, after injection. Sitagliptin decreases migration of splenic CD4+ T-cells through a pathway involving Rac1/vasodilator-stimulated phosphoprotein, whereas its inhibitory effects on the migration of lymph node CD4+ T-cells involve incretin-activation of the NF-κB pathway.

CONCLUSIONS

Benefits of sitagliptin treatment in diabetic NOD mice may be mediated through selective effects on subpopulations of T-cells that are related to autoimmunity.
Association of Testosterone and Sex Hormone–Binding Globulin With Metabolic Syndrome and Insulin Resistance in Men
Authors: Li Chaoyang , Ford Earl S. , Li Benyi , Giles Wayne H. , Liu Simin
Published: April 2010

OBJECTIVE

We sought to assess the associations of testosterones and sex hormone–binding globulin (SHBG) with metabolic syndrome and insulin resistance in men.

RESEARCH DESIGN AND METHODS

We defined metabolic syndrome according to the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Among men aged ≥20 years who participated in the Third National Health and Nutrition Examination Survey (n = 1,226), the Cox proportional hazards model was used to estimate the prevalence ratio and 95% CI of metabolic syndrome according to circulating concentrations of testosterones and SHBG.

RESULTS

After adjustment for age, race/ethnicity, smoking status, alcohol intake, physical activity level, LDL cholesterol, C-reactive protein, and insulin resistance, men in the first quartile (lowest) (prevalence ratio 2.16 [95% CI 1.53–3.06]) and second quartile of total testosterone (2.51 [1.86–3.37]) were more likely to have metabolic syndrome than men in the fourth quartile (highest, referent group) (P < 0.001 for linear trend). Similarly, men in the first quartile of SHBG (2.17 [1.32–3.56]) were more likely to have metabolic syndrome than men in the fourth quartile (P = 0.02 for linear trend). No significant associations of calculated free testosterone (P = 0.31 for linear trend) and bioavailable testosterone (P = 0.11 for linear trend) with metabolic syndrome were detected after adjustment for all possible confounders.

CONCLUSIONS

Low concentrations of total testosterone and SHBG were strongly associated with increased likelihood of having metabolic syndrome, independent of traditional cardiovascular risk factors and insulin resistance.
The Importance of Caloric Restriction in the Early Improvements in Insulin Sensitivity After Roux-en-Y Gastric Bypass Surgery
Authors: Isbell James M. , Tamboli Robyn A. , Hansen Erik N. , Saliba Jabbar , Dunn Julia P. , Phillips Sharon E. , Marks-Shulman Pamela A. , Abumrad Naji N.
Published: April 2010

OBJECTIVE

Many of the metabolic benefits of Roux-en-Y gastric bypass (RYGB) occur before weight loss. In this study we investigated the influence of caloric restriction on the improvements in the metabolic responses that occur within the 1st week after RYGB.

RESEARCH METHODS AND DESIGN

A mixed meal was administered to nine subjects before and after RYGB (average 4 ± 0.5 days) and to nine matched, obese subjects before and after 4 days of the post-RYGB diet.

RESULTS

Weight loss in both groups was minimal; the RYGB subjects lost 1.4 ± 5.3 kg (P = 0.46) vs. 2.2 ± 1.0 kg (P = 0.004) in the calorically restricted group. Insulin resistance (homeostasis model assessment of insulin resistance) improved with both RYGB (5.0 ± 3.1 to 3.3 ± 2.1; P = 0.03) and caloric restriction (4.8 ± 4.1 to 3.6 ± 4.1; P = 0.004). The insulin response to a mixed meal was blunted in both the RYGB and caloric restriction groups (113 ± 67 to 65 ± 33 and 85 ± 59 to 65 ± 56 nmol · l−1 · min−1, respectively; P < 0.05) without a change in the glucose response. Glucagon-like peptide 1 levels increased (9.2 ± 8.6 to 12.2 ± 5.5 pg · l−1 · min−1; P = 0.04) and peaked higher (45.2 ± 37.3 to 84.8 ± 33.0 pg/ml; P = 0.01) in response to a mixed meal after RYGB, but incretin responses were not altered after caloric restriction.

CONCLUSIONS

These data suggest that an improvement in insulin resistance in the 1st week after RYGB is primarily due to caloric restriction, and the enhanced incretin response after RYGB does not improve postprandial glucose homeostasis during this time.
Antidepressant Use Before and After the Diagnosis of Type 2 Diabetes
Authors: Kivimäki Mika , Tabák Adam G. , Lawlor Debbie A. , Batty G. David , Singh-Manoux Archana , Jokela Markus , Virtanen Marianna , Salo Paula , Oksanen Tuula , Pentti Jaana , Witte Daniel R. , Vahtera Jussi
Published: April 2010

OBJECTIVE

To examine antidepressant use before and after the diagnosis of diabetes.

RESEARCH DESIGN AND METHODS

This study was a longitudinal analysis of diabetic and nondiabetic groups selected from a prospective cohort study of 151,618 men and women in Finland (the Finnish Public Sector Study, 1995–2005). We analyzed the use of antidepressants in those 493 individuals who developed type 2 diabetes and their 2,450 matched nondiabetic control subjects for each year during a period covering 4 years before and 4 years after the diagnosis. For comparison, we undertook a corresponding analysis on 748 individuals who developed cancer and their 3,730 matched control subjects.

RESULTS

In multilevel longitudinal models, the odds ratio for antidepressant use in those who developed diabetes was 2.00 (95% CI 1.57–2.55) times greater than that in nondiabetic subjects. The relative difference in antidepressant use between these groups was similar before and after the diabetes diagnosis except for a temporary peak in antidepressant use at the year of the diagnosis (OR 2.66 [95% CI 1.94–3.65]). In incident cancer case subjects, antidepressant use substantially increased after the cancer diagnosis, demonstrating that our analysis was sensitive for detecting long-term changes in antidepressant trajectories when they existed.

CONCLUSIONS

Awareness of the diagnosis of type 2 diabetes may temporarily increase the risk of depressive symptoms. Further research is needed to determine whether more prevalent use of antidepressants noted before the diagnosis of diabetes relates to effects of depression, side effects of antidepressant use, or a common causal pathway for depression and diabetes.
Maternal Family History of Diabetes Is Associated With a Reduced Risk of Cardiovascular Disease in Women With Type 2 Diabetes
Authors: Bruce David G. , Van Minnen Kylie , Davis Wendy A. , Mudhar Jaspreet , Perret Michael , Subawickrama Dayani P. , Venkitachalam Stephanie , Ravine David , Davis Timothy M.E.
Published: April 2010

OBJECTIVE

To investigate whether parental family history of diabetes influences cardiovascular outcomes in type 2 diabetes.

RESEARCH DESIGN AND METHODS

We studied 1,294 type 2 diabetic patients (mean age 64.1 years, 51.2% female) recruited to a community-based cohort study from 1993 to 1996 and followed until mid-2006. A data linkage system assessed all-cause and cardiac mortality, incident myocardial infarction, and stroke. Cox proportional hazards modeling was used to determine the influence of maternal or paternal family history on these outcomes.

RESULTS

A maternal family history of diabetes was reported by 20.4% of the cohort, 8.3% reported paternal family history, and 2.0% reported both parents affected. Maternal and paternal family history was associated with earlier age of diabetes onset, and maternal family history was associated with worse glycemic control. For all patients, maternal family history was significantly associated with reduced risk of all-cause mortality and cardiac mortality. When analyzed by sex, maternal family history had no effect on male patients, whereas female patients with diabetic mothers had significantly reduced hazard ratios for death from all causes (0.63 [95% CI 0.41–0.96]; P = 0.033), for death from cardiac causes (0.32 [0.14–0.72]; P = 0.006), and for first myocardial infarction (0.45 [0.26–0.76]; P = 0.003). Paternal family history status was not associated with these outcomes.

CONCLUSIONS

A maternal family history of diabetes confers relative protection against cardiovascular disease in female patients but not in male patients with type 2 diabetes. Paternal family history is associated with risks equivalent to those without a family history of diabetes. Some of the clinical heterogeneity of type 2 diabetes is related to maternal transmission effects with differential impact on male and female patients.
Refraining Individual Responsibility for Sustainable Consumption: Lessons from Environmental Justice and Ecological Citizenship
Authors: Middlemiss Lucie
Published: April 2010

In this paper I consider the concept of responsibility within sustainable consumption. The paper was inspired by interviews with individuals engaged in community action for sustainability, where respondents held a rather individualistic conception of responsibility. In order to develop a deeper understanding of responsibility I compare sustainable consumption, environmental justice and ecological citizenship literatures. This leads me to develop a new conceptual framework which explains responsibility in relation to the ecological footprint. This framework recognises both the responsibility of the individual for sustainable practice and the limitations on individual action due to their context. It also allows for differentiation between individuals’ responsibilities given people's circumstances and their ability to engage with change.
Morality and Climate Change: Is Leaving your TV on Standby a Risky Behaviour?
Authors: Butler Catherine
Published: April 2010

There is a growing literature which examines the ways in which individualised responsibilisation of ‘risky behaviours’ also entails moralisation. In UK discourses about climate change, certain individualised behaviours (e.g. leaving appliances on standby) are designated as responsible and/or good and correspondingly as irresponsible and/or bad. In this context, the decision to engage or not engage in these types of behaviour can be seen as becoming increasingly moralised. Drawing on focus group discussions with members of the British lay public (participant n96), this paper brings together public(s) (re)production of and negotiated responses to the moral undertones of this aspect of climate change discourse with theories of risk, morality and responsibility to develop important insights for conceptualising climate change mitigation.
Person-Affecting Moral Theory, Non-Identity and Future People
Authors: Huseby Robert
Published: April 2010

Many of our actions will affect the welfare of future people. For instance, continued emissions of greenhouse gases (GHG) may lead to future environmental degradation, which will negatively affect people's lives. If we continue GHG-emissions, are we harming future people? In light of the non-identity problem, apparently, we are not. This article assesses three recent attempts (by Carter, Page and Kumar) at grounding concern for future generations in person-affecting moral theory. Although these attempts are promising, the conclusion is that none is completely successful. It seems, then, that we have reason to incorporate a limited measure of consequentialism into person-affecting morality. More precisely, I suggest that we should adopt a version of telic sufficientarianism.
Wilderness as the Place between Philosophy and Theology: Questioning Martin Drenthen on the Otherness of Nature
Authors: Clingerman Forrest
Published: April 2010

This essay addresses how the idea of wilderness is a point of conversation between environmental philosophy and environmental theology. This topic is approached through a conversation with the environmental philosophy of Martin Drenthen. First, I discuss the respective aims of environmental philosophy and environmental theology. Second, I summarise the work of Drenthen on wilderness and otherness. Third, I compare this vision of environmental philosophy and a theological concept of Divine Otherness. Finally I sketch how this exploration is part of a theological account of wilderness. Taking seriously Drenthen's view that wilderness is the otherness at the intersection of nature and culture, wilderness can be understood as indicative of Divine Otherness. Thus wilderness is a unique place where theological and philosophical thinking traverse and challenge each other.
Journeying between Home and Nature: A Geo-Phenomenological Exploration and its Insights for Learning
Authors: Hung Ruyu
Published: April 2010

‘Home’ and ‘nature’ are usually taken as two opposite concepts in relation to human geographical experience. However, drawing on the perspective of geo-phenomenology, this paper argues that the meanings of nature and home overlap to the extent that it is possible to experience nature as home. Moreover, it can be shown from the paradoxically interwoven senses of nature and of home that there is a dynamic process of a to and fro journey between nature and home. Fertile educational implications can be drawn out from the invisible journey: first, the dynamic experience between nature and home elicits a learning about differences; and secondly, the experience of nature as home, which can inspire feelings for nature, implies an ethical dimension of learning to treat nature as carefully as home.
Cytokine Secretion Is Distinct from Secretion of Cytotoxic Granules in NK Cells
Authors: Reefman Esther , Kay Jason G. , Wood Stephanie M. , Offenhäuser Carolin , Brown Darren L. , Roy Sandrine , Stanley Amanda C. , Low Pei Ching , Manderson Anthony P. , Stow Jennifer L.
Published: April 2010

NK cells are renowned for their ability to kill virally infected or transformed host cells by release of cytotoxic granules containing granzymes and perforin. NK cells also have important regulatory capabilities chiefly mediated by secretion of cytokines, such as IFN-γ and TNF. The secretory pathway for the release of cytokines in NK cells is unknown. In this study, we show localization and trafficking of IFN-γ and TNF in human NK cells in compartments and vesicles that do not overlap with perforin or other late endosome granule markers. Cytokines in post-Golgi compartments colocalized with markers of the recycling endosome (RE). REs are functionally required for cytokine release because inactivation of REs or mutation of RE-associated proteins Rab11 and vesicle-associated membrane protein-3 blocked cytokine surface delivery and release. In contrast, REs are not needed for release of perforin from preformed granules but may be involved at earlier stages of granule maturation. These findings suggest a new role for REs in orchestrating secretion in NK cells. We show that the cytokines IFN-γ and TNF are trafficked and secreted via a different pathway than perforin. Although perforin granules are released in a polarized fashion at lytic synapses, distinct carriers transport both IFN-γ and TNF to points all over the cell surface, including within the synapse, for nonpolarized release.
Differential but Direct Abolishment of Human Regulatory T Cell Suppressive Capacity by Various TLR2 Ligands
Authors: Oberg Hans-Heinrich , Ly Thi Thuy Hoa , Ussat Sandra , Meyer Tim , Kabelitz Dieter , Wesch Daniela
Published: April 2010

CD4+CD25high regulatory T cells (Tregs) control cellular immune responses and maintain peripheral tolerance. We investigated whether TLR2 ligands are able to abrogate Treg-induced suppression in humans based on different reports about effects of triacylated lipopeptide Pam3CSK4 in mice. Pretreatment of human Tregs with a mixture of TLR2 ligands Pam2CSK4, FSL-1, and Pam3CSK4 reduced the Treg-mediated suppression of CD4+CD25− responder T cells in the majority of the analyzed donors. Differential effects of individual TLR2 ligands are explained by usage of different TLR2 heterodimers in the recognition of Pam2CSK4, FSL-1, and Pam3CSK4. In contrast to the murine system, TLR2 ligand-mediated abrogation of human Treg function was not associated with a downregulation of FoxP3 transcription factor. Furthermore, our results excluded an effect of TLR2 ligands on granzyme A/B release by human Tregs as a potential mechanism to abolish Treg-mediated suppression. Our data suggest that a downregulation of p27Kip1 and restoration of Akt phosphorylation in human Tregs pretreated with TLR2 ligands result in a reversal of suppression on responder T cells. Moreover, our data indicate that a mixture of TLR2 ligands can be used to modulate human Treg activity.
Plasma Cells and Nonplasma B Cells Express Differing IgE Repertoires in Allergic Sensitization
Authors: Rogosch Tobias , Kerzel Sebastian , Sikula Larisa , Gentil Katrin , Liebetruth Michael , Schlingmann Karl-Peter , Maier Rolf F. , Zemlin Michael
Published: April 2010

The selection of allergen-specific B cells into the plasma cell (PC) pool is a critical step in the immune dysregulation that leads to the production of IgE in allergic diseases. We sought to characterize the murine IgE repertoire. In particular, we questioned whether the IgE repertoire of plasmablasts (PBs)/PCs differs from the IgE repertoire of non-PCs. Therefore, we sorted splenocytes from OVA-sensitized BALB/c mice into CD138pos (PBs/PCs) and CD19pos/CD138neg (non-PCs) B cell fractions. Using reverse transcription PCR, we amplified, cloned, and sequenced IgE mRNA transcripts and analyzed the Ig H chain repertoire. As a reference, we characterized the IgM repertoire of the same animals. Compared to IgM, the IgE sequences contained a significantly higher level of somatic mutations and displayed an oligoclonal expansion with clonotype restriction. Interestingly, we found two phenotypically distinct IgE-producing B cell subpopulations that differed in their repertoire of H chain transcripts; IgE transcripts from PBs/PCs showed significantly more signs of Ag-driven selection than transcripts from non-PCs, including 1) a higher number of somatic mutations, 2) increased clustering of replacement mutations in the CDRs, and 3) biased third CDR of the heavy Ig chain composition. In conclusion, PBs/PCs and non-PCs from OVA-sensitized mice express distinct IgE repertoires, suggesting that 1) the repertoire of IgE-expressing PBs/PCs represents a highly biased selection from the global B cell repertoire and 2) Ag-driven affinity maturation is a major force that selects IgE-producing B cells into the CD138pos PC pool.
Hypertonicity-Induced Expression of Monocyte Chemoattractant Protein-1 through a Novel Cis-Acting Element and MAPK Signaling Pathways
Authors: Kojima Ryoji , Taniguchi Hajime , Tsuzuki Aya , Nakamura Kanako , Sakakura Yumi , Ito Mikio
Published: April 2010

MCP1 is upregulated by various stimuli, including LPS, high glucose, and hyperosmolality. However, the molecular mechanisms of transcriptional regulation of the MCP1 gene under hyperosmolar conditions are poorly understood. Treatment of NRK52E cells with NaCl or mannitol resulted in significant elevation of MCP1 mRNA and protein in a time- and dose-dependent manner. Treatment with a p38MAPK inhibitor (SB203580), an ERK inhibitor (PD98059), or an MEK inhibitor (U0126), suppressed the increase in MCP1 expression caused by hypertonic NaCl, whereas a JNK inhibitor (SP600125) and an AP1 inhibitor (curcumin) failed to attenuate MCP1 mRNA expression by NaCl. In the 5′-flanking region of the MCP1 gene, there is a sequence motif similar to the consensus TonE/ORE as well as the consensus C/E binding protein (BP), NF-κB, and AP1/Sp1 sites. Luciferase activity in cells transfected with reporter constructs containing a putative TonE/ORE element (MCP1-TonE/ORE) enhanced reporter gene expression under hypertonic stress. Results of electrophoretic gel mobility shift assay showed a slow migration of the MCP1-TonE/ORE probe, representing the binding of TonEBP/OREBP/NFAT5 to this enhancer element. These results indicate that the 5′-flanking region of MCP1 contains a hypertonicity-sensitive cis-acting element, MCP1-TonE/ORE, as a novel element in the MCP1 gene. Furthermore, p38MAPK and MEK–ERK pathways appear to be, at least in part, involved in hypertonic stress-mediated regulation of MCP1 expression through the MCP1-TonE/ORE.
A Threonine-Based Targeting Signal in the Human CD1d Cytoplasmic Tail Controls Its Functional Expression
Authors: Liu Jianyun , Shaji Daniel , Cho Sungyoo , Du Wenjun , Gervay-Hague Jacquelyn , Brutkiewicz Randy R.
Published: April 2010

CD1d molecules are MHC class I-like molecules that present lipids to a unique subpopulation of T cells called NKT cells. The cytoplasmic tail of human CD1d possesses a tyrosine-based endosomal targeting motif (YXXZ). As such, these molecules traffic through the endocytic pathway, where it is believed that they are loaded with the antigenic lipid that stimulates NKT cells. In the current study, it was found that the T322 residue in the human CD1d tail is a major signal controlling transport to the cell surface and thus its functional expression. Mimicking the phosphorylation of this residue or removal of the entire cytoplasmic tail negates its ability to regulate CD1d trafficking, resulting in lysosomal targeting and degradation. These results demonstrate an important role of a heretofore unknown signal in the cytoplasmic tail of CD1d that may have relevance to other type I integral membrane proteins that traverse through the endocytic pathway.
SHIP Influences Signals from CD48 and MHC Class I Ligands That Regulate NK Cell Homeostasis, Effector Function, and Repertoire Formation
Authors: Fortenbery Nicole R. , Paraiso Kim H. T. , Taniguchi Masaru , Brooks Colin , Ibrahim Leina , Kerr William G.
Published: April 2010

Previously, we showed that 2B4 is a dominant inhibitory receptor in SHIP-deficient NK cells that prevents efficient cytolysis of complex targets. We show in this study that 2B4 deficiency restores homeostatic control and cytolytic function to SHIP-deficient NK cells. However, 2B4−/−SHIP−/− NK cells still exhibit a profound disruption of their NK receptor repertoire and are compromised for induction of IFN-γ by several NK-activating receptors, including NKp46, NK.1.1, and NKG2D. In addition, we find that 2B4−/− NK cells have an extensively disrupted repertoire, including a supernormal frequency of NKp46+ NK cells. Consequently IFN-γ is induced on a much higher percentage of 2B4−/− NK cells following engagement of NKp46. We also find that both SHIP and 2B4 are required to prevent expression of Ly49B, a myeloid lineage MHC class I receptor not normally expressed by the NK lineage. Finally, when SHIP-deficient NK cells are on an H-2d background, they exhibit supernormal levels of Ly49A and possess normal cytolytic function against MHC-matched tumor targets and enhanced cytolysis of MHC mismatched tumor targets. However, despite normal or elevated cytolytic function, H2d SHIP−/− NK cells exhibit poor induction of IFN-γ like their H2b+ or 2B4−/− counterparts, demonstrating a uniform requirement for SHIP in induction of IFN-γ downstream of key NK activating receptors. These findings reveal a complex interplay of SHIP, 2B4, and MHC in the regulation of homeostasis, effector function, and repertoire formation in the NK cell lineage.
Human CD1D Gene Expression Is Regulated by LEF-1 through Distal Promoter Regulatory Elements
Authors: Chen Qiao-Yi , Zhang Tao , Pincus Seth H. , Wu Shixiu , Ricks David , Liu Donald , Sun Zhongsheng , Maclaren Noel , Lan Michael S.
Published: April 2010

CD1d-expressing cells present lipid Ag to CD1d-restricted NKT cells, which play an important role in immune regulation and tumor rejection. Lymphoid enhancer-binding factor-1 (LEF-1) is one of the regulators of the Wnt signaling pathway, which is a powerful regulator in cellular growth, differentiation, and transformation. There is little evidence connecting Wnt signaling to CD1d expression. In this study, we have identified LEF-1 as a regulator of the expression of the gene encoding the human CD1d molecule (CD1D). We found that LEF-1 binds specifically to the CD1D promoter. Overexpression of LEF-1 in K562 or Jurkat cells suppresses CD1D promoter activity and downregulates endogenous CD1D transcripts, whereas knockdown of LEF-1 using LEF-1–specific small interfering RNA increases CD1D transcripts in K562 and Jurkat cells but there are different levels of surface CD1d on these two cell types. Chromatin immunoprecipitation showed that the endogenous LEF-1 is situated at the CD1D promoter and interacts with histone deacetylase-1 to facilitate the transcriptional repressor activity. Knockdown of LEF-1 using small interfering RNA potentiates an acetylation state of histone H3/H4, supporting the notion that LEF-1 acts as a transcriptional repressor for the CD1D gene. Our finding links LEF-1 to CD1D and suggests a role of Wnt signaling in the regulation of the human CD1D gene.
Cell-Intrinsic Defects in the Proliferative Response of Antiviral Memory CD8 T Cells in Aged Mice upon Secondary Infection
Authors: Decman Vilma , Laidlaw Brian J. , DiMenna Lauren J. , Abdulla Sarah , Mozdzanowska Krystyna , Erikson Jan , Ertl Hildegund C. J. , Wherry E. John
Published: April 2010

Although previous studies have demonstrated delayed viral clearance and blunted effector T cell responses in aged mice during infection, memory CD8 T cells and especially secondary responses have received less attention. In this study, we show that modest differences in the number of memory CD8 T cells formed in aged versus young animals were associated with altered memory CD8 T cell differentiation. Aged immune mice had increased morbidity and mortality upon secondary viral challenge, suggesting changes in T cell immunity. Indeed, virus-specific memory CD8 T cells from aged mice showed substantially reduced proliferative expansion upon secondary infection using multiple challenge models. In addition, this defect in recall capacity of aged memory CD8 T cells was cell-intrinsic and persisted upon adoptive transfer into young mice. Thus, the poor proliferative potential of memory T cells and altered memory CD8 T cell differentiation could underlie age-related defects in antiviral immunity.
Gene Coexpression Analysis in Single Cells Indicates Lymphomyeloid Copriming in Short-Term Hematopoietic Stem Cells and Multipotent Progenitors
Authors: Gautreau Laetitia , Boudil Amine , Pasqualetto Valérie , Skhiri Lamia , Grandin Laure , Monteiro Marta , Jais Jean-Philippe , Ezine Sophie
Published: April 2010

Progressive restriction to a differentiation pathway results from both activation and silencing of particular gene expression programs. To identify the coexpression and the expression levels of regulatory genes during hematopoietic stem cell (HSC) differentiation toward the T cell branch, we applied a new single-cell RT-PCR technique to analyze the simultaneous expression of 13 genes in 9 functionally purified populations from the bone marrow and the thymus. We report in this paper that Lin−Sca1+ckit+ HSCs display, at the single-cell level, a homogeneous and high transcriptional activity as do early thymic progenitors. Moreover, the coexpression of lymphoid and myeloid genes is an early event detected in ∼30% of short-term HSC and most multipotent progenitors, suggesting novel sources for the generation of early thymic progenitors, common lymphoid progenitors (CLPs), and common myeloid progenitors. Loss of multipotency in Lin−Sca1+ckit+ cells directed to the lymphoid branch is characterized by Lmo2 and Gata2 gene expression downregulation. Indeed, highest levels of Gata2 expression are detected only in long-term and short-term HSC populations. Complete shutdown of Pu1 gene expression in all triple-negative (TN)3 stage thymic pre-T cells is indicative of total T cell commitment. Interestingly, this is also observed in 30% of TN2 cells and 25% of CLP in the bone marrow, suggesting a possible initiation of T cell engagement in TN2 and CLP. Also, our strategy highlights similar gene patterns among HSCs and intrathymic progenitors, proposing, therefore, that identical activation signals are maintained until further maturation and generation of CD4 and CD8 coreceptors bearing thymocytes.
Regulatory B Cells (B10 Cells) Have a Suppressive Role in Murine Lupus: CD19 and B10 Cell Deficiency Exacerbates Systemic Autoimmunity
Authors: Watanabe Rei , Ishiura Nobuko , Nakashima Hiroko , Kuwano Yoshihiro , Okochi Hitoshi , Tamaki Kunihiko , Sato Shinichi , Tedder Thomas F. , Fujimoto Manabu
Published: April 2010

B cells play critical roles in the pathogenesis of lupus. To examine the influence of B cells on disease pathogenesis in a murine lupus model, New Zealand Black and New Zealand White F1 hybrid (NZB/W) mice were generated that were deficient for CD19 (CD19−/− NZB/W mice), a B cell-specific cell surface molecule that is essential for optimal B cell signal transduction. The emergence of anti-nuclear Abs was significantly delayed in CD19−/− NZB/W mice compared with wild type NZB/W mice. However, the pathologic manifestations of nephritis appeared significantly earlier, and survival was significantly reduced in CD19−/− NZB/W mice compared with wild type mice. These results demonstrate both disease-promoting and protective roles for B cells in lupus pathogenesis. Recent studies have identified a potent regulatory B cell subset (B10 cells) within the rare CD1dhiCD5+ B cell subset of the spleen that regulates acute inflammation and autoimmunity through the production of IL-10. In wild type NZB/W mice, the CD1dhiCD5+B220+ B cell subset that includes B10 cells was increased by 2.5-fold during the disease course, whereas CD19−/− NZB/W mice lacked this CD1dhiCD5+ regulatory B cell subset. However, the transfer of splenic CD1dhiCD5+ B cells from wild type NZB/W mice into CD19−/− NZB/W recipients significantly prolonged their survival. Furthermore, regulatory T cells were significantly decreased in CD19−/− NZB/W mice, but the transfer of wild type CD1dhiCD5+ B cells induced T regulatory cell expansion in CD19−/− NZB/W mice. These results demonstrate an important protective role for regulatory B10 cells in this systemic autoimmune disease.
Protective and Pathogenic Roles for B Cells during Systemic Autoimmunity in NZB/W F1 Mice
Authors: Haas Karen M. , Watanabe Rei , Matsushita Takashi , Nakashima Hiroko , Ishiura Nobuko , Okochi Hitoshi , Fujimoto Manabu , Tedder Thomas F.
Published: April 2010

Delineating the relative contributions of B lymphocytes during the course of autoimmune disease has been difficult. Therefore, the effects of depleting all mature B cells using a potent CD20 mAb, or of depleting circulating and marginal zone B cells using a ligand-blocking CD22 mAb, were compared in NZB/W F1 mice, a model for human systemic lupus erythematosus. Single low-dose mAb treatments depleted B cells efficiently in both NZB/W F1 and C57BL/6 mice. Prophylactic B cell depletion by repeated CD20 mAb treatments prolonged survival during pristane-accelerated lupus in NZB/W F1 mice, whereas CD22 mAb had little effect. Despite effective B cell depletion, neither mAb treatment prevented autoantibody generation. In addition, CD20, CD22, and control mAb-treated NZB/W F1 mice developed anti-mouse IgG autoantibodies in contrast to parental NZB and NZW strains, which may have reduced the effectiveness of B cell depletion. Despite this, low-dose CD20 mAb treatment initiated in 12–28-wk-old mice, and administered every 4 wk thereafter, significantly delayed spontaneous disease in NZB/W F1 mice. By contrast, B cell depletion initiated in 4-wk-old mice hastened disease onset, which paralleled depletion of the IL-10–producing regulatory B cell subset called B10 cells. B10 cells were phenotypically similar in NZB/W F1 and C57BL/6 mice, but were expanded significantly in young NZB/W F1 mice. Thus, B cell depletion had significant effects on NZB/W F1 mouse survival that were dependent on the timing of treatment initiation. Therefore, distinct B cell populations can have opposing protective and pathogenic roles during lupus progression.
Keratinocyte-Associated B7-H1 Directly Regulates Cutaneous Effector CD8+ T Cell Responses
Authors: Ritprajak Patcharee , Hashiguchi Masaaki , Tsushima Fumihiko , Chalermsarp Narumon , Azuma Miyuki
Published: April 2010

Keratinocytes (KCs) may play important roles for maintenance of peripheral tolerance in the upper layers of the skin. Coinhibitory signals mediated via the programmed death (PD)-1 and its ligand B7-H1 (PD-L1/CD274) are crucial for the downregulation of T cell immune responses and for the maintenance of peripheral tolerance. In this study, to investigate the role of KC-expressed B7-H1 in the regulation of T cell immune responses, we generated transgenic (tg) mice overexpressing B7-H1 under the control of keratin 14 (K14) promoter (K14-B7-H1 tg). K14-B7-H1 tg mice displayed impaired contact hypersensitivity (CH) responses to primary and secondary hapten challenges. The K14-B7-H1 tg mice did not exhibit substantial impairment of cutaneous dendritic cell migration after sensitization and of hapten-specific proliferation and IFN-γ production of CD4+ and CD8+ T cells in the draining lymph nodes, suggesting that overexpression of B7-H1 on KCs did not affect the induction phase of the CH response. The systemic or s.c. injection of hapten-sensitized T cells into the K14-B7-H1 tg mice did not efficiently induce the CH response. IFN-γ expression and apoptosis of KCs in the challenged ears were impaired in K14-B7-H1 tg mice. IFN-γ production by presensitized CD8+ T cells stimulated with hapten-pulsed KCs was markedly impaired for the KCs obtained from the K14-B7-H1 tg mice but was restored by the addition of an anti–B7-H1 mAb. These results suggest that KC-associated B7-H1 directly downregulates the effector function of CD8+ T cells by associating with PD-1 at local inflammatory sites and that it plays a role in peripheral T cell tolerance against exogenous Ags.
Th17 Polarized Cells from Nonobese Diabetic Mice Following Mycobacterial Adjuvant Immunotherapy Delay Type 1 Diabetes
Authors: Nikoopour Enayat , Schwartz Jordan A. , Huszarik Katrina , Sandrock Christian , Krougly Olga , Lee-Chan Edwin , Singh Bhagirath
Published: April 2010

IL-17–producing T cells are regarded as potential pathogenic T cells in the induction of autoimmune diseases. Previously, we have shown that injection of adjuvants containing Mycobacterium, such as CFA or bacillus Calmette-Guérin, can prevent type 1 diabetes in NOD mice. We injected NOD mice with mycobacterial products s.c. and analyzed the IL-17–producing cells from the draining lymph nodes and spleen by restimulating whole-cell populations or CD4+ T cells in vitro with or without IL-17–polarizing cytokines. Mice receiving CFA had a concomitant rise in the level of IL-17, IL-22, IL-10, and IFN-γ in the draining lymph node and spleen. Adoptive transfer of splenocytes from CFA-injected NOD mice polarized with TGF-β plus IL-6 or IL-23 delayed the development of diabetes in recipient mice. IL-17–producing cells induced by CFA maintained their IL-17–producing ability in the recipient mice. Injection of CFA also changed the cytokine profile of cells in pancreatic tissue by increasing IL-17, IL-10, and IFN-γ cytokine gene expression. We suggest that the rise in the level of IL-17 after adjuvant therapy in NOD mice has a protective effect on type 1 diabetes development.
Docosahexaenoic Acid-Enriched Fish Oil Attenuates Kidney Disease and Prolongs Median and Maximal Life Span of Autoimmune Lupus-Prone Mice
Authors: Halade Ganesh V. , Rahman Md Mizanur , Bhattacharya Arunabh , Barnes Jeffrey L. , Chandrasekar Bysani , Fernandes Gabriel
Published: April 2010

The therapeutic efficacy of individual components of fish oils (FOs) in various human inflammatory diseases still remains unresolved, possibly due to low levels of n-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) or lower ratio of DHA to EPA. Because FO enriched with DHA (FO-DHA) or EPA (FO-EPA) has become available recently, we investigated their efficacy on survival and inflammatory kidney disease in a well-established animal model of human systemic lupus erythematosus. Results show for the first time that FO-DHA dramatically extends both the median (658 d) and maximal (848 d) life span of (NZB × NZW)F1 (B × W) mice. In contrast, FO-EPA fed mice had a median and maximal life span of ∼384 and 500 d, respectively. Investigations into possible survival mechanisms revealed that FO-DHA (versus FO-EPA) lowers serum anti-dsDNA Abs, IgG deposition in kidneys, and proteinuria. Further, FO-DHA lowered LPS-mediated increases in serum IL-18 levels and caspase-1–dependent cleavage of pro–IL-18 to mature IL-18 in kidneys. Moreover, FO-DHA suppressed LPS-mediated PI3K, Akt, and NF-κB activations in kidney. These data indicate that DHA, but not EPA, is the most potent n-3 fatty acid that suppresses glomerulonephritis and extends life span of systemic lupus erythematosus-prone short-lived B × W mice, possibly via inhibition of IL-18 induction and IL-18–dependent signaling.
Intercellular Adhesion Molecule-1 Enrichment near Tricellular Endothelial Junctions Is Preferentially Associated with Leukocyte Transmigration and Signals for Reorganization of These Junctions To Accommodate Leukocyte Passage
Authors: Sumagin Ronen , Sarelius Ingrid H.
Published: April 2010

Leukocyte transmigration occurs at specific locations (portals) on the endothelium, but the nature of these portals is not clear. Using intravital confocal microscopy of anesthetized mouse cremaster muscle in combination with immunofluorescence labeling, we showed that in microvessels transmigration is mainly junctional and preferentially occurs at tricellular endothelial junctional regions. Our data suggest that enrichment of ICAM-1 near ∼43% of these junctions makes these locations preferred for transmigration by signaling the location of a nearby portal, as well as preparing the endothelial cell (EC) junctions, to accommodate leukocyte passage. Blockade of the extracellular domain of the ICAM-1 significantly reduced transmigration (by 68.8 ± 4.5%) by reducing the ability of leukocytes to get to these portals. In contrast, blockade of the cytoplasmic tail of ICAM-1 reduced transmigration (by 71.1 ± 7.0%) by disabling VE-cadherin rearrangement. Importantly, venular convergences are optimally equipped to support leukocyte transmigration. Differences in EC morphology result in a significantly higher number of tricellular junctions in convergences compared with straight venular regions (20.7 ± 1.2 versus 12.43 ± 1.1/6000 μm2, respectively). Consequently, leukocyte adhesion and transmigration are significantly higher in convergences compared with straight regions (1.6- and 2.6-fold, respectively). Taken together, these data identify an important role for EC morphology and expression patterns of ICAM-1 in leukocyte transmigration.
Cutting Edge: Human Latency-Associated Peptide+ T Cells: A Novel Regulatory T Cell Subset
Authors: Gandhi Roopali , Farez Mauricio F. , Wang Yue , Kozoriz Deneen , Quintana Francisco J. , Weiner Howard L.
Published: April 2010

Regulatory T cells (Tregs) play an important role in the maintenance of peripheral tolerance. Several molecules including TGF-β have been linked to the function and differentiation of Tregs. In this study, we describe a unique population of T cells expressing a membrane bound form of TGF-β, the latency-associated peptide (LAP), and having regulatory properties in human peripheral blood. These CD4+LAP+ T cells lack Foxp3 but express TGF-βR type II and the activation marker CD69. CD4+LAP+ T cells are hypoproliferative compared with CD4+LAP− T cells, secrete IL-8, IL-9, IL-10, IFN-γ, and TGF-β upon activation, and exhibit TGF-β– and IL-10–dependent suppressive activity in vitro. The in vitro activation of CD4+LAP− T cells results in the generation of LAP+ Tregs, which is further amplified by IL-8. In conclusion, we have characterized a novel population of human LAP+ Tregs that is different from classic CD4+Foxp3+CD25high natural Tregs.