bluuebunny/crossref_metadata_2025_split huggingface dataset:
The battlefield of perforin/granzyme cell death pathways
Authors: Hoves Sabine , Trapani Joseph A , Voskoboinik Ilia 
Published: November 2009

Abstract
The review discusses the controversies in the field of cytotoxic lymphocyte secretory granule death pathways.
A pore-forming protein, PRF, and serine proteases, Grz, are key effector molecules of CL. These toxins are stored within secretory granules, which exocytose their contents in response to immune synapse formation between the CL and virus-infected or transformed target cell. There, PRF and Grz synergize to induce various apoptotic death pathways and to maintain immune homeostasis. Mechanistic aspects of the synergy and apoptotic mechanisms are still not fully understood, and the current review will address some of the hotly debated controversies in the field.
High Glucose Potentiates Collagen Synthesis and Bone Morphogenetic Protein-2-Induced Early Osteoblast Gene Expression in Rat Spinal Ligament Cells
Authors: Li Hai , Jiang Lei-Sheng , Dai Li-Yang 
Published: November 2009

Abstract
Type 2 diabetes mellitus (T2DM) is an independent risk factor for ossification of the posterior longitudinal ligament, but the mechanism is unclear. We isolated cells from rat cervical spine ligaments and studied the effects of high glucose on expression of osteoblast genes to provide insight into molecular mechanism. Using these cells, high glucose stimulated the synthesis of type I collagen and significantly potentiated expression of early osteoblast genes (Runx2; alkaline phosphatase, ALP; and osteopontin, OP) induced by bone morphogenetic protein-2 (BMP-2). Notably, these effects of high glucose were fully mimicked and augmented by H2O2, although blocked by the reactive oxygen species inhibitor N-acetyl cysteine. Furthermore, exposure of these cells to high glucose significantly suppressed the phosphorylation of p38MAPK while enhancing the phosphorylation of protein kinase C (PKC) in the cells. Consistent with these observations, an inhibitor of p38 augmented the potentiation of high glucose on BMP-2-induced early osteogenic gene expression, whereas the PKC inhibitor repressed the effect of high glucose on type I collagen synthesis of the cells. In conclusion, high glucose, via production of reactive oxygen species, subsequent activation of PKC, and inhibition of p38, enhances type I collagen synthesis and expression of early osteogenesis genes induced by BMP-2 in rat spinal ligament cells. Hyperglycemia may play an important role in the onset or progression of ossification of the posterior longitudinal ligament by promoting the responsiveness of ligament cells to osteogenic differentiation.
On the Confusion of Planck Feedback Parameters
Authors: Kimoto Kyoji 
Published: November 2009

The Planck feedback parameter Λ0 is the most fundamental quantity in the theory of global warming, because the surface temperature change ΔTs,0 is calculated by—(radiative forcing due to CO2 doubling)/Λ0 in the absence of feedbacks other than that of surface temperature change. The following three groups of Planck feedback parameters are found in the literature depending on the choice of temperature Ts and the outgoing long wave radiation (OLR) at the top of atmosphere in equation of Λ0 = −4OLR/Ts, which is derived from the Stefan-Boltzmann Law. GROUP A: Ts = 288K and OLR = 231–243W/m2 Λ0 = −3.21 − −3.37(W/m2)/K GROUP B: Ts = 255K and OLR = 242W/m2, Λ0 = −3.8(W/m2)/K GROUP C: Ts = 288K and OLR = 492–514W/m2 Λ0 = −6.8 – −7.1(W/m2)/K This study shows that Λ0 of GROUP C is a theoretically relevant choice for Ts and OLR, rather than those of GROUP A and GROUP B, while the IPCC adopted Λ0 of GROUP A. Although the surface temperature change Δ Ts is 3.0K with Λ0 = −3.21(W/m2)/K for CO2 doubling when lapse rate, water vapor, surface albedo and cloud feedbacks are included in the IPCC AR4, it is shown to be 0.5–0.75K with Λ0 = −6.8(W/m2)/K in the present study. Since the IPCC overestimates the threat of carbon dioxide by 4–6 times, the revaluation will be needed for the CO2 reduction policies in terms of cost and potential hazards.
The evolution of fertility expectations over the life course
Authors: Hayford Sarah R. 
Published: November 2009

Abstract
In low-fertility contexts, how many children people have is largely a product of how many children they want. However, the social, institutional, and individual factors that influence how many children people want are not well understood. In particular, there is scant evidence about how fertility expectations change over the life course. This article provides an empirical description of changes in women's expected fertility over the entire span of childbearing years. Using data from the National Longitudinal Survey of Youth, 1979 cohort, group-based trajectory analysis illuminates common patterns in the evolution of fertility intentions and identifies individual characteristics associated with these patterns. Factors related to family formation, such as marriage and whether a woman has a child at an early age, are found to be the most consistent correlates of patterns of change in expected family size.
The increasing risk of poverty across the American life course
Authors: Sandoval Daniel A. , Rank Mark R. , Hirschl Thomas A. 
Published: November 2009

Abstract
This article extends the emerging body of life course research on poverty by empirically identifying the incidence, chronicity, and age pattern of American poverty and how these dimensions have changed during the period 1968-2000. Using the Panel Study of Income Dynamics, we construct a series of life tables that estimate the risk of poverty for adults during their 20s, 30s, 40s, 50s, 60s, and 70s, and compare these estimates for Americans in the 1970s, 1980s, and 1990s. Our empirical results suggest that the risk of acute poverty increased substantially, particularly in the 1990s. This observed increase was especially pronounced for individuals in their 20s, 30s, and 40s; for all age groups with respect to extreme poverty; and for white males. On the other hand, the risk of chronic poverty declined during the 1990s (as measured by the percentage of the poor who experienced five or more years of poverty within a 10-year interval). The results in this article tell a very different story than the Census Bureau's yearly cross-sectional rates, which have shown little overall change in the U.S. poverty rate during this 30-year period. In contrast, a life course approach reveals a rising economic risk of acute poverty for individuals, one that is consistent with recent observations and research suggesting that a growing number of Americans will eventually find themselves in an economically precarious position.
Use of phenol red thread tests to evaluate tear production in clinically normal Amazon parrots and comparison with Schirmer tear test findings
Authors: Storey Eric S. , Carboni Deborah A. , Kearney Michael T. , Tully Thomas N. 
Published: November 2009

Abstract
Objective—To determine phenol red thread test (PRTT) values in eyes of clinically normal Hispaniolan Amazon parrots before and after topical application of an ophthalmic anesthetic agent and compare findings with Schirmer tear test (STT) values.
Design—Evaluation study.
Animals—24 Amazona ventralis parrots from a research colony.
Procedures—On 4 occasions (1-week intervals), all birds underwent a thorough ophthalmic examination of both eyes, which included (in sequence) performance of a PRTT and an STT; topical ocular application of proparacaine hydrochloride; and performance of another PRTT and another STT. Correlations between PRTT and STT values recorded with and without topical anesthesia were assessed.
Results—Without topical anesthesia, mean ± SD PRTT value was 12.5 ± 5.0 mm/15 s (range, 1 to 25 mm/15 s). With topical anesthesia, the PRTT value was 12.6 ± 5.4 mm/15 s (range, 2 to 24 mm/15 s). Without topical anesthesia, mean STT value was 7.9 ± 2.6 mm/min (range, 0 to 13 mm/min). With topical anesthesia, the STT value was 5.1 ± 3.3 mm/min (range, 0 to 18 mm/min). The correlation of PRTT and STT values recorded with or without topical anesthesia was weak (r = 0.51 and r = 0.32, respectively).
Conclusions and Clinical Relevance—Results indicated that the PRTT and STT were both viable methods for measurement of tear production in Hispaniolan Amazon parrots. Topical application of an ophthalmic anesthetic agent did not have a significant effect on the PRTT values but significantly decreased the STT values.
Evaluation of deafness in American Paint Horses by phenotype, brainstem auditory-evoked responses, and endothelin receptor B genotype
Authors: Magdesian K. Gary , Williams D. Colette , Aleman Monica , LeCouteur Richard A. , Madigan John E. 
Published: November 2009

Abstract
Objective—To evaluate deafness in American Paint Horses by phenotype, clinical findings, brainstem auditory-evoked responses (BAERs), and endothelin B receptor (EDNBR) genotype.
Design—Case series and case-control studies.
Animals—14 deaf American Paint Horses, 20 suspected-deaf American Paint Horses, and 13 nondeaf American Paint Horses and Pintos.
Procedures—Horses were categorized on the basis of coat color pattern and eye color. Testing for the EDNBR gene mutation (associated with overo lethal white foal syndrome) and BAERs was performed. Additional clinical findings were obtained from medical records.
Results—All 14 deaf horses had loss of all BAER waveforms consistent with complete deafness. Most horses had the splashed white or splashed white–frame blend coat pattern. Other patterns included frame overo and tovero. All of the deaf horses had extensive head and limb white markings, although the amount of white on the neck and trunk varied widely. All horses had at least 1 partially heterochromic iris, and most had 2 blue eyes. Ninety-one percent (31/34) of deaf and suspected-deaf horses had the EDNBR gene mutation. Deaf and suspected-deaf horses were used successfully for various performance events. All nondeaf horses had unremarkable BAER results.
Conclusions and Clinical Relevance—Veterinarians should be aware of deafness among American Paint Horses, particularly those with a splashed white or frame overo coat color pattern, blend of these patterns, or tovero pattern. Horses with extensive head and limb markings and those with blue eyes appeared to be at particular risk.
Dendritic Cells Secrete the Immunosuppressive HLA-G Molecule upon CTLA4-Ig Treatment: Implication in Human Renal Transplant Acceptance
Authors: Bahri Rajia , Naji Abderrahim , Menier Catherine , Charpentier Bernard , Carosella Edgardo D. , Rouas-Freiss Nathalie , Durrbach Antoine 
Published: November 2009

Abstract
CTLA4-Ig (Belatacept) is a new recombinant molecule that interferes with the signal of T lymphocyte activation and prevents acute rejection after renal transplantation. HLA-G acts as a naturally tolerogenic molecule in humans. In this study, we analyzed whether HLA-G contributes to CTLA4-Ig-mediated graft acceptance. Our results demonstrate that patients treated with CTLA4-Ig displayed significantly higher soluble HLA-G (sHLA-G) plasma concentrations (72 ± 14 ng/ml) than patients treated with calcineurin inhibitors (5 ± 1 ng/ml) or healthy donors (5 ± 5 ng/ml). Notably, sHLA-G purified from plasma of CTLA4-Ig-treated patients was biologically active as it inhibited allogeneic T cell proliferation in vitro. Dendritic cells (DC) were identified as one of the cellular sources of sHLA-G in CTLA4-Ig-treated patients. Supporting this observation, we showed that DC generated in vitro in presence of CTLA4-Ig released sHLA-G in response to allostimulation. These CTLA4-Ig-treated DC acted as tolerogenic APC through sHLA-G secretion as they suppressed T cell alloproliferation, which could be restored by using a neutralizing anti-HLA-G Ab. These data define a novel pathway by which CTLA4-Ig immunomodulates allogenic response through posttranscriptional regulation of HLA-G expression in DC. CTLA4-Ig-mediated HLA-G release appears as a critical factor in T cell alloresponse inhibition, thereby contributing to the immunosuppressive effect and graft acceptance.
IL-9 Regulates Pathology during Primary and Memory Responses to Respiratory Syncytial Virus Infection
Authors: Dodd Jonathan S. , Lum Eda , Goulding John , Muir Roshell , Van Snick Jacques , Openshaw Peter J. M. 
Published: November 2009

Abstract
IL-9 is a cytokine of great current interest associated with allergic/Th2 responses. High levels of IL-9 are present in bronchial secretions from infants with respiratory syncytial virus (RSV) bronchiolitis. To test its effects in RSV disease with a Th2 profile, BALB/c mice were vaccinated with recombinant vaccinia virus expressing the RSV G protein. On RSV challenge, immunized mice developed augmented disease characterized by enhanced pulmonary Th2 and local IL-9 production peaking on days 7–10 of RSV infection. Depletion with anti-IL-9 Ab at vaccination or RSV challenge enhanced viral clearance. Depletion only at challenge had no effect on disease severity, whereas depletion at immunization and challenge enhanced Th1 responses, inhibited virus-specific IgG1 production, and enhanced disease severity. By contrast, depletion of IL-9 at immunization boosted IgG2a and inhibited the Th2 response and disease during subsequent infection without a concomitant increase in type 1 cytokines. Adoptive transfer of secondary memory CD4 T cells from the spleens of IL-9-depleted mice into naive recipients replicated many of the effects of depletion, indicating that IL-9 acts via CD4 T cells. Therefore, IL-9 is a previously unknown but key modulator of antiviral immunity, regulating T and B cell responses and having potent and specific effects on viral lung disease.
SHP-2 Expression Negatively Regulates NK Cell Function
Authors: Purdy Amanda K. , Campbell Kerry S. 
Published: November 2009

Abstract
Src homology region 2-containing protein tyrosine phosphatase-2 (SHP-2) is required for full activation of Ras/ERK in many cytokine and growth factor receptor signaling pathways. In contrast, SHP-2 inhibits activation of human NK cells upon recruitment to killer cell Ig-like receptors (KIR). To determine how SHP-2 impacts NK cell activation in KIR-dependent or KIR-independent signaling pathways, we employed knockdown and overexpression strategies in NK-like cell lines and analyzed the consequences on functional responses. In response to stimulation with susceptible target cells, SHP-2-silenced NK cells had elevated cytolytic activity and IFN-γ production, whereas cells overexpressing wild-type or gain-of-function mutants of SHP-2 exhibited dampened activities. Increased levels of SHP-2 expression over this range significantly suppressed microtubule organizing center polarization and granzyme B release in response to target cells. Interestingly, NK-target cell conjugation was only reduced by overexpressing SHP-2, but not potentiated in SHP-2-silenced cells, indicating that conjugation is not influenced by physiological levels of SHP-2 expression. KIR-dependent inhibition of cytotoxicity was unaffected by significant reductions in SHP-2 levels, presumably because KIR were still capable of recruiting the phosphatase under these limiting conditions. In contrast, the general suppressive effect of SHP-2 on cytotoxicity and cytokine release was much more sensitive to changes in cellular SHP-2 levels. In summary, our studies have identified a new, KIR-independent role for SHP-2 in dampening NK cell activation in response to tumor target cells in a concentration-dependent manner. This suppression of activation impacts microtubule organizing center-based cytoskeletal rearrangement and granule release.
Peroxisome Proliferator-Activated Receptor γ Ligands Enhance Human B Cell Antibody Production and Differentiation
Authors: Garcia-Bates Tatiana M. , Baglole Carolyn J. , Bernard Matthew P. , Murant Thomas I. , Simpson-Haidaris Patricia J. , Phipps Richard P. 
Published: November 2009

AbstractProtective humoral immune responses critically depend on the optimal differentiation of B cells into Ab-secreting cells. Because of the important role of Abs in fighting infections and in successful vaccination, it is imperative to identify mediators that control B cell differentiation. Activation of B cells through TLR9 by CpG-DNA induces plasma cell differentiation and Ab production. Herein, we examined the role of the peroxisome proliferator-activated receptor (PPAR)γ/RXRα pathway on human B cell differentiation. We demonstrated that activated B cells up-regulate their expression of PPARγ. We also show that nanomolar levels of natural (15-deoxy-Δ12,14-prostaglandin J2) or synthetic (rosiglitazone) PPARγ ligands enhanced B cell proliferation and significantly stimulated plasma cell differentiation and Ab production. Moreover, the addition of GW9662, a specific PPARγ antagonist, abolished these effects. Retinoid X receptor (RXR) is the binding partner for PPARγ and is required to produce an active transcriptional complex. The simultaneous addition of nanomolar concentrations of the RXRα ligand (9-cis-retinoic acid) and PPARγ ligands to CpG-activated B cells resulted in additive effects on B cell proliferation, plasma cell differentiation, and Ab production. Furthermore, PPARγ ligands alone or combined with 9-cis-retinoic acid enhanced CpG-induced expression of Cox-2 and the plasma cell transcription factor BLIMP-1. Induction of these important regulators of B cell differentiation provides a possible mechanism for the B cell-enhancing effects of PPARγ ligands. These new findings indicate that low doses of PPARγ/RXRα ligands could be used as a new type of adjuvant to stimulate Ab production.
SOCS3 in T and NKT Cells Negatively Regulates Cytokine Production and Ameliorates ConA-Induced Hepatitis
Authors: Nakaya Mako , Hashimoto Masayuki , Nakagawa Ryusuke , Wakabayashi Yu , Ishizaki Takuma , Takada Ichiro , Komai Kyoko , Yoshida Hiroki , Yoshimura Akihiko 
Published: November 2009

Abstract
Suppressor of cytokine signaling 3 (SOCS3), a negative-feedback molecule for cytokine signaling, has been implicated in protection against liver injury. Previous studies have shown that overexpression of SOCS3 in the liver by adenovirus or membrane permeable recombinant protein protected the liver from various injuries. However it remained uncertain in which type of cells SOCS3 suppresses liver injury. In this study, we demonstrated that forced expression of SOCS3 in T and NKT cells suppressed ConA-induced hepatitis using T and NKT cell-specific SOCS3 transgenic (Lck-SOCS3 Tg) mice. IFN-γ and IL-4 production was reduced in Lck-SOCS3 Tg mice as well as splenocytes treated with ConA. IFN-γ and IL-4 levels were also reduced in Lck-SOCS3 Tg mice administrated with α-galactosylceramide, suggesting that SOCS3 in NKT cells has suppressive function. Sustained expression of SOCS3 in an NKT cell line also resulted in reduced expression of various cytokines and transcription factors. In contrast, T and NKT cell-specific SOCS3 conditional knockout (Lck-SOCS3 cKO) mice were hypersensitive to ConA-mediated hepatitis. Isolated SOCS3-deficient NKT cells produced higher levels of IFN-γ and IL-4. These data indicate that SOCS3 plays a negative regulatory role in NKT cell activation and that forced expression of SOCS3 in NKT cells is effective in preventing hepatitis.
TLR2 Promotes Th2/Th17 Responses via TLR4 and TLR7/8 by Abrogating the Type I IFN Amplification Loop
Authors: Wenink Mark H. , Santegoets Kim C. M. , Broen Jacobus C. A. , van Bon Lenny , Abdollahi-Roodsaz Shahla , Popa Calin , Huijbens Richard , Remijn Thijs , Lubberts Erik , van Riel Piet L. C. M. , van den Berg Wim B. , Radstake Timothy R. D. J. 
Published: November 2009

Abstract
TLR2 plays an important role in the removal of Gram-positive bacteria; contrastingly, it also appears to have important protective effects against unrestrained inflammation and subsequent organ injury during infection and autoimmunity. We hypothesized that TLR2 tunes the phenotype of dendritic cells (DCs) activated through other TLRs, thereby fulfilling a crucial role in the modulation of the immune response. TLR2 potently inhibited TLR4- and TLR7/8-induced cytokine production by human DCs. The inhibitory effect of TLR2 on the release of TNF-α but not of IL-12p70 was mediated by PI3K. TLR2 inhibits the production of IL-12p70 by dampening the type 1 IFN amplification loop. When DCs were triggered with the potent synergistic combination of LPS (TLR4) and R848 (TLR7/8) in conjunction with a TLR2 ligand, a clear shift to more Th2- and Th17-prone responses in the naive and memory T cell subpopulations was observed. This shift in T cell responses was inherent to the inability of TLR2-stimulated DCs to produce IL-12p70 and was dependent on the production of IL-1 and IL-6.
Prostacyclin Inhibits IFN-γ-Stimulated Cytokine Expression by Reduced Recruitment of CBP/p300 to STAT1 in a SOCS-1-Independent Manner
Authors: Strassheim Derek , Riddle Suzzette R. , Burke Danielle L. , Geraci Mark W. , Stenmark Kurt R. 
Published: November 2009

Abstract
Increasing evidence indicates that pulmonary arterial hypertension is a vascular inflammatory disease. Prostacyclin (PGI2) is widely used to treat pulmonary arterial hypertension and is believed to benefit patients largely through vasodilatory effects. PGI2 is also increasingly believed to have anti-inflammatory effects, including decreasing leukocyte cytokine production, yet few mechanistic details exist to explain how these effects are mediated at the transcriptional level. Because activated monocytes are critical sources of MCP-1 and other cytokines in cardiovascular inflammation, we examined the effects of iloprost on IFN-γ- and IL-6-stimulated cytokine production in human monocytes. We found that iloprost inhibited IFN-γ- and IL-6-induced MCP-1, IL-8, RANTES, and TNF-α production in monocytes, indicating wide-ranging anti-inflammatory action. We found that activation of STAT1 was critical for IFN-γ-induced MCP-1 production and demonstrated that iloprost inhibited STAT1 activation by several actions as follows: 1) iloprost inhibited the phosphorylation of STAT1-S727 in the transactivation domain, thereby reducing recruitment of the histone acetylase and coactivator CBP/p300 to STAT1; 2) iloprost selectively inhibited activation of JAK2 but not JAK1, both responsible for activation of STAT1 via phosphorylation of STAT1-Y701, resulting in reduced nuclear recruitment and activation of STAT1; and 3) SOCS-1, which normally terminates IFN-γ-signaling, was not involved in iloprost-mediated inhibition of STAT1, indicating divergence from the classical pathway for terminating IFN-γ-signaling. We conclude that PGI2 exerts anti-inflammatory action by inhibiting STAT1-induced cytokine production, in part by targeting the transactivation domain-induced recruitment of the histone acetylase CBP/p300.