bluuebunny/crossref_metadata_2025 huggingface dataset:
Unveiling Perspectives: Primary School Teachers' Reflections on Task-Based Language Teaching in China
Authors: Hu Yiting
Published: January 2024

This qualitative study offers a purposive exploration into the firsthand experiences of Grade 5 English teachers in Hebei Province, China, immersed in the implementation of task-based language teaching (TBLT). Through thematic analysis, the research identifies crucial themes—Learner-Centered Approach, Integration of Real-World Tasks, All Language Skills Integration, Reflective and Iterative Learning, Increased Student Engagement, and Improved Language Proficiency. These findings, deeply rooted in established TBLT principles, highlight the significance of tailored teaching, authentic tasks, and holistic language skill development. Despite inherent limitations, notably a confined sample size, the study's practical implications for curriculum design and teacher development underscore its relevance in advancing effective language education methodologies. This research contributes valuable insights, urging the thoughtful integration of TBLT principles into language education policies and practices.
An Overview of Anthropogenic Changes in Land Use and Land Cover, with Specific Attention to Climate Change and Unsustainable Agriculture
Authors: Gupta Hitesh , Kumar Sandeep , Pandey Rajnish , Thapliyal Shubham , Shaji Ashline , Kumar Amit
Published: January 2024

The worldwide need for food and the alterations in bioenergy demands associated with shifts in land use and land cover changes (LULCC) have given rise to environmental apprehensions, including global warming and climate change. There is substantial evidence indicating that we are currently witnessing human-induced transformations that could potentially result in a sixth mass extinction event. This study seeks to explore the connections between land use and land cover change (LULCC), forests, biodiversity, the carbon cycle, hydrology, climate, and various biogeochemical feedback mechanisms. These interrelationships play a crucial role in shaping future environmental outcomes and influencing climate change. Additionally, the review critically assesses existing research on the correlation between LULCC and climate, along with associated processes. The paper delves into ongoing investigations surrounding LULCC, its ecological repercussions, and its influence on the regulatory mechanisms of terrestrial ecosystems, ecosystem services, atmospheric chemistry, and the climate. It underscores the importance of developing land-use strategies rooted in a scientific evaluation of LULCC to promote sustainability and wider economic development, with a particular emphasis on addressing climate change. Global agreements and protocols also call for land use strategies that consider the implications of environmental degradation.
The Effect of Integrated Nutrient Management on Growth, Yield Attributes and Yield of Transplanted Rice under Irrigated Condition (Oryza sativa L.)
Authors: Diwedi Namrata , Singh Sudhakar , Pandey Deepak , Singh P. K. , Chanda S. S. , Tiwari H. N. , Singh D. K. , Singh Gajendra
Published: January 2024

The present investigation was carried out in kharif season 2022-23 at Agronomy Research Farm of Chandra Bhanu Gupta Krishi Snatakottar Mahavidyalaya, Bakshi ka Talab, Lucknow (U.P). The 8 treatments comprised of T1- RDF(IF), T2- 100% RDF+25 kg ha-1 ZnSO4 (B), T3-100% RDF+2 foliar spray of ZnSO4, T4- RDF+50 kg ha-1  FeSO4 (B),T5-100% RDF+ZnSO4 25 kg ha-1  (B) + FeSO4 @ 50 kg ha-1 (B), T6- 75% RDF (IF)+25% RDN (FYM), T7- 50% RDF (IF)+50% RDN (FYM),T8-100% RDF through FYM were laid out in Randomized Block Design (RBD). The soil was silty-loam texture with slightly alkaline pH 8.1, organic carbon 0.70 %, available nitrogen 270.00 kg ha-1, available phosphorus 27.0 kg ha-1, and available potash 262.0 kg ha-1 during 2022-2023. The values of growth contributing characters viz., plant height (cm), number of tillers per m2 (439.73), dry matter accumulation (g m -2 ) (829.62), at harvest and significantly highest (6.33) leaf area index (LAI) was recorded under 100% RDF + 2 foliar spray of ZnSO4 and yield attributes and yield  like number of effective tillers per m-2 (200.66), panicles weight (g)(4.51), length of panicle (cm) (28.33), number of grains panicle-1 (175.33), test weight (g) (29.10), grain yield (47.85), straw yield (q ha-1 ) (64.75) of rice were significantly higher under T3- 100% RDF + 2 foliar spray of ZnSO4 compared to other treatment. The nitrogen content (%), and its uptake (kg ha-1), and protein content (%), and its production (kg ha-1) in grain and straw was significantly higher under T3-100% RDF + 2 foliar spray of ZnSO4. The Fe and Zn content (mg kg-1) and its uptake (kg ha-1) in grain and straw was higher under T3-100% RDF + 2 foliar spray of ZnSO4. Economics analysis viz gross return (123514), net return (84107) and benefit cost ratio (2.13) was recorded highest with T3-100% RDF + 2 foliar spray of ZnSO4 while lowest with T8- 100% RDF through FYM. Thus for obtaining better yield and profit apply T3-100% RDF + 2 foliar spray of ZnSO4.
Assessment of Health Care Providers Attitudes and Practices Concerning Medication Errors in Saudi Arabia
Authors: Alanzi Shrooq Eid
Published: January 2024

Introduction: Medication errors are one of the leading causes of patients’ morbidity and mortality in health care settings

Objective: Assess awareness, attitude and practices of health care providers toward medication errors in Saudi Arabia.

Methodology: Cross-sectional study design was used in the period of three months, from 01 July to 30th November, 2023. participants were selected randomly. 329 health care providers including physicians, pharmacists and nurses working in different hospitals, primary health care centers and private clinics in different regions of Saudi Arabia, participated in the study. Dat was analyzed using Microsoft excel program.

Results: The mean score of good knowledge about medication errors among respondents was 77%, average score of good attitudes toward medication errors among respondents was 72%. 74% of respondents were willing to inform supervisor if they had noticed a medication error. The causes for not reporting medication error were fear of any legal consequences (41%), self-management (23%), busy with work (15%) and did not know whom to inform (21%). Less than half (48%) of study subjects had previously filled an adverse drug reaction form.

Conclusion: Medication errors play a significant role role in the quality of health of our patients.  Health care providers in Saudi Arabia have good knowledge and positive attitude toward medication errors. However, medication error reporting is still not sufficiently done.
The Effectiveness of Modified Pilates Program with and without Kinesiotaping on Postnatal Urinary Stress Incontinence: A Randomized Clinical Trial
Authors: Chintamani Radhika
Published: January 2024

Introduction: Urinary Stress Incontinence is very common condition seen in postnatal woman. Without pelvic floor strengthening this condition will lead to social inhibition. The rate of urinary stress incontinence is more in normal vaginal delivery compared to C-Section. Few authors have demonstrated the effectiveness of Kegal exercise and Pilates on such woman with urinary stress incontinence. There is dirth in the literature related to effect of Kinesiotaping in reduction of urinary stress incontinence.

Research Objective: The objective of the research was to find out the effect of Kinesiotape along with the Modified Pilates program on subjects with postnatal urinary incontinence.

Methodology: This is an experimental study with randomised clinical trial design and the study setting was Bruhat Bangalore Mahanagar Palike, and the included 50 postnatal women who underwent vaginal delivery. The sample was divided into two groups: Group A (25) were subjected to Modified Pilates Program with Kinesiotaping and Group B (25) were subjected to Modified Pilates Program alone. The intervention was conducted for 6 weeks. The outcome measures like: PERFECT Scheme, Questionnaire for Urinary Incontinence Diagnosis and Urogenital Distress Inventory were assessed both pre and post therapy at 6th week.

Results: Pre therapy both groups showed no statistical significance. Post therapy; Group A showed significant result with respect to all three outcome measures PERFECT (<0.0001), QUID (<0.001) and UDI (<0.001) and Group B showed significance only with respect to PERFECT Scheme (<0.05).

Conclusion: The study concluded that Modified Pilates will no doubt strengthen the pelvic floor muscle; but Kinesiotape addition to it will improve the strength by maintaining it and thus increasing the quality of life of the patient. Thus, using kinesiotape during the pelvic floor rehabilitation of Postnatal women with stress incontinence will provide benefit to the patient.

Summary: The current article concludes that Modified Pilates will strengthen the pelvic floor because of the abdominal cylinder involved along with Kinesiotape will add on to reduction in urinary incontinence because of the stimulation of sacral plexus.
Microbial Analysis and Antibiogram of Bacteria and Fungi Isolated from Meat Sellers Tables in Dutsin-Ma Metropolis, Katsina State
Authors: Wata I.  , Abdullahi K.  , Abdulmalik Umaru
Published: January 2024

The goal of the research project was to carry out microbiological analysis and antibiogram of  bacteria and fungi associated with meat vendor tables in the city of Dutsin-Ma. This study made use of twenty samples in total. Five distinct locations at Wednesday Market and Darawa were chosen, and two samples from each table were taken using swab sticks. For analysis, the samples were then brought to the Federal University of Dutsin-ma microbiology laboratory department. The agars that were initially employed to isolate the bacteria and fungus were MacConkey, nutrient, mannitol salt, bile esculin, salmonella-shigella, eosin methylene blue, and potato dextrose agars. Bacterial species were identified using gram staining and biochemical tests while lactophenol cotton blue staining was used for the identification of fungal species. Bacterial isolates identified include Escherichia coli, Salmonella species, Klebsiella pneumonia, Bacillus subtilis, Streptococcus species and Staphylococcus aureus while the fungal isolates are Aspergillus flavus, A. niger, A. fumigatus, and Oidiodendron griseum. The antimicrobial susceptibility test findings showed that while some of the bacterial isolates were responsive to certain drugs, others were resistant. The results of this study's investigations therefore demonstrated how heavily polluted meat vendors' tables are with a wide variety of bacteria. This can be explained by the unsanitary procedures used in the meat sale industry as well as other environmental issues.  Therefore, it is imperative that the government authorities tasked with these duties make sure that the vendors of these meat products adhere to standard and hygienic procedures.  Raising public knowledge of the risks of foodborne illnesses associated with eating raw meats is another important goal of public health awareness campaigns.
Pengaruh Elemen Persisten Terhadap Kualitas Street Front Kawasan Kota Kediri
Authors: Suprapto Christopher Daniel , Sunaryo Rony Gunawan
Published: January 2024

Pusat Kota Kediri merupakan kawasan awal dalam morfologi kota Kediri yang merupakan pusat perdagangan yang dulunya merupakan kawasan persawahan. Selain itu, tipologi bangunan Kota Kediri dipengaruhi oleh beberapa faktor seperti Kolonial, Tionghoa maupun Eropa. Seiring berjalannya waktu, area pusat Kota Kediri dipenuhi oleh street front pertokoan ruko tipikal di sepanjang jalan. Kualitas street front merupakan salah satu pembentuk identitas dan karakter kawasan. Penelitian bertujuan untuk mengetahui kualitas street front di kawasan Kediri Kota, dengan menganalisis pengaruh perkembangan kawasan terhadap kualitas street front dan mengidentifikasi tipologi yang menghasilkan kualitas street front tertentu. Penelitian dilakukan pada urban tissue seluas 1000 m x 1000 m di sekitar pusat Kota Kediri. Hasil penelitian menunjukan adanya berbagai macam kualitas street front pada kawasan tersebut. Pada kawasan ini, rata rata street front mendapat nilai acceptable sedangkan kualitas vibrant sangat sedikit. Kualitas vibrant didapatkan ketika adanya aktivitas, detail pada bangunan, fasad, fasilitas dan fungsi bangunan yang beragam.
On‐line monitoring of batch processes using a PARAFAC representation
Authors: Meng X. , Morris A. J. , Martin E. B.
Published: February 2003

For assured through‐batch process performance monitoring, a number of established bilinear and trilinear modelling techniques require data to be available for the entire duration of the batch to realize the on‐line application of the nominal model. Various strategies have been proposed for the in‐filling of those yet unknown values. A methodology is presented where the unknown observations are calculated as a weighted combination of the scores up to the current time point in the new batch and those previously computed from a reference data set. This approach is investigated for the trilinear technique of parallel factor analysis (PARAFAC). Modified confidence limits are then proposed for the bivariate scores plot for on‐line monitoring with a PARAFAC model. The identification of those variables indicative of causing changes in process operation has been accomplished through the application of contribution plots. Based on such plots, a methodology, with associated confidence limits, is proposed for the location of those variables whose behaviour differs from that encapsulated within the reference data set. The approach is demonstrated and compared with existing techniques on a benchmark simulation of a semi‐batch emulsion polymerization that has been used in similar studies. Copyright © 2003 John Wiley & Sons, Ltd.
Managing ISO 14001 implementation in the United Kingdom Continental Shelf (UKCS)
Authors: Strachan Peter A. , Sinclair Ivor McKay , Lal David
Published: February 2003

The activities and operations of the oil and gas industry have a significant propensity to affect the natural environment. The UK oil and gas industry, like the chemical and pharmaceutical industries, is a highly regulated industry and attracts a high level of public interest, so much so that the UK Government is keen to encourage the adoption of voluntary environmental management initiatives such as ISO 14001. In responding to the UK Government's agenda, some oil and gas enterprises have now implemented this environmental management system. This article examines the implementation of ISO 14001 in the first batch of oil and gas enterprises to have done so. Through undertaking structured face‐to‐face interviews with senior corporate staff in eight firms this article examines the drivers, implementation barriers and the benefits accrued from their participation in this management system. In contrast with some other industries, information on the oil and gas industry's experience with, and perception of, ISO 14001 is somewhat limited. Against this backdrop, the paper attempts to address these weaknesses and provide a starting point for future research in the area of corporate social responsibility and environmental management systems. The paper concludes with a number of recommendations as to how to promote the adoption of environmental management systems more widely in the oil and gas industry. Copyright © 2003 John Wiley & Sons, Ltd. and ERP Environment.
Corporate socially responsible (CSR) practices in the context of Greek industry
Authors: Bichta Constantina
Published: February 2003

This paper sets out to describe the level of corporate environmental responsibility of the Greek industrial sector. While the level of corporate socially responsible behaviour has been widely explored in the context of Northern European industry, the theoretical work surrounding the level of CSR practices of Greek industry is underdeveloped.

A qualitative study was designed to increase awareness about the level of environmental responsibility of two Greek firms, which represented the chemical/fertilizer and metal sectors. The empirical findings suggest that a number of factors, both internal and external, determine the level of environmental policy and performance of the two companies. The environmental policy of the companies appears also to relate to the sector of operation. The paper concludes that the Greek business actor should look at his workforce in order to accelerate the environmental activities of the organization. With regard to the theory of CSR, it is argued that the development of a model of CSR is aided by the study and identification of factors that support and/or undermine the socially responsible behaviour of the European corporate sector. Copyright © 2003 John Wiley & Sons, Ltd. and ERP Environment.
Humoral and cellular immune responses to proinsulin in adults with newly diagnosed type 1 diabetes
Authors: Narendran Parth , Williams Alistair J. , Elsegood Kathryn , Leech Nicola J. , Dayan Colin M.
Published: February 2003

Background

Type 1 diabetes (T1D) is an autoimmune disease characterized by immunity against pancreatic islet‐derived proteins. The object of this study was to measure antibody and T‐cell responses against proinsulin (PI), an islet‐derived protein, and to map its dominant T‐cell epitopes.

Methods

Antibody responses to proinsulin, insulin, glutamic acid decarboxylase (GAD), protein tyrosine phosphatase IA‐2 and islet‐cell antigen were measured in 116 newly diagnosed diabetic subjects aged 16 to 40 years. T‐cell proliferative responses to proinsulin and proinsulin peptides were measured in 33 of these diabetic subjects and in 21 healthy control subjects.

Results

22% of diabetic subjects but no control subjects expressed antibodies to proinsulin. A strong correlation existed between antibody levels to proinsulin and insulin within diabetic subjects. Similar proportions of diabetic (12%) and healthy (9.5%) subjects displayed T‐cell responses to proinsulin. There was no correlation between antibody and T‐cell responses to proinsulin within subjects. Amino acid region 56 to 72 was identified as the major T‐cell epitope of proinsulin, though significant responses to region 14 to 37 were also present.

Conclusion

Elevated proinsulin autoantibodies in diabetic subjects confirm proinsulin is an important autoantigen in type 1 diabetes. Though elevated cellular immunity to proinsulin protein was not detected, two dominant T‐cell epitopes of proinsulin were identified that span the C‐peptide and insulin junctions. Immunity to proinsulin was lower than that reported for childhood‐onset type 1 diabetes and we propose that, like insulin, proinsulin may be targeted less frequently in adulthood. Copyright © 2002 John Wiley & Sons, Ltd.
Effect of enalapril and losartan on the events that precede diabetic nephropathy in rats
Authors: Aparecido Volpini Rildo , Giovanini Alves da Silva Cleonice , Silva Costa Roberto , Machado Coimbra Terezila
Published: February 2003

Background

Mesangial cell proliferation, phenotype change, and increased transforming growth factor‐β (TGF‐β) precede mesangial expansion in diabetic rats. Experiments using mesangial cell culture have shown that angiotensin II increases TGF‐β production by these cells. The aim of the present study was to investigate the effect of enalapril and losartan on the events that precede diabetic nephropathy in rats. It was also analyzed if the determination of urinary TGF‐β could be a mean for the evaluation of therapeutic efficacy in this disease.

Methods

Eighty‐two female Wistar rats were made diabetic by intravenous injection of streptozotocin diluted in citrate buffer, and citrate buffer alone was injected into the control group (N = 34). Ten days later, the right kidney was removed. Thirty diabetic rats were treated with enalapril, DMN + E, in drinking water (20 mg/L) and 24 with losartan, DMN + L (50 mg/L). Urinary TGF‐β was determined 90 days after STZ or buffer injection, the animals were killed, and the kidneys were removed for histological and immunohistochemical studies.

Results

The immunostaining for TGF‐β and fibronectin in the cortical tubulointerstitium and glomeruli was higher in untreated diabetic rats (p < 0.001). Treatment with enalapril or losartan reduced this increase. The urinary TGF‐β excretion (pg/mg urinary creatinine) was 48.6 ± 5.9 in control animals, 603.9 ± 80.41 in untreated diabetic rats, 279.3 ± 47.0 in diabetic rats treated with enalapril, and 243.7 ± 40.0 in rats treated with losartan.

Conclusions

We concluded that enalapril or losartan treatment can modify events that precede diabetic nephropathy by reducing TGF‐β and fibronectin expression in glomeruli and tubulointerstitium as well as urinary TGF‐β content. Copyright © 2002 John Wiley & Sons, Ltd.
A new look at viruses in type 1 diabetes
Authors: Jun Hee‐Sook , Yoon Ji‐Won
Published: February 2003

Type 1 diabetes (T1D) results from the destruction of pancreatic beta cells. Genetic factors are believed to be a major component for the development of T1D, but the concordance rate for the development of diabetes in identical twins is only about 40%, suggesting that nongenetic factors play an important role in the expression of the disease. Viruses are one environmental factor that is implicated in the pathogenesis of T1D. To date, 14 different viruses have been reported to be associated with the development of T1D in humans and animal models. Viruses may be involved in the pathogenesis of T1D in at least two distinct ways: by inducing beta cell‐specific autoimmunity, with or without infection of the beta cells, [e.g. Kilham rat virus (KRV)] and by cytolytic infection and destruction of the beta cells (e.g. encephalomyocarditis virus in mice). With respect to virus‐mediated autoimmunity, retrovirus, reovirus, KRV, bovine viral diarrhoea‐mucosal disease virus, mumps virus, rubella virus, cytomegalovirus and Epstein‐Barr virus (EBV) are discussed. With respect to the destruction of beta cells by cytolytic infection, encephalomyocarditis virus, mengovirus and Coxsackie B viruses are discussed. In addition, a review of transgenic animal models for virus‐induced autoimmune diabetes is included, particularly with regard to lymphocytic choriomeningitis virus, influenza viral proteins and the Epstein‐Barr viral receptor. Finally, the prevention of autoimmune diabetes by infection of viruses such as lymphocytic choriomeningitis virus is discussed. Copyright © 2002 John Wiley & Sons, Ltd.
NF‐ATc2 induces apoptosis in Burkitt's lymphoma cells through signaling via the B cell antigen receptor
Authors: Kondo Eisaku , Harashima Akira , Takabatake Takami , Takahashi Hideo , Matsuo Yoshinobu , Yoshino Tadashi , Orita Kunzo , Akagi Tadaatsu
Published: February 2003

Cross‐linking of the B cell antigen receptor (BCR) with an anti‐IgM antibody has been shown to induce dramatic apoptosis in type I Burkitt's lymphoma (BL) cells. However, the apoptotic mechanism triggered via BCR remains unknown. Here we reports a mechanism of BCR ligation‐induced apoptosis involving protein phosphatase calcineurin and its specific substrate, transcriptional factor NF‐AT. In response to BCR cross‐linking, endogenous calcineurin was rapidly activated, and this facilitated nuclear translocation of NF‐ATc2, a subtype of NF‐AT members. Interestingly, nuclear‐imported NF‐ATc2 functioned pro‐apoptotically in BL cells. The effect of NF‐ATc2 was efficiently blocked with FK506, which prevented its nuclear translocation through inactivation of calcineurin. In addtion, TR3 induction during BCR cross‐linking was reduced by FK506 and the VIVIT peptide, which is a highly selective inhibitor for NF‐AT. This strongly suggests that activation of NF‐ATc2 by calcineurin is essential for TR3 recruitment, and that TR3 can be considered as a candidate for death effector in BCR‐mediated apoptosis. Therefore, NF‐ATc2 plays a crucial role in BCR‐mediated apoptosis in type IBL, providing greater insight into unique BL characteristics through BCR signaling.
c‐kit+ FcR+ myelocytes are increased in cancer and prevent the proliferation of fully cytolytic T cells in the presence of immune serum
Authors: Beck Christian , Schreiber Karin , Schreiber Hans , Rowley Donald A.
Published: February 2003

Immunogenic cancers induce both IgG antibodies and CD8+ cytotoxic T lymphocytes (CTL). Rejection of almost all immunogenic tumors depends ultimately on CTL. When tumors grow progressively, IgG continues to be produced but CTL may no longer be demonstrable. Using syngeneic mixed lymphocyte tumor cell cultures, we found that proliferation of fully activated proliferating CTL is prevented by a small subpopulation of immature myeloid c‐kit+ FcR+ cells, for convenience referred to as "barrier cells". Both, FcR on barrier cells and IgG linked to TGF‐β (IgG‐TGF‐β) present in immune serum, are obligatory for barrier cells to prevent proliferation of CTL, suggesting that IgG‐TGF‐β binds FcR to activate suppression. Growing tumors increase barriercells in the spleen. Interfering with the cells or molecules essential for barrier cells to prevent proliferation of CTL may enhance tumor and other CD8+ CTL‐mediated immunity.
CD1a and CD1b surface expression is independent from de novo synthesized glycosphingolipids
Authors: Manolova Vania , Hirabayashi Yoshio , Mori Lucia , Libero Gennaro De
Published: February 2003

CD1 molecules resemble classical MHC molecules in structure, bind self and bacterial glycolipids and present them to T cells. Whether the CD1 antigen‐binding groove becomes filled during maturation and traffic to the cell surface is an important and still unsolved biological question. As most cell types synthesize complex glycosphingolipids (GSL), which also stimulate CD1‐restricted T cells, it could be possible that these ligands associate with nascent CD1 molecules. Here, we show that treatment of cells with drugs blocking at different levels the de novo and salvage pathways of GSL synthesis does not prevent surface expression of CD1a and CD1b. Furthermore, transfection of CD1A and CD1B genes in a mutant cell line unable to synthesize glucosylceramides and galactosylceramides showed normal surface expression of both CD1 molecules. Lack of GSL did not induce intracellular CD1 accumulation as indicated by confocal microscopy. The same results were obtained by transfecting the Lec series of mutants, which are deficient in sugar addition to glycolipids and glycoproteins. These findings demonstrate that endogenous de novo synthesized GSL are not mandatory for CD1a and CD1b negotiating surface expression.
Generation of an effective anti‐tumor immunity after immunization with xenogeneic antigens
Authors: Sioud Mouldy , Sørensen Dag
Published: February 2003

Central and peripheral tolerance mechanisms are expected to hamper the generation of effective immunity against tumors. To break self tolerance against malignant gliomas, we assessed the therapeutic potential of self/foreign antigen cross‐reactivity in an immunocompetent rat glioma model. Immunotherapy of tumors using xenogeneic human glioma membrane proteins (HGP) as a vaccine inhibitedtumor growth, whereas no significant effect was obtained with rat glioma membrane proteins (RGP). In contrast to RGP, HGP elicited a specific IgG immune response that cross‐reacted with RGP. This immune response was found to be mainly a Th1 type response. On tumor sections stained with hematoxylin and eosin, glioma cells are sparse and apoptotic in HGP‐immunized rats, whereas control tumors showed condensed and viable cells. Tumor‐specific CTL were induced in HGP‐immunized rats. Immunohistochemical analysis revealed that a significant number of CD8+ and CD4+ cells infiltrated into tumors from HGP‐vaccinated rats, whereas RGP vaccination led to only few tumor‐infiltrating T cells. Taken together, the data establish the in vivo applicability of the cross‐stimulation between self and foreign antigens as an alternative way to break tolerance against the poorly immunogenic gliomas.
Association of T cell antigen CD7 with type II phosphatidylinositol‐4 kinase, a key component in pathways of inositol phosphate turnover
Authors: Subrahmanyam Gosukonda , Rudd Christopher E. , Schneider Helga
Published: February 2003

CD7 is a 40‐kDa glycoprotein that is expressed on prothymocytes and persists during T cell differentiation. CD7 has been demonstrated to generate, like other costimulatory molecules, intracellular signals that modulate T cell function. However, although it binds to phosphatidylinositol 3‐kinase (PI 3‐kinase), the signaling events mediated by CD7 are not completely understood. In this context, phosphatidylinositol 4‐kinase (PI 4‐kinase) is a key enzyme involved in a variety of events, from the modeling of the actin cytoskeleton to the activation of protein kinase C. In this study, we show for the first time that PI 4‐kinase of 55 kDa can associate with CD7. The enzyme activity was insensitive to wortmannin, but was inhibited by adenosine, a characteristic for type II PI 4‐kinase. Together, our findings demonstrate that type II PI 4‐kinases are integral components of the CD7 signaling pathway and may play a role of CD7 in co‐stimulation and thymic differentiation.
Membrane‐bound form of fractalkine induces IFN‐γ production by NK cells
Authors: Yoneda Osamu , Imai Toshio , Nishimura Miyuki , Miyaji Michihiko , Mimori Tsuneyo , Okazaki Toshiro , Domae Naochika , Fujimoto Hiroko , Minami Yasuhiro , Kono Takeshi , Bloom Eda T. , Umehara Hisanori
Published: February 2003

Natural killer (NK) cells participate in both innate and adaptive immunity, in part by their prompt secretion of cytokines including IFN‐γ, a pro‐inflammatory cytokine with an important role in Th1 polarization. To assess the involvement of fractalkine in inflammatory processes, we examined the effect of fractalkine on IFN‐γ production by NK cells. Although soluble chemokines, including MCP‐1 and RANTES as well as fractalkine, had a negligible effect on IFN‐γ production, immobilized fractalkine markedly induced IFN‐γ production by NK cells in a dose‐dependent manner. Pretreatment of NK cells with the phosphatidylinositol 3‐kinase (PI 3‐K) inhibitor, wortmannin, completely inhibited the production of IFN‐γ induced by fractalkine, and pretreatment with the protein tyrosine kinase inhibitor, herbimycin A, partially suppressed the response, suggesting that augmentation of IFN‐γ production in response to fractalkine treatment of NK cells involves signaling through PI 3‐K and protein tyrosine kinases. Furthermore, co‐culture of NK cells with fractalkine‐transfected 293E cells markedly enhanced IFN‐γ production by NK cells compared with co‐culture with control 293E cells. These findings may indicate a paracrine feedback loop system in which endothelial cells may be activated to produce more fractalkine, and also suggest a role for fractalkine expressed on endothelial cells in Th1 polarization through the stimulation of IFN‐γ production by NK cells.
Experimental African trypanosomiasis: IFN‐γ mediates early mortality
Authors: Shi Meiqing , Pan Wanling , Tabel Henry
Published: February 2003

In this study, we demonstrate that Kupffer cells in the livers of highly susceptible BALB/c mice infected with Trypanosoma congolense were loaded with trypanosomal antigen and appeared highly activated. This was associated with an enlarged capillary bed in the livers and decreased blood pressure of these mice towards the terminal stage. Blocking of murine IL‐10 receptor (IL‐10R)in vivo shortened the survival time of highly susceptible T. congolense‐infected BALB/c mice. Anti‐IL‐10R treatment decreased the survival of relatively resistant T. congolense‐infected C57BL/6 mice dramatically. Blocking of the IL‐10R also significantly shortened the survival time of mice infected with T. brucei. The acute death of trypanosome‐infected mice treated with anti‐IL‐10R antibodies in vivo was associated with focal liver necrosis, with significantly increased plasma levels of IL‐6, IL‐10, IL‐12p40 and IFN‐γ and enhanced synthesis of IL‐6, IL‐12p40 and IFN‐γ by spleen cell cultures. Anti‐IL‐10R‐induced death of T. congolense‐infected C57BL/6 mice could be prevented by administration of a neutralizing antibody specific forIFN‐γ. We conclude that phagocytosis of a critical number of trypanosomes by Kupffer cells leads to a systemic inflammatory response syndrome and, depending on the degree of Kupffer cell activation, is followed by death that is mediated by IFN‐γ. The role of trypanosome‐pulsed macrophages, T cells and genetic influences is discussed in a synopsis.
Soluble HLA‐A,‐B,‐C and ‐G molecules induce apoptosis in T and NK CD8+ cells and inhibit cytotoxic T cell activity through CD8 ligation
Authors: Contini Paola , Ghio Massimo , Poggi Alessandro , Filaci Gilberto , Indiveri Francesco , Ferrone Soldano , Puppo Francesco
Published: February 2003

There is convincing evidence that soluble HLA‐A,‐B,‐C (sHLA‐A,‐B,‐C) and soluble HLA‐G (sHLA‐G) antigens can induce apoptosis in CD8+ activated T cells although there is scanty and conflicting information about the mechanism(s) by which sHLA‐A,‐B,‐C antigens and sHLA‐G antigens induce apoptosis. In this study we have compared the apoptosis‐inducing ability of sHLA‐A,‐B,‐C antigens with that of sHLA‐G1 antigens in CD8+ T lymphocytes and CD8+ NK cells. Furthermore we have compared the inhibitory effect of sHLA‐A,‐B,‐C antigens and of sHLA‐G1 antigens on theactivity of EBV‐specific CD8+ cytotoxic T lymphocytes (CTL). sHLA molecules were purified from serum and from the supernatant of HLA class I‐negative cells transfected with one gene encoding either classical or non‐classical HLA class I antigens. Both classical and non‐classical sHLA class I molecules trigger apoptosis in CD8+ T lymphocytes and in CD8+ NK cells, which lack the T cell receptor, and their apoptotic potency is comparable. The binding of sHLA‐A,‐B,‐C and sHLA‐G1 molecules to CD8 leads to Fas ligand (FasL) up‐regulation, soluble FasL (sFasL) secretion and CD8+ cell apoptosis by Fas/sFasL interaction. Moreover, classical and non‐classical sHLA class I molecules inhibit the cytotoxic activity of EBV‐specific CD8+ CTL. As the amount ofsHLA‐G molecules detectable in normal serum is significantly lower than that of sHLA‐A,‐B,‐C molecules, the immunomodulatory effects of sHLA class I molecules purified from serum are likely to be mainly attributable to classical HLA class I antigens. As far as the potential in vivo relevance of these findings is concerned, we suggest that classical sHLA class I molecules may play a major immunoregulatory role in clinical situations characterized by activation of the immune system and elevated sHLA‐A,‐B,‐C serum levels. In contrast, non‐classical HLA class I molecules may exert immunomodulatory effects in particular conditions characterized by elevated sHLA‐G levels such as pregnancy and some neoplastic diseases.
Anti‐CD28 has a potent adjuvant effect on the antibody response to soluble antigens mediated through CTLA‐4 by‐pass
Authors: Carlring Jennifer , Barr Tom A. , Buckle Anne‐Marie , Heath Andrew W.
Published: February 2003

With the surge in potential new vaccines produced as recombinant proteins or synthetic peptides has come a pressing need to identify safe, potent immunological adjuvants to enhance immunogenicity of these antigens. CD28 is an important costimulatory molecule for T cells, and it has been shown that cell surface expression of its ligands, CD80 and CD86, can enhance cellular immune responses against tumor cells, however, these tumor cells do not normally express the ligands. Many new vaccines will be based upon soluble recombinant antigens, and in vaccination with these antigens CD80 and CD86 would normally be expressed on activated antigen‐presenting cells and additional stimulation through CD28 would not be predicted to enhance responses further. However, we show here that, surprisingly, CD28 antibody can very strongly enhance immune responses against soluble proteins, but only when directly attached to the antigen. The mode of action of CD28 antibodies appears to be linked to their ability to signal through CD28, but not to bind the negative feedback regulatory antigen, CTLA‐4. CD28 stimulants may represent novel, highly effective and safe immunological adjuvants for usewith a wide range of prophylactic and therapeutic vaccines.
NKT cells are dispensable in the induction of oral tolerance but are indispensable in the abrogation of oral tolerance by prostaglandin E
Authors: Ishimitsu Ryotaro , Yajima Toshiki , Nishimura Hitoshi , Kawauchi Hideyuki , Yoshikai Yasunobu
Published: February 2003

NK1.1+ α β T cells (NKT cells) regulate the Th1/Th2 balance in response to dietary Ag, which may be involved in regulation of oral tolerance. OVA‐specific IgE and IgG1 Ab levels were significantly lower following an i.p. injection of OVA (in CFA) in C57BL/6 mice orally given a single, high dose (25 mg) of OVA than in those orally given PBS. The oral tolerance was normally induced in Jα281–/– mice which lack Vα14+ NKT cells, suggesting that NKT cells are dispensable for induction of oral tolerance. Treatment with PGE1 or PGE2 abrogated the oral tolerance in Jα281+/+ mice; this abrogation was accompanied by an OVA‐specific Th2‐dominant response. The abrogation of oral tolerance by PGE1 was not evident in Jα281–/– mice. Treatment with PGE1 induced an early increase in IL‐4 production by liver NKT cells in normal mice and neutralization of the early IL‐4 by administration of anti‐IL‐4 mAb abolished PGE1‐induced abrogation of oral tolerance. These results suggest that liver NKT cells producing IL‐4 are responsible for the down‐regulation of oral tolerance that is caused by the PGE molecules.
Selective intracellular retention of virally induced NKG2D ligands by the human cytomegalovirus UL16 glycoprotein
Authors: Welte Stefan A. , Sinzger Christian , Lutz Stefan Z. , Singh‐Jasuja Harpreet , Sampaio Kerstin Laib , Eknigk Ute , Rammensee Hans‐Georg , Steinle Alexander
Published: February 2003

Human cytomegalovirus (HCMV) has evolved a multitude of molecular mechanisms to evade the antiviral immune defense of the host. Recently, using soluble recombinant molecules, the HCMV UL16 glycoprotein was shown to interact with some ligands of the activating immunoreceptor NKG2D and, therefore, may also function as a viral immunomodulator. However, the role of UL16 during the course of HCMV infection remained unclear. Here, we demonstrate that HCMV infection of fibroblasts induces expression of all known NKG2D ligands (NKG2DL). However, solely MICA and ULBP3 reach the cellular surface to engage NKG2D, whereas MICB, ULBP1 and ULBP2 are selectively retained in the endoplasmic reticulum by UL16. UL16‐mediated reduction of NKG2DL cell surface density diminished NK cytotoxicity. Thus, UL16 functions by capturing activating ligands for cytotoxic lymphocytes that are synthesized in response to HCMV infection.
Intramuscular transfer of naked calcitonin gene‐related peptide gene prevents autoimmune diabetes induced by multiple low‐dose streptozotocin in C57BL mice
Authors: Sun Wei , Wang Liuyi , Zhang Zhenmin , Chen Mingzhe , Wang Xian
Published: February 2003

The imbalance of Th1/Th2 subsets is an important pathogenic mechanism for insulin‐dependent diabetes mellitus (IDDM). Calcitonin gene‐related peptide (CGRP) has been found to play important roles in the regulation of T lymphocytes. We hypothesize that exogenous CGRP administration during insulitis may modulate the balance of Th lymphocytes, thereby providing a therapeutic intervention for IDDM. We established CGRP gene transfer by naked plasmid injection into the skeletal muscles with electroporation enhancement. The effect of CGRP gene transfer on pathogenesis of IDDM was observedin autoimmune diabetic C57BL mice induced by multiple low‐dose streptozotocin (MLDS) administration. The treatment significantly decreased morbidity of diabetes, ameliorated hyperglycemia and insulin deficiency, and inhibited lymphocyte infiltration into the islets, indicating the protection of β cells against autoimmune destruction. CGRP gene transfer significantly inhibited T cell proliferation and secretion of the Th1 cytokine IFN‐γ, increased the level of the Th2 cytokine IL‐10, but had no effect on IL‐4 and TGF‐β1 secretion. CGRP gene transfer also decreased IL‐12 and IFN‐γ levels in peritoneal effusion. Our results demonstrate that CGRP gene transfer selectively suppresses the pro‐inflammatory Th1 subsets and promote anti‐inflammatory Th2 subsets, resulting in amelioration of β cell destruction and reduction of IDDM occurrence in mice with MLDS‐induced diabetes.
Differential requirements for JAK2 and TYK2 in T cell proliferation and IFN‐γ production induced by IL‐12 alone or together with IL‐18
Authors: Sugimoto Naotoshi , Nakahira Masakiyo , Ahn Hyun‐Jong , Micallef Mark , Hamaoka Toshiyuki , Kurimoto Masashi , Fujiwara Hiromi
Published: February 2003

IL‐12 activates TYK2 and Janus kinase (JAK)‐2 to induce the phosphorylation of various signal transducers and activators of transcription (STAT) proteins. However, little is known regarding how these JAK exhibit the distinct biological effects of IL‐12. Using two JAK inhibitors, tyrphostin A1 (A1) for TYK2 and tyrphostin B42 (B42) for JAK2, we investigated the involvement of JAK2 and TYK2 in IL‐12‐induced T cell proliferation and IFN‐γ production. B42, but not A1, inhibited T cell proliferation along with down‐regulation of IL‐12‐induced c‐Myc expression and STAT5 phosphorylation. In contrast, A1 but not B42 inhibited STAT4/STAT3 phosphorylation and IFN‐γ production. IL‐18, but not IL‐12, induced activator protein‐1 (AP‐1) responsible for high levels of IFN‐γ promoter activation. However, this IL‐18 effect depended on the interaction of AP‐1 with STAT4. A1 prevented AP‐1 binding by inhibiting STAT4 involvement and down‐regulated synergistic IFN‐γ promoter activation. These results indicate that JAK2 activation is required for IL‐12‐mediated T cell growth, whereas the TYK2‐STAT4 signaling pathway is critical for IFN‐γ expression that is mediated by IL‐12 alone and enhanced synergistically by combination with IL‐18.
Double‐edged effect of Vγ9/Vδ2 T lymphocytes on viral expression in an in vitro model of HIV‐1/mycobacteria co‐infection
Authors: Biswas Priscilla , Ferrarini Marina , Mantelli Barbara , Fortis Claudio , Poli Guido , Lazzarin Adriano , Manfredi Angelo A.
Published: February 2003

A reciprocal influence exists between mycobacteria and HIV: HIV‐infected individuals are more susceptible to mycobacterial infections and, on the other hand, mycobacterial infection results inacceleration of HIV disease progression. Vγ9/Vδ2 T lymphocytes are known to participate in the defense against intracellular pathogens, including Mycobacterium tuberculosis. Indeed, they kill mycobacteria‐infected macrophages and, upon recognition of mycobacterial Ag, release TNF‐α and IFN‐γ, which are also up‐regulators of HIV expression. To assess whether mycobacteria‐activated γ δ T lymphocytes contribute to the enhancement of HIV replication, we established an in vitro model mimicking HIV and mycobacteria co‐infection with the latently HIV‐infected promonocytic U1 cell line and Vγ9/Vδ2 peripheral lymphocytes stimulated with mycobacterial Ag. γ δ T cell activation determined two distinct, but connected effects, namely U1cell death and HIV expression. Both effects were mainly mediated by release of TNF‐α and IFN‐γ from activated γ δ lymphocytes, although Fas‐FasL interaction also contributed to U1 apoptosis. The final outcome on U1 survival, and thus, on HIV expression, highly depended on mycobacterial Ag concentration coupled to the differential secretory potency of γ δ cells. In particular, the induction of viral expression prevailed at low Ag concentration and with lower cytokine production by mycobacteria‐activated γ δ cells. Notably, during the course of HIV infection, Vγ9/Vδ2 lymphocytes are reported to be functionally impaired and may thus indirectly influence the progression of HIV disease. In addition, a predominant inhibition of viral replication was encountered when mycobacteria‐activated γ δ T cells were co‐cultured with primary HIV‐infected macrophages. Thus, we suggest that specific recognition of mycobacterial Ag by γ δ T lymphocytes in co‐infected individuals may modulate viral replication through the complex array of soluble factors released.
A major role for tapasin as a stabilizer of the TAP peptide transporter and consequences for MHC class I expression
Authors: Garbi Natalio , Tiwari Neeraj , Momburg Frank , Hämmerling Günter J.
Published: February 2003

Tapasin is a member of the MHC class I loading complex where it bridges the TAP peptide transporter to class I molecules. The main role of tapasin is assumed to be the facilitation of peptide loading and optimization of the peptide cargo. Here, we describe another important function for tapasin. In tapasin‐deficient (Tpn–/–) mice the absence of tapasin was found to have a dramatic effect on the stability of the TAP1/TAP2 heterodimeric peptide transporter. Steady‐state expression of TAP protein was reduced more than 100‐fold from about 3×104 TAP molecules per wild‐type splenocyte to about 1×102 TAP per Tpn–/– splenocyte. Thus, a major function of murine tapasin appears to be the stabilization of TAP. The low amount of TAP moleculesin Tpn–/– lymphocytes is likely to contribute to the severe impairment of MHC class I expression. Surprisingly, activation of Tpn–/– lymphocytes yielded strongly enhanced class I expression comparable to wild‐type levels, although TAP expression remained low and in the magnitude of several hundred molecules per cell. The high level of class I on activated Tpn–/– cells depended on peptides generated by the proteasome as indicated by blockade with the proteasome‐specific inhibitor lactacystin. Lymphocyte activation induced an increase in ubiquitinated proteins that are cleaved into peptides by the proteasome. These findings suggest that in the presence of a large peptide pool in the cytosol, a small number of TAP transporters is sufficient to translocate enough peptides for high class I expression. However, these class I molecules were less stable than those of wild‐type cells, indicating that tapasin is not only required for stabilization of TAP butalso for optimization of the spectrum of bound peptides.
Computation and analysis of multiple structural change models
Authors: Bai Jushan , Perron Pierre
Published: February 2003

In a recent paper, Bai and Perron (1998) considered theoretical issues related to the limiting distribution of estimators and test statistics in the linear model with multiple structural changes. In this companion paper, we consider practical issues for the empirical applications of the procedures. We first address the problem of estimation of the break dates and present an efficient algorithm to obtain global minimizers of the sum of squared residuals. This algorithm is based on the principle of dynamic programming and requires at most least‐squares operations of orderO(T2) for any number of breaks. Our method can be applied to both pure and partial structural change models. Second, we consider the problem of forming confidence intervals for the break dates under various hypotheses about the structure of the data and the errors across segments. Third, we address the issue of testing for structural changes under very general conditions on the data and the errors. Fourth, we address the issue of estimating the number of breaks. Finally, a few empirical applications are presented to illustrate the usefulness of the procedures. All methods discussed are implemented in a GAUSS program. Copyright © 2002 John Wiley & Sons, Ltd.