Miracle-dz/UniFAR-FTUs huggingface dataset:
Ferritin and FasL (CD95L) mediate density dependent apoptosis in primary rat hepatocytes

Based on a recent description of an apoptosis stimulating property for hepatocyte derived isoferritins, this investigation demonstrates that ferritin, released in vitro from hepatocytes substantially contributes to density dependent apoptosis in primary hepatocytes and is significantly (P ≤ 0.05) inhibited by anti‐H‐ferritin antibody rH02. Furthermore, total protein release and albumin secretion rapidly decline in a time and density dependent mode under serum‐free conditions, whereas ferritin secretion, which is upregulated at initial stages of primary culture is not affected by cell density. Supplementation with dexamethasone (DEX) or proliferative stimulation by epidermal growth factor (EGF) and insulin strongly suppresses density dependent apoptosis. Both regimens have previously been shown to inhibit isoferritin mediated apoptosis in hepatocytes, most likely by interrupting proapotitc mitochondrial signalling. Finally, FasL/Fas also participates in density dependent apoptosis, since apoptosis is significantly (P ≤ 0.005) reduced in high density cultures supplemented with an anti‐FasL antibody. This antibody has also been shown to neutralise ferritin mediated apoptosis in primary hepatocytes, suggesting a linkage of ferritin and Fas in density dependent apoptosis. In conclusion, ferritin contributes to apoptosis in primary hepatocytes in an autocrine, density dependent mode, involving Fas stimulation and proapoptotic mitochondrial signalling. With respect to liver physiology, these findings may indicate that ferritin plays a yet unrecognised role as an acute phase signalling molecule in early stages of tissue repair and liver regeneration, and may also be responsible for the limited ability to propagate human hepatocytes in culture and the limited expansion of donor cells in the recipient liver upon cell transplantation. J. Cell. Physiol. 217: 800–808, 2008. © 2008 Wiley‐Liss, Inc.
Early life events in asthma—diet

It has been hypothesized that the recent increase in the prevalence of asthma may, in part, be a consequence of changing diet. There is now increasing interest in the possibility that childhood asthma may be influenced by maternal diet during pregnancy and/or diet during early childhood. A number of observational studies and a childhood fish oil supplementation study provide little support for the notion that early childhood intake of polyunsaturated fatty acids (PUFAs) influence the development of childhood asthma. Recent work however, suggests that supplementation of maternal diet with fish oil is associated with altered neonatal immune responses to allergens. Further work is required to establish whether this immunological observation is translated into clinical outcomes. Two birth cohorts have now reported reduced maternal intake of vitamin E, zinc and vitamin D during pregnancy to be associated with increased asthma and wheezing outcomes in children up to the age of 5 years. Early life diet could modulate the likelihood of childhood asthma by affecting fetal airway development and/or influencing the initial early life interactions between allergens and the immune system. In animal models, vitamin E, zinc and vitamin D have been shown to modify fetal lung development and vitamin E, zinc, vitamin D and PUFA can modulate T‐cell responses. Further research, particularly, early life intervention studies need to be carried out to establish whether early life dietary intervention can be used as a public health measure to reduce the prevalence of childhood asthma. Pediatr Pulmonol. 2007; 42:663–673. © 2007 Wiley‐Liss, Inc.
Access to Justice and Land Disputes in Ghana’s State Courts: The Litigants’ Perspective

Abstract The majority of land in Ghana is still held under a diversity of customary tenures, embedded in family, community and chiefly institutions; but land disputes may be adjudicated in a variety of institutions: informal arbitrations and family tribunals, chiefs’ courts, quasi-legal state agencies and the formal state courts. Current debates on how to protect the land rights of the majority of customary land holders revolve around the respective merits of customary and non-state regulation (said to be accessible, flexible and socially embedded), and state systems, which are said to offer more certainty, impartiality and non-discriminatory codes and procedures. In Ghana, however, customary and state legal codes have been integrated for some time, and the state courts, which are frequently used as first instance adjudicators, apply customary rules. Does this mean that in Ghana the merits of customary law can be combined with the certainty and enforceability of state court dispute settlement? Based primarily on survey and interview data, the research analyses how litigants in three selected state courts perceived the experience of taking their land cases to court. It was found that, in spite of the problems and delays associated with the state courts, there was a very strong demand for authoritative and enforceable remedies which only the state could provide. It was also found that the justice offered by the state courts was not as alien or inappropriate as commonly supposed. Particularly in the Magistrates Court, judges were well respected and their procedures seen as sufficiently flexible and user-friendly. Moreover, the extreme reluctance to entertain out-of- court settlements casts doubt on the notion that proposals to move to more use of ADRs will be successful if they fail to offer equivalent authority, fairness and enforceability.
LIGHT AND ELECTRON MICROSCOPIC STUDIES ON AN AUTONOMOUS STILBESTROL-INDUCED PITUITARY TUMOR IN RATS.

The morphology of an autonomous diethylstilbestrol-induced pituitary tumor (Furth’s tumor MtT-F4) has been studied by light and electron microscopy. This tumor, besides having mammotrophic and somatotrophic activities, exerts an adrenocorticotrophic effect. The cells of the tumors contain minute, faintly stainable granules. In electron micrographs, there is but one type of secretory granule, measuring up to about 350 ran m diameter. It has the same appearance as the acidophil granules of the so-called growth hormone type. The findings are discussed with respect to the possibility that the pituitary gland contains pluripotent cells whose secretion can be differentiated to satisfy functional demands and that this causes them to present morphological characteristics of either basophils or acidophils. (Endocrinology 75: 893, 1964)
Neuronal K+/Cl– co‐transporter (KCC2) transgenes lacking neurone restrictive silencer element recapitulate CNS neurone‐specific expression and developmental up‐regulation of endogenous KCC2 gene

The K+/Cl– co‐transporter KCC2 maintains the low intracellular chloride concentration required for fast synaptic inhibition and is exclusively expressed in neurones of the CNS. Here, we show that the KCC2 gene (alias SLC12a5) has multiple transcription start sites and characterize the activity of 6.8 kb of mouse KCC2 gene regulatory sequence (spanning 1.4 kb upstream from exon 1 to exon 2) using luciferase reporters. Overexpression of neurone‐restrictive silencer factor repressed the reporter activity in vitro, apparently via a neurone restrictive silencer element (NRSEKCC2) within intron 1 of the mouse KCC2 gene. In transgenic mice, however, KCC2 reporters with or without deletion of the NRSEKCC2 were expressed exclusively in neurones and predominantly in the CNS with a similar pattern and developmental up‐regulation as endogenous KCC2. Moreover, a third transgene with just a 1.4‐kb KCC2 promoter region lacking the NRSEKCC2‐bearing intron 1 was still expressed predominantly in neural tissues. Thus, developmental up‐regulation of the KCC2 gene does not require NRSEKCC2 and the 1.4‐kb KCC2 promoter is largely sufficient for neurone‐specific expression of KCC2.
Active standing and passive tilting similarly reduce the slope of spontaneous baroreflex in healthy subjects.

Non-invasive assessment of the sensitivity of cardiac baroreflex was performed by recording each RR-interval and each blood pressure cycle (Finapres). In sequences of at least three cardiac cycles in which systolic blood pressure and RR-interval had changed in the same direction, the slope of linear regression of RR duration as a function of the change in systolic arterial pressure was taken for estimating the sensitivity of the spontaneous cardiac baroreflex. This technique was used in healthy humans to examine how a postural change from supine to upright by either active standing up or 60 degrees head-up tilting modified the sensitivity of the spontaneous baroreflex. We observed that the slope of the spontaneous baroreflex averaged 14.6 +/- 2 ms.mm Hg-1 during rest in the supine position, and decreased to 7.8 +/- 1.2 ms.mm Hg-1 (p < 0.05) after active standing, while the number of sequences was significantly increased in the upright as compared to the supine position. Head-up tilting by 60 degrees led to values similar to those following active standing. The adjustment of baroreflex slope to either postural change occurred in a few seconds, so that posture-characteristic values were obtained from five-minute records. We conclude that non-invasive recording of spontaneous sequences of related changes in blood pressure and RR-interval during several minutes provides reproducible values of the slope of cardiac baroreflex in the supine and upright position. This easy and reliable determination of the sensitivity of the cardiac baroreflex might prove to be useful when assessment of baroreflex function is needed.
Biochemical Antioxidant Levels Respond to Supplementation with an Enriched Drink in Frail Elderly People

Objective: To investigate whether a drink enriched with essential vitamins and minerals can improve biochemical status of enzymatic and non-enzymatic antioxidants in frail elderly people. Methods: A six-month randomized, double blind, placebo controlled intervention study. Frail elderly people 65 years of age or older, with a body mass index (BMI) below 25 kg/m2 and residing in a home for the elderly or in sheltered housing. Enriched (with essential vitamins and minerals in 30% to 150% of RDA and higher levels of antioxidants) drink (n = 28) or placebo (n = 27) to be taken twice a day in addition to the normal food consumed. Plasma levels of vitamin C, vitamin E, antioxidant capacity (TEAC), cysteine, uric acid and whole blood levels of total thiol and glutathione peroxidase (GSH-Px), dietary intake. Results: Changes in vitamin E (16 ± 2 vs. 2 ± 1 mmol/L), vitamin C (37 ± 5 vs. 1 ± 5 mmol/L), TEAC (38 ± 15 vs. −10 ± 11 mmol/L Trolox eq) and cysteine (17 ± 10 vs. 0.4 ± 6 mmol/L) were significantly different between groups (p < 0.05). There was a trend towards significant changes in erythrocyte glutathione peroxidase (−0.2 ± 3 vs. −10 ± 7 U/mg Hb, p = 0.097). Baseline dietary intake of antioxidant vitamins was below 2/3 RDA for a substantial proportion (43% to 76%) of subjects. Conclusions: Supplementation with an enriched drink can raise plasma levels of enzymatic and non-enzymatic antioxidants in frail elderly people.
Lipocalin-2 Protein Deficiency Ameliorates Experimental Autoimmune Encephalomyelitis

Background: The role of LCN2 in EAE is not clear. Results: LCN2 expression increased in EAE. Lcn2 deficiency attenuated EAE symptoms and pathology. LCN2 enhanced glial expression of inflammatory mediators and peripheral encephalitogenic T cell activation in vitro and in vivo. Conclusion: Both central and peripheral LCN2 contributed to EAE development. Significance: LCN2 can be targeted for treatment of multiple sclerosis. Lipocalin-2 (LCN2) plays an important role in cellular processes as diverse as cell growth, migration/invasion, differentiation, and death/survival. Furthermore, recent studies indicate that LCN2 expression and secretion by glial cells are induced by inflammatory stimuli in the central nervous system. The present study was undertaken to examine the regulation of LCN2 expression in experimental autoimmune encephalomyelitis (EAE) and to determine the role of LCN2 in the disease process. LCN2 expression was found to be strongly increased in spinal cord and secondary lymphoid tissues after EAE induction. In spinal cords astrocytes and microglia were the major cell types expressing LCN2 and its receptor 24p3R, respectively, whereas in spleens, LCN2 and 24p3R were highly expressed in neutrophils and dendritic cells, respectively. Furthermore, disease severity, inflammatory infiltration, demyelination, glial activation, the expression of inflammatory mediators, and the proliferation of MOG-specific T cells were significantly attenuated in Lcn2-deficient mice as compared with wild-type animals. Myelin oligodendrocyte glycoprotein-specific T cells in culture exhibited an increased expression of Il17a, Ifng, Rorc, and Tbet after treatment with recombinant LCN2 protein. Moreover, LCN2-treated glial cells expressed higher levels of proinflammatory cytokines, chemokines, and MMP-9. Adoptive transfer and recombinant LCN2 protein injection experiments suggested that LCN2 expression in spinal cord and peripheral immune organs contributes to EAE development. Taken together, these results imply LCN2 is a critical mediator of autoimmune inflammation and disease development in EAE and suggest that LCN2 be regarded a potential therapeutic target in multiple sclerosis.
Glycolytic and Non-glycolytic Functions of Mycobacterium tuberculosis Fructose-1,6-bisphosphate Aldolase, an Essential Enzyme Produced by Replicating and Non-replicating Bacilli*

Background: New drugs active against persistent Mycobacterium tuberculosis are needed. Results: The fructose-1,6-bisphosphate aldolase (FBA-tb) is essential for growth of M. tuberculosis, is expressed by replicating and non-replicating bacilli, and displays plasminogen binding activity. Conclusion: FBA-tb is an essential TB enzyme that might also play a role in host/pathogen interactions. Significance: FBA-tb shows potential as a novel anti-TB therapeutic target. The search for antituberculosis drugs active against persistent bacilli has led to our interest in metallodependent class II fructose-1,6-bisphosphate aldolase (FBA-tb), a key enzyme of gluconeogenesis absent from mammalian cells. Knock-out experiments at the fba-tb locus indicated that this gene is required for the growth of Mycobacterium tuberculosis on gluconeogenetic substrates and in glucose-containing medium. Surface labeling and enzymatic activity measurements revealed that this enzyme was exported to the cell surface of M. tuberculosis and produced under various axenic growth conditions including oxygen depletion and hence by non-replicating bacilli. Importantly, FBA-tb was also produced in vivo in the lungs of infected guinea pigs and mice. FBA-tb bound human plasmin(ogen) and protected FBA-tb-bound plasmin from regulation by α2-antiplasmin, suggestive of an involvement of this enzyme in host/pathogen interactions. The crystal structures of FBA-tb in the native form and in complex with a hydroxamate substrate analog were determined to 2.35- and 1.9-Å resolution, respectively. Whereas inhibitor attachment had no effect on the plasminogen binding activity of FBA-tb, it competed with the natural substrate of the enzyme, fructose 1,6-bisphosphate, and substantiated a previously unknown reaction mechanism associated with metallodependent aldolases involving recruitment of the catalytic zinc ion by the substrate upon active site binding. Altogether, our results highlight the potential of FBA-tb as a novel therapeutic target against both replicating and non-replicating bacilli.
A second family with autosomal recessive spondylometaphyseal dysplasia and early death

We report on a consanguineous Lebanese family in which two sibs had pre‐ and post‐natal growth retardation, developmental delay, large anterior fontanel, prominent forehead, low‐set ears, depressed nasal bridge, short nose, anteverted nares, increased nasal width, prominent abdomen, and short limbs. Radiographs disclosed the presence of wormian bones, platyspondyly, decreased interpedicular distance at the lumbar vertebrae, square iliac bones, horizontal acetabula, trident acetabula, hypoplastic ischia, partial agenesis of the sacrum, ribs with cupped ends, short long bones with abnormal modeling, slight widening of the distal femoral metaphyses, and delayed epiphyseal ossification. Both sibs had a severe cardiomegaly and died at around 24 months from a heart failure. Differential diagnosis suggests that this is a second family presenting a newly described early lethal chondrodysplasia first reported by [Mégarbané et al. (2008); Am J Med Genet Part A 146A:2916–2919]. © 2014 Wiley Periodicals, Inc.
Impaired Motor Coordination in Mice That Lackpunc

ABSTRACT The punc gene, encoding a member of the neural cell adhesion molecule family expressed in the developing central nervous system, limbs, and inner ear, was identified. To extend studies of the normal expression pattern of punc and to determine its function, a mouse strain bearing a lacZ/neo insertion in a 5′ coding exon was created. The complex pattern of puncexpression in embryos from embryonic day 9.5 (E9.5) to E11.5 was mimicked accurately by β-galactosidase (β-Gal) activity. As development proceeded, the distribution of β-Gal activity was increasingly restricted, finally becoming confined to the brain and inner ear by E15.5. In the adult, β-Gal activity was detected in several regions of the inner ear and brain and was particularly strong in the cerebellar Bergmann glia. Genetic analysis of this null allele demonstrated that punc is not required for normal embryogenesis. Interestingly, comparisons of β-Gal activity andpunc transcripts in heterozygous and homozygous mutant individuals demonstrated that punc is negatively autoregulated in some tissues. Adult punc-deficient mice were overtly normal and had normal hearing. Compared with control littermates, however, homozygous mutants had significantly reduced retention times on the Rotarod, suggesting a role for Bergmann glia-expressed Punc in the cerebellar control of motor coordination.
THE ENDONASAL MICROSCOPIC APPROACH FOR PITUITARY ADENOMAS AND OTHER PARASELLAR TUMORS: A 10‐YEAR EXPERIENCE

THE DIRECT ENDONASAL transsphenoidal approach to the sella with the operating microscope was initially described more than 20 years ago. Herein, we describe the technique, its evolution, and lessons learned over a 10-year period for treating pituitary adenomas and other parasellar pathology. From July 1998 to January 2008, 812 patients underwent a total of 881 operations for a pituitary adenoma (n = 605), Rathke's cleft cyst (n = 59), craniopharyngioma (n = 26), parasellar meningioma (n = 23), chordoma (n = 18), or other pathological condition (n = 81). Of these, 118 operations (13%) included an extended approach to the suprasellar, infrasellar/clival, or cavernous sinus regions. Endoscopic assistance was used in 163 cases (19%) overall, including 36% of the last 200 cases in the series and 18 (72%) of the last 25 extended endonasal cases. Surgical complications included 19 postoperative cerebrospinal fluid leaks (2%), 6 postoperative hematomas (0.7%), 4 carotid artery injuries (0.4%), 4 new permanent neurological deficits (0.4%), 3 cases of bacterial meningitis (0.3%), and 2 deaths (0.2%). The overall complication rate was higher in the first 500 cases in the series and in extended approach cases. Major technical modifications over the 10-year period included increased use of shorter (60–70 mm) endonasal speculums for greater instrument maneuverability and visualization, the micro-Doppler probe for cavernous carotid artery localization, endoscopy for more panoramic visualization, and a graded cerebrospinal fluid leak repair protocol. These changes appear to have collectively and incrementally made the approach safer and more effective. In summary, the endonasal approach provides a minimally invasive route for removal of pituitary adenomas and other parasellar tumors.
Extracellular matrix proteins secreted from both the endometrium and the embryo are required for attachment: A study using a co‐culture model of rat blastocysts and Ishikawa cells

Integrins are expressed in a highly regulated manner at the maternal‐fetal interface during implantation. However, the significance of extracellular matrix (ECM) ligands during the integrin‐mediated embryo attachment to the endometrium is not fully understood. Thus, the distribution of fibronectin in the rat uterus and blastocyst was studied at the time of implantation. Fibronectin was absent in the uterine luminal epithelial cells but was intensely expressed in the trophoblast cells and the inner cell mass suggesting that fibronectin secreted from the blastocyst may be a possible bridging ligand for the integrins expressed at the maternal‐fetal interface. An Arg‐Gly‐Asp (RGD) peptide was used to block the RGD recognition sites on integrins, and the effect on rat blastocyst attachment to Ishikawa cells was examined. There was a significant reduction in blastocyst attachment when either the blastocysts or the Ishikawa cells were pre‐incubated with the RGD‐blocking peptide. Thus, successful attachment of the embryo to the endometrium requires the interaction of integrins on both the endometrium and the blastocyst with the RGD sequence of ECM ligands, such as fibronectin. Pre‐treatment of both blastocysts and Ishikawa cells with the RGD peptide also inhibited blastocyst attachment, but not completely, suggesting that ECM bridging ligands that do not contain the RGD sequence are also involved in embryo attachment. J. Morphol. 2013. © 2012 Wiley Periodicals, Inc.
Inability to Induce Tolerance Through Direct Antigen Presentation

Both the direct and indirect antigen presentation pathways are important mechanisms for T cell‐mediated allograft rejection. Studies using knockout mice and monoclonal antibodies have demonstrated that CD4+ T cells are both necessary and sufficient for the rejection of allogeneic tissues, including skin, heart, and islet. Furthermore, combined blockade of the CD28/B7 and CD154/CD40 costimulatory pathways induces tolerance in multiple CD4+ T‐cell dependent allograft models. In this study, we addressed the T‐cell requirement for costimulation in direct antigen presentation. We demonstrated that class II‐specific alloreactive T‐cell receptor transgenic T cells were sufficient to mediate allograft rejection independent of costimulatory blockade. Analysis of the costimulatory capacity of different antigen presenting cell (APC) populations demonstrated that APCs resident within the donor skin, Langerhans cells, are potent stimulators not requiring CD28‐ or CD154‐dependent costimulation for direct major histocompatibility complex (MHC) antigen presentation. These results complement previous work examining the role of costimulation on CD8+ T cells, supporting a model in which the effectiveness of costimulatory blockade in the setting of transplantation may be selective for the indirect pathway of MHC alloantigen presentation.