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(22 References)

Kim, S. H., J. W. Creemers, et al. (2002). "Proteolytic processing of familial British dementia-associated BRI variants: evidence for enhanced intracellular accumulation of amyloidogenic peptides." J Biol Chem 277(3): 1872-7.

            Different mutations in the BRI(2) gene cause rare neurodegenerative conditions, termed familial British dementia (FBD) and familial Danish dementia (FDD). The mutant genes encode BRI-L and BRI-D, the precursors of fibrillogenic ABri and ADan peptides, respectively. We previously reported that furin processes both BRI-L and its wild type counterpart, BRI, resulting in the secretion of C-terminal peptides; elevated levels of peptides were generated from BRI-L. In the present study, we show that inducible expression of alpha1-antitrypsin Portland, a furin inhibitor, inhibits the endoproteolysis of BRI and BRI-L in a dose-dependent manner. Moreover, comparison of the activities of several proprotein convertases reveals that furin is most efficient in endoproteolysis of BRI and BRI-L; PACE4, PC6A, PC6B, and LPC show much lower activities. Interestingly, LPC also exhibits enhanced cleavage of BRI-L compared with BRI. Finally, we demonstrate that BRI-D is also processed by furin and, like BRI-L, the cleavage of BRI-D is more efficient than that of BRI. Interestingly, while the ABri peptide is detected both intracellularly and in the medium, the ADan peptide accumulates predominantly in intracellular compartments. We propose that intracellular accumulation of amyloidogenic ADan or ABri peptides results in the neuronal damage leading to FDD and FBD, respectively.

Austen, B., O. El-Agnaf, et al. (2002). "Properties of neurotoxic peptides related to the BRI gene." Biochem Soc Trans 30(4): 557-9.

            Mutations in the BRI gene are thought to cause dementias in members of families. The clinical symptoms are similar to those of Alzheimer's disease, but with additional ocular and hearing deficits, and spasticity. The mutations lead to the release of the 34-residue peptides, ABri and ADan, in the brains of afflicted individuals. We have synthesized the peptides in their straight-chain and oxidized cyclic forms and shown that the oxidized form of ABri and reduced form of ADan are toxic to human neuronal cell lines in culture. Neurotoxicity correlates with the extent of formation of SDS-stable non-fibrillar low-molecular-mass oligomers (SSNFOs).

Aharinejad, S., M. Fink, et al. (2002). "Efficient carboplatin single therapy in a mouse model of human testicular nonseminomatous germ cell tumor." J Urol 167(1): 368-74.

            PURPOSE: Cisplatin based combination therapy has shown excellent clinical results in patients with testicular nonseminomatous germ cell tumor but chemotherapy induced morbidity and reduced patient compliance are limiting factors in this regimen. To decrease cisplatin based combination therapy induced morbidity we examined carboplatin versus etoposide single therapy in an animal model. MATERIALS AND METHODS: A total of 180 SCID mice bearing testicular nonseminomatous germ cell tumor xenografts received 120 mg./kg. carboplatin as a single cycle, 60 or 30 mg./kg. carboplatin cycled twice, 80, 50 or 30 mg./kg. etoposide cycled twice, or Ringer solution as the control. An additional 20 sham treated and 20 untreated mice also served as controls. Histological and immunocytochemical testing, in vivo microscopy, vascular corrosion casting, serum tumor markers, complete blood count and real-time polymerase chain reaction were used to monitor therapy efficacy. RESULTS: Carboplatin at 60 mg./kg. cycled twice eradicated the tumor and significantly reduced vascular density and vascular endothelial growth factor-A messenger RNA (p <0.05). Elevated tumor markers returned to baseline after carboplatin administration. Therapy was well tolerated, resulting thrombocytopenia disappeared 6 weeks after therapy and the animals were tumor-free 6 months after treatment. Although 120 mg./kg. carboplatin eradicated the tumor, it resulted in extensive mortality and morbidity. Single treatment 30, 50 and 80 mg./kg. etoposide failed. CONCLUSIONS: Carboplatin single therapy was highly effective in our nonseminomatous germ cell tumor model and it may be examined in future clinical trials in patients with high risk stage I nonseminomatous germ cell cancer for reducing cisplatin based combination therapy induced morbidity. Vascular density and vascular endothelial growth factor messenger RNA were elevated in our animal model and deserve further study in nonseminomatous germ cell tumor cases as potential risk factors.

Aharinejad, S., D. Abraham, et al. (2002). "Colony-stimulating Factor-1 Antisense Treatment Suppresses Growth of Human Tumor Xenografts in Mice." Cancer Res 62(18): 5317-24.

            Matrix metalloproteinases (MMPs) foster cellular invasion by disrupting extracellular matrix barriers and thereby facilitate tumor development. MMPs are synthesized by both cancer cells and adjacent stromal cells, primarily macrophages. The production of macrophages is regulated by colony-stimulating factor-1 (CSF-1). Tissue CSF-1 expression increased significantly in embryonic and colon cancer xenografts. We, therefore, hypothesized that blocking CSF-1 may suppress tumor growth by decelerating macrophage-mediated extracellular matrix breakdown. Cells expressing CSF-1 and mice xenografted with CSF-1 receptor (c-fms)- and CSF-1-negative malignant human embryonic or colon cancer cells were treated with mouse CSF-1 antisense oligonucleotides. Two weeks of CSF-1 antisense treatment selectively down-regulated CSF-1 mRNA and protein tissue expression in tumor lysates. CSF-1 blockade suppressed the growth of embryonic tumors to dormant levels and the growth of the colon carcinoma by 50%. In addition, tumor vascularity and the expression of MMP-2 and angiogenic factors were reduced. Six-month survival was observed in colon carcinoma mice only after CSF-1 blockade, whereas controls were all dead at day 65. These results suggest that human embryonic and colon cancer cells up-regulate host CSF-1 and MMP-2 expression. Because the cancer cells used were CSF-1 negative, CSF-1 antisense targeted tumor stromal cell CSF-1 production. CSF-1 blockade could be a novel strategy in treatment of solid tumors.

Lewis, P. A., S. Piper, et al. (2001). "Expression of BRI-amyloid beta peptide fusion proteins: a novel method for specific high-level expression of amyloid beta peptides." Biochim Biophys Acta 1537(1): 58-62.

            In order to develop transgenic animal models that selectively overexpress various Abeta peptides, we have developed a novel expression system that selectively expresses Abeta40 or Abeta42 in the secretory pathway. This system utilizes fusion constructs in which the sequence encoding the 23-amino-acid ABri peptide at the carboxyl terminus of the 266-amino-acid type 2 transmembrane protein BRI is replaced with a sequence encoding either Abeta40 or Abeta42. Constitutive processing of the resultant BRI-Abeta fusion proteins in transfected cells results in high-level expression and secretion of the encoded Abeta peptide. Significantly, expression of Abeta42 from the BRI-Abeta42 construct resulted in no increase in secreted Abeta40, suggesting that the majority of Abeta42 is not trimmed by carboxypeptidase to Abeta40 in the secretory pathway.

Holton, J. L., J. Ghiso, et al. (2001). "Regional distribution of amyloid-Bri deposition and its association with neurofibrillary degeneration in familial British dementia." Am J Pathol 158(2): 515-26.

            Familial British dementia (FBD), pathologically characterized by cerebral amyloid angiopathy (CAA), amyloid plaques, and neurofibrillary degeneration, is associated with a stop codon mutation in the BRI gene resulting in the production of an amyloidogenic fragment, amyloid-Bri (ABri). The aim of this study was to assess the distribution of ABri fibrillar and nonfibrillar lesions and their relationship to neurofibrillary pathology, astroglial and microglial response using immunohistochemistry, confocal microscopy, and immunoelectron microscopy in five cases of FBD. Abnormal tau was studied with immunoblotting. We present evidence that ABri is deposited throughout the central nervous system in blood vessels and parenchyma where both amyloid (fibrillar) and pre-amyloid (nonfibrillar) lesions are formed. Ultrastructurally amyloid lesions appear as bundles of fibrils recognized by an antibody raised against ABri, whereas Thioflavin S-negative diffuse deposits consist of amorphous electron-dense material with sparse, dispersed fibrils. In contrast to nonfibrillar lesions, fibrillar ABri is associated with a marked astrocytic and microglial response. Neurofibrillary tangles and neuropil threads occurring mainly in limbic structures, are found in areas affected by all types of ABri lesions whereas abnormal neurites are present around amyloid lesions. Immunoblotting for tau revealed a triplet electrophoretic migration pattern. Our observations confirm a close link between ABri deposition and neurodegeneration in FBD.

Ghiso, J. A., J. Holton, et al. (2001). "Systemic amyloid deposits in familial British dementia." J Biol Chem 276(47): 43909-14.

            Familial British dementia (FBD) is an early onset inherited disorder that, like familial Alzheimer's disease (FAD), is characterized by progressive dementia, amyloid deposition in the brain, and neurofibrillary degeneration of limbic neurons. The primary structure of the amyloid subunit (ABri) extracted from FBD brain tissues (Vidal, R., Frangione, B., Rostagno, A., Mead, S., Revesz, T., Plant, G., and Ghiso, J. (1999) Nature 399, 776-781) is entirely different and unrelated to any previously known amyloid protein. Patients with FBD have a single nucleotide substitution at codon 267 in the BRI2 gene, resulting in an arginine replacing the stop codon and a longer open reading frame of 277 amino acids instead of 266. The ABri peptide comprises the 34 C-terminal residues of the mutated precursor ABriPP-277 and is generated via furin-like proteolytic processing. Here we report that carriers of the Stop-to-Arg mutation have a soluble form of the amyloid peptide (sABri) in the circulation with an estimated concentration in the range of 20 ng/ml, several fold higher than that of soluble Abeta. In addition, ABri species identical to those identified in the brain were also found as fibrillar components of amyloid deposits predominantly in the blood vessels of several peripheral tissues, including pancreas and myocardium. We hypothesize that the high concentration of the soluble de novo created amyloidogenic peptide and/or the insufficient tissue clearance are the main causative factors for the formation of amyloid deposits outside the brain. Thus, FBD constitutes the first documented cerebral amyloidosis associated with neurodegeneration and dementia in which the amyloid deposition is also systemic.

Ghiso, J., T. Revesz, et al. (2001). "Chromosome 13 dementia syndromes as models of neurodegeneration." Amyloid 8(4): 277-84.

            Two hereditary conditions, familial British dementia (FBD) and familial Danish dementia (FDD), are associated with amyloid deposition in the central nervous system and neurodegeneration. The two amyloid proteins, ABri and ADan, are degradation products of the same precursor molecule BriPP bearing different genetic defects, namely a Stop-to-Arg mutation in FBD and a ten-nucleotide duplication-insertion immediately before the stop codon in FDD. Both de novo created amyloid peptides have the same length (34 amino acids) and the same post-translational modification (pyroglutamate) at their N-terminus. Neurofibrillary tangles containing the classical paired helical filaments as well as neuritic components in many instances co-localize with the amyloid deposits. In both disorders, the pattern of hyperphosphorylated tau immunoreactivity is almost indistinguishable from that seen in Alzheimer's disease. These issues argue for the primary importance of the amyloid deposits in the mechanism(s) of neuronal cell loss. We propose FBD and FDD, the chromosome 13 dementia syndromes, as models to study the molecular basis of neurofibrillary degeneration, cell death and amyloid formation in the brain.

El-Agnaf, O. M., J. M. Sheridan, et al. (2001). "Effect of the disulfide bridge and the C-terminal extension on the oligomerization of the amyloid peptide ABri implicated in familial British dementia." Biochemistry 40(12): 3449-57.

            Familial British dementia (FBD) is a rare neurodegenerative disorder and shares features with Alzheimer's disease, including amyloid plaque deposits, neurofibrillary tangles, neuronal loss, and progressive dementia. Immunohistochemical and biochemical analysis of plaques and vascular amyloid of FBD brains revealed that a 4 kDa peptide named ABri is the main component of the highly insoluble amyloid deposits. In FBD patients, the ABri peptide is produced as a result of a point mutation in the usual stop codon of the BRI gene. This mutation produces a BRI precursor protein 11 amino acids longer than the wild-type protein. Mutant and wild-type precursor proteins both undergo furin cleavage between residues 243 and 244, producing a peptide of 34 amino acids in the case of ABri and 23 amino acids in the case of the wild-type (WT) peptide. Here we demonstrate that the intramolecular disulfide bond in ABri and the C-terminal extension are required to elongate initially formed dimers to oligomers and fibrils. In contrast, the shorter WT peptide did not aggregate under the same conditions. Conformational analyses indicate that the disulfide bond and the C-terminal extension of ABri are required for the formation of beta-sheet structure. Soluble nonfibrillar ABri oligomers were observed prior to the appearance of mature fibrils. A molecular model of ABri containing three beta-strands, and two beta-hairpins annealed by a disulfide bond, has been constructed, and predicts a hydrophobic surface which is instrumental in promoting oligomerization.

El-Agnaf, O. M., S. Nagala, et al. (2001). "Non-fibrillar oligomeric species of the amyloid ABri peptide, implicated in familial British dementia, are more potent at inducing apoptotic cell death than protofibrils or mature fibrils." J Mol Biol 310(1): 157-68.

            Familial British dementia (FBD) is an autosomal dominant neurodegenerative disorder, with biochemical and pathological similarities to Alzheimer's disease. FBD is associated with a point mutation in the stop codon of the BRI gene. The mutation extends the length of the wild-type protein by 11 amino acids, and following proteolytic cleavage, results in the production of a cyclic peptide (ABri) 11 amino acids longer than the wild-type (WT) peptide produced from the normal gene BRI. ABri was found to be the main component of amyloid deposits in FBD brains. However, pathological examination of FBD brains has shown the presence of ABri as non-fibrillar deposits as well as amyloid fibrils. Taken together, the genetic, pathological and biochemical data support the hypothesis that ABri deposits play a central role in the pathogenesis of FBD. Here we report that ABri, but not WT peptide, can oligomerise and form amyloid-like fibrils. We show for the first time that ABri induces apoptotic cell death, whereas WT is not toxic to cells. Moreover, we report the novel findings that non-fibrillar oligomeric species of ABri are more toxic than protofibrils and mature fibrils. These findings provide evidence that non-fibrillar oligomeric species are likely to play a critical role in the pathogenesis of FBD and suggest that a similar process may also operate in other neurodegenerative diseases.

Bhargava, D., B. Bhusnurmath, et al. (2001). "Tonsillar actinomycosis: a clinicopathological study." Acta Trop 80(2): 163-8.

            Actinomycosis has been known to involve virtually every anatomic site in the body. Although actinomycosis has been identified in resected tonsils, its possible role in adeno-tonsillar disease has received little attention. A clinicopathological study of 302 patients who had adeno-tonsillar surgery is presented. Tonsillar actinomycosis was present in 86 (28.5%) patients. The statistical analysis revealed a significant association (P<0.0001) of actinomycosis and tonsillar hypertrophy (56.8%) compared to only 10.3% in the recurrent tonsillitis group. A statistically significant association (P<0.0001) of tonsillar actinomycosis and sickle cell anaemia, beta thalassaemia, bronchial asthma and beta haemolytic streptococcal infections was also seen. This data supports a predisposition of the above conditions to tonsillar actinomycosis and adeno-tonsillar hypertrophy and a possible etiopathologic role of this organism in adeno-tonsillar hypertrophy and disease. Although the clinical association of actinomycosis and tonsillar hypertrophy and beta haemolytic streptococcal infection has been described before the association of actinomycosis with sickle cell anaemia, beta thalassaemia and bronchial asthma is being observed for the first time in literature.

Baler, R. (2001). "Clockless yeast and the gears of the clock: how do they mesh?" J Biol Rhythms 16(6): 516-22.

            In spite of its apparent weakness as a clock model, the budding yeast has spawned a technique that has revolutionized our ability to study specific protein-protein interactions like those at the core of the molecular timekeeping mechanisms. Here, the author will summarize the evolution, power, and limitations of this technique and highlight its potential and actual contributions to the field of chronobiology.

Yamada, M. (2000). "Cerebral amyloid angiopathy: an overview." Neuropathology 20(1): 8-22.

            Cerebral amyloid angiopathy (CAA) is characterized by amyloid deposition in cortical and leptomeningeal vessels. Several cerebrovascular amyloid proteins (amyloid beta-protein (Abeta), cystatin C (ACys), prion protein (AScr), transthyretin (ATTR), gelsolin (AGel), and ABri (or A-WD)) have been identified, leading to the classification of several types of CAA. Sporadic CAA of Abeta type is commonly found in elderly individuals and patients with Alzheimer's disease. Cerebral amyloid angiopathy is an important cause of cerebrovascular disorders including lobar cerebral hemorrhage, leukoencephalopathy, and small cortical hemorrhage and infarction. We review the clinicopathological and molecular aspects of CAA and discuss the pathogenesis of CAA with future perspectives.

Vidal, R., T. Revesz, et al. (2000). "A decamer duplication in the 3' region of the BRI gene originates an amyloid peptide that is associated with dementia in a Danish kindred." Proc Natl Acad Sci U S A 97(9): 4920-5.

            Familial Danish dementia (FDD), also known as heredopathia ophthalmo-oto-encephalica, is an autosomal dominant disorder characterized by cataracts, deafness, progressive ataxia, and dementia. Neuropathological findings include severe widespread cerebral amyloid angiopathy, hippocampal plaques, and neurofibrillary tangles, similar to Alzheimer's disease. N-terminal sequence analysis of isolated leptomeningeal amyloid fibrils revealed homology to ABri, the peptide originated by a point mutation at the stop codon of gene BRI in familial British dementia. Molecular genetic analysis of the BRI gene in the Danish kindred showed a different defect, namely the presence of a 10-nt duplication (795-796insTTTAATTTGT) between codons 265 and 266, one codon before the normal stop codon 267. The decamer duplication mutation produces a frame-shift in the BRI sequence generating a larger-than-normal precursor protein, of which the amyloid subunit (designated ADan) comprises the last 34 C-terminal amino acids. This de novo-created amyloidogenic peptide, associated with a genetic defect in the Danish kindred, stresses the importance of amyloid formation as a causative factor in neurodegeneration and dementia.

Kim, S. H., R. Wang, et al. (2000). "Familial British dementia: expression and metabolism of BRI." Ann N Y Acad Sci 920: 93-9.

            Vidal et al. (1999. Nature 399: 776-778) discovered that the underlying genetic lesion in familial British dementia (FBD) is a T-A transversion at the termination codon of a membrane protein, termed BRI. The mutation creates an arginine codon; translational read-through generates a novel protein, termed BRI-L, that is extended by 11 amino acids at the carboxyl-terminus. BRI-L is the precursor of the ABri peptide, a component of amyloid deposits in FBD brain. We demonstrate that both BRI and its mutant counterpart are constitutively processed by furin, resulting in the secretion of carboxyl-terminal peptide derivatives that correspond to all, or part of, ABri. Notably, elevated levels of peptides are generated from the mutant BRI precursor, suggesting that subtle conformational alterations at the carboxyl-terminus may influence furin-mediated processing. We have examined BRI/BRI-L processing by other members of the prohormone convertase (PC) family (PACE4, LPC, PC 5/6) and found that these enzymes also process BRI, albeit inefficiently. Moreover, BRI-L processing by the other PC members is severely compromised. Finally, our electron microscopic studies reveal that synthetic ABri peptides assemble into insoluble beta-pleated fibrils. Collectively, our results support the view that enhanced furin-mediated processing of mutant BRI generates amyloidogenic peptides that initiate the pathogenesis of FBD.

Ghiso, J., R. Vidal, et al. (2000). "A newly formed amyloidogenic fragment due to a stop codon mutation causes familial British dementia." Ann N Y Acad Sci 903: 129-37.

            Familial British dementia (FBD) is an early-onset autosomal dominant disorder characterized by progressive cognitive impairment, spasticity, and cerebellar ataxia. Hippocampal neurofibrillar degeneration and widespread parenchymal and vascular amyloid deposits are the main neuropathological lesions. Amyloid fibrils are composed of a novel 34 amino acid subunit (ABri) with no sequence identity to any known amyloid molecule. The peptide derives from a larger precursor protein codified by a single gene BRI on chromosome 13. Affected family members have a single base substitution at the stop codon of the BRI gene that generates a longer open-reading frame resulting in a larger precursor protein. The release of the 34 C-terminal amino acids from the mutated precursor originates the ABri amyloid subunit. Our discovery of a new amyloid associated with the development of dementia supports the concept that amyloid peptides may be of primary importance in the initiation of neurodegeneration.

Ghiso, J., R. Vidal, et al. (2000). "Amyloidogenesis in familial British dementia is associated with a genetic defect on chromosome 13." Ann N Y Acad Sci 920: 84-92.

            Familial British dementia (FBD) is a disorder characterized by the presence of amyloid deposits in cerebral blood vessels and brain parenchyma coexisting with neurofibrillary tangles in limbic areas. The amyloid subunit (ABri) is a 4 kDa fragment of a 266 amino acid type II single-spanning transmembrane precursor protein encoded by the BRI gene located on chromosome 13. In FBD patients, a single base substitution at the stop codon of this gene generates a larger 277-residue precursor (ABriPP-277). Proteolytic processing by a furin-like enzyme at the C-terminus of the elongated precursor generates the 34 amino acid ABri that undergoes rapid aggregation and fibrillization. ABri is structually unrelated to all known amyloids including A beta, the main component of the amyloid lesions in Alzheimer's disease (AD), indicating that cerebral deposition of amyloid molecules other than A beta can trigger similar neuropathological changes leading to neuronal loss and dementia. These data support the concept that amyloid deposition in the vascular wall and brain parenchyma is of primary importance in the initiation of neurogeneration.

Abri, O., Z. Szabo, et al. (2000). "A New Operating Room Concept for Minimal Invasive Surgery." Surg Technol Int IX: 61-66.

Vidal, R., B. Frangione, et al. (1999). "A stop-codon mutation in the BRI gene associated with familial British dementia." Nature 399(6738): 776-81.

            Familial British dementia (FBD), previously designated familial cerebral amyloid angiopathy-British type, is an autosomal dominant disorder of undetermined origin characterized by progressive dementia, spasticity, and cerebellar ataxia, with onset at around the fifth decade of life. Cerebral amyloid angiopathy, non-neuritic and perivascular plaques and neurofibrillary tangles are the predominant pathological lesions. Here we report the identification of a unique 4K protein subunit named ABri from isolated amyloid fibrils. This highly insoluble peptide is a fragment of a putative type-II single-spanning transmembrane precursor that is encoded by a novel gene, BRI, located on chromosome 13. A single base substitution at the stop codon of this gene generates a longer open reading frame, resulting in a larger, 277-residue precursor. Release of the 34 carboxy-terminal amino acids from the mutated precursor generates the ABri amyloid subunit. The mutation creates a cutting site for the restriction enzyme XbaI, which is useful for detecting asymptomatic carriers. Antibodies against the amyloid or homologous synthetic peptides recognize both parenchymal and vascular lesions in FBD patients. A point mutation at the stop codon of BRI therefore results in the generation of the ABri peptide, which is deposited as amyloid fibrils causing neuronal disfunction and dementia.

Kim, S. H., R. Wang, et al. (1999). "Furin mediates enhanced production of fibrillogenic ABri peptides in familial British dementia." Nat Neurosci 2(11): 984-8.

            The genetic lesion underlying familial British dementia (FBD), an autosomal dominant neurodegenerative disorder, is a T-A transversion at the termination codon of the BRI gene. The mutant gene encodes BRI-L, the precursor of ABri peptides that accumulate in amyloid deposits in FBD brain. We now report that both BRI-L and its wild-type counterpart, BRI, were constitutively processed by the proprotein convertase, furin, resulting in the secretion of carboxyl-terminal peptides that encompass all or part of ABri. Elevated levels of peptides were generated from the mutant BRI precursor. Electron microscopic studies revealed that synthetic ABri peptides assembled into irregular, short fibrils. Collectively, our results support the view that enhanced furin-mediated processing of mutant BRI generates fibrillogenic peptides that initiate the pathogenesis of FBD.

Blades, B. S. (1999). "Aurignacian lithic economy and early modern human mobility: new perspectives from classic sites in the Vezere valley of France." J Hum Evol 37(1): 91-120.

            During the past decade the chronology and hominin attributions of the Aurignacian have been revised or called into question. These controversies have coincided with an increased appreciation for the social complexity of Aurignacian culture in the realms of organic technologies and mobiliary and parietal manifestations of symbolic behavior. Lithic raw material procurement and reduction intensity evidence from Aurignacian occupations at the Vezere Valley sites of Abri Pataud, Le Facteur, and La Ferrassie may reflect complex group mobility strategies. The lithic components under consideration were always dominated by cherts available within a few kilometers radius. Assemblages associated with the early Aurignacian have elevated proportions of cherts from distant sources. Lithic retouch data indicate that some early Aurignacian assemblages reflect greater extent and/or intensity of marginal retouch compared with the later Aurignacian. Lithic reduction data, however, reveal evidence of greater core reduction intensity during the later Aurignacian. Flexible strategies of residential mobility, possibly in response to changes in the subsistence environment, may account for some of the variability between early and later Aurignacian assemblages. Similar shifts in raw material procurement were evidently associated with the Middle Paleolithic in southwestern France. However, Aurignacian populations may have acquired most lithic materials by movement directly to sources, while certain non-utilitarian materials were probably obtained via some form of indirect social exchange. This suggested coexistence of direct and indirect procurement mechanisms serves to distinguish Aurignacian assemblages from earlier Middle Paleolithic deposits and emphasizes that socially-directed intensification was one of the fundamental elements of the suite of cultural changes referred to as the Middle-Upper Paleolithic transition.

Miyao, H., T. Arao, et al. (1998). "Kaikasaponin III and soyasaponin I, major triterpene saponins of Abrus cantoniensis, act on GOT and GPT: influence on transaminase elevation of rat liver cells concomitantly exposed to CCl4 for one hour." Planta Med 64(1): 5-7.

            The antihepatotoxic activities of soyasaponin I and kaikasaponin III, triterpenoidal saponins isolated from Abri Herba, the whole plant of Abrus cantoniensis, were studied on liver injury induced by CCl4 in primary cultured rat hepatocytes. The antihepatotoxic activities of these saponins and glycyrrhizin (positive control) were demonstrated by measuring the levels of glutamic pyruvic transaminase (GPT) and glutamic oxaloacetic transaminase (GOT). Soyasaponin I inhibited the elevation of GOT and GPT activities. The activities were comparable to those of glycyrrhizin. On the other hand, kaikasaponin III was more effective than soyasaponin I and glycyrrhizin. Kaikasaponin III showed the antihepatotoxic activity at less than 100 micrograms/ml. Furthermore, the highest activity was observed even in the lower doses (50, 100 micrograms/ml). However, soyasaponin I and kaikasaponin III showed some toxicity at the highest dose (500 micrograms/ml), though glycyrrhizin did not show toxicity at any dose.