Breast cancer is a genetic disease arising from a series of germ-line and/or somatic DNA changes in a variety of genes, including BRCA1 and BRCA2. DNA modi®ca-tions have been shown to occur by a number of mechanisms that include DNA methylation. In some cases, the aberrant methylation of CpGs within 5' regulatory regions has led to suppression of gene activity. In this report we describe a variation in the pattern of DNA methylation within the regulatory region of the BRCA1 gene. We found no evidence of methylation at CpGs within the BRCA1 promoter in a variety of normal human tissues. However, screening of a series of randomly sampled breast carcinomas revealed the presence of CpG methylation adjacent to the BRCA1 transcription start site. One such methylated CpG occurs at a putative CREB (cAMP-responsive element binding) transcription factor binding site in the BRCA1 promoter. Gelshift assays with methylated and unmethylated BRCA1/CREB binding site oligonucleotides demonstrate that this site is sensitive to site-speci®c CpG methylation. These data suggest that aberrant DNA methylation at regulatory sequences in the BRCA1 locus may play a role in the transcriptional inactivation of the BRCA1 gene within subclones of breast tumors. This study represents the ®rst evidence suggesting a role for DNA methylation in the transcriptional inactivation of the BRCA1 in human breast cancer.

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The irreversible capacity of carbon electrodes for lithium is a critical parameter which must be minimized in practical Li ion cells. This paper reports studies of the origin of the irreversible capacity in high-capacity carbons derived from sugar, and for comparison, in graphitic carbons made from mesocarbon microbeads. Tablet electrodes (-0.4 mm thick) of sugar carbon or of mesocarbon microbeads (mixed with 10% pitch) were prepared by pyrolysis of the precursors at 1050°C under a vacuum of about 10 mTorr. Tablets exposed to different gases were used in carbon/Li coin cells, in order to study the effect of different gas exposures on irreversible capacities, Crr, for Li insertion. Carbon electrodes exposed only to argon or nitrogen demonstrated a dramatic reduction in irreversible capacity: C,,. 50 and 10 mAh/g for sugar carbon and mesocarbon microbead tablet cells, respectively, compared to C 180 and 30 mAh/g for the corresponding conventional doctor-blade spread electrode cells where the electrodes had been exposed to laboratory air for several days. Tablet electrodes were also exposed to C02, 02, water, steam, and air, respectively, for different periods of time. Tablets exposed to each of these reactive gases showed a dramatic increase in irreversible capacity. The irreversible capacity for hard carbons results from two sources: (i) electrolyte decomposition on nominally clean carbon surfaces and (ii) reactions with surface groups which form on carbons exposed to reactive gases. The amount of irreversible capacity from the latter source depends on the gas exposure time and involves reactions with species such as hydroxyl, carboxyl functional groups, or adsorbed water. lnfroduction Lithium-ion cells currently represent the state of the art in small rechargeable batteries' due to their higher voltage, higher energy density, and longer shelf life compared with conventional rechargeable batteries. The technology is based on the use of suitably chosen lithium intercalation compounds for the electrodes. Usually a lithium transition metal oxide is used for the cathode and a carbonaceous material for the anode. One of the problems arising from the use of carbon anodes is the irreversible reaction during the first discharge or first lithiation. The capacity related to the irreversible reaction is unusable, because Li consumed in the first discharge cannot be reversibly recovered. In commercial Li-ion cells, the loss of lithium is normally compensated by the use of excess cathode material; therefore, the irreversible capacity leads to a decrease in energy density and an increase in cost. Irreversible reactions can also cause evolution of gases.2 This is particularly undesirable when cells are held in thin-walled flat cases, because the generation of gases causes swelling.It is widely recognized that part of the irreversible capacity arises from electrolyte decomposition followed by the formation of a passivation layer2 or solid electrolyte interface (SEI)3 on the carbon surface. Matsumura et al.4 showed that a large ...

Table sugar was pyrolyzed under various conditions. Carbons of pyrolyzed sugar demonstrated high capacity for Li intercalation, exceeding that of graphite. Experiments were carried out to search for optimal pyrolyzing conditions. The electrochemical behavior of these carbons was found to depend on the pyrolysis temperature, heating rate, argon gas flow rate, and morphology of the precursors. Pyrolysis of sugar was also carried out under vacuum, which is equivalent to a high argon gas flow. Carbons of pyrolyzed sugar under optimal conditions showed large reversible capacity, °=650 mAh/g, small irreversible capacity, 170 mAh/g, and small hysteresis between discharge and charge in carbon/Li metal electrochemical test cells. Pyrolyzed sugar carbons are therefore potential candidates as anode materials in Li-ion batteries. InfroductionRecent work by many groups'-4 has demonstrated that

Mutations of ephrin B1 in humans result in craniofrontonasal syndrome. Because little is known of the role and mechanism of action of ephrin B1 in bone, we examined the function of osteoblast-produced ephrin B1 in vivo and identified the molecular mechanism by which ephrin B1 reverse signaling regulates bone formation. Targeted deletion of the ephrin B1 gene in type 1␣2 collagen-producing cells resulted in severe calvarial defects, decreased bone size, bone mineral density, and trabecular bone volume, caused by impairment in osterix expression and osteoblast differentiation. Coimmunoprecipitation of the TAZ complex with TAZspecific antibody revealed a protein complex containing ephrin B1, PTPN13, NHERF1, and TAZ in bone marrow stromal (BMS) cells. Activation of ephrin B1 reverse signaling with soluble EphB2-Fc led to a time-dependent increase in TAZ dephosphorylation and shuttling from cytoplasm to nucleus. Treatment of BMS cells with exogenous EphB2-Fc resulted in a 4-fold increase in osterix expression as determined by Western blotting. Disruption of TAZ expression using specific lentivirus small hairpin RNA (shRNA) decreased TAZ mRNA by 80% and ephrin B1 reverse signaling-mediated increases in osterix mRNA by 75%. Knockdown of NHERF1 expression reduced basal levels of osterix expression by 90% and abolished ephrin B1-mediated induction of osterix expression. We conclude that locally produced ephrin B1 mediates its effects on osteoblast differentiation by a novel molecular mechanism in which activation of reverse signaling leads to dephosphorylation of TAZ and subsequent release of TAZ from the ephrin B1/NHERF1/TAZ complex to translocate to the nucleus to induce expression of the osterix gene and perhaps other osteoblast differentiation genes. Our findings provide strong evidence that ephrin B1 reverse signaling in osteoblasts is critical for BMS cell differentiation and bone formation.Osteoporosis is a common disease characterized by an agedependent decrease in bone mineral density (BMD) and a microarchitectural deterioration of bone tissue, with a consequent increase in the risk of developing fragility fractures of the hip, spine, and other skeletal sites (19). The decrease in bone mass occurs when the body fails to form enough new bone to replace the amount of old bone resorbed leading to reduced bone strength. There are two major known causes of osteoporosis: low peak BMD, which is typically achieved by around age 30, and high bone loss rate, which occurs particularly after menopause and during the natural process of aging. The accumulation of peak bone mass depends on bone growth during early skeletal development and the balance between osteoblastic bone formation and osteoclastic bone resorption during the postnatal growth period. Therefore, understanding the regulatory factors that govern bone development, bone size, bone mineralization, and bone quality during active growth periods as well as bone homeostasis during menopause and aging is essential for development of therapeutics to prevent osteoporosi...