An analog-AI chip for energy-efficient speech recognition and transcription.

Models of artificial intelligence (AI) that have billions of parameters can achieve high accuracy across a range of tasks1,2, but they exacerbate the poor energy efficiency of conventional general-purpose processors, such as graphics processing units or central processing units. Analog in-memory computing (analog-AI)3-7 can provide better energy efficiency by performing matrix-vector multiplications in parallel on 'memory tiles'. However, analog-AI has yet to demonstrate software-equivalent (SWeq) accuracy on models that require many such tiles and efficient communication of neural-network activations between the tiles. Here we present an analog-AI chip that combines 35 million phase-change memory devices across 34 tiles, massively parallel inter-tile communication and analog, low-power peripheral circuitry that can achieve up to 12.4 tera-operations per second per watt (TOPS/W) chip-sustained performance. We demonstrate fully end-to-end SWeq accuracy for a small keyword-spotting network and near-SWeq accuracy on the much larger MLPerf8 recurrent neural-network transducer (RNNT), with more than 45 million weights mapped onto more than 140 million phase-change memory devices across five chips.

Interaction of GH polymorphism with body weight and endocrine functions in Japanese black calves.

We assessed the interaction of GH gene polymorphisms (AA, AB and BB genotypes) with body weight and measures of endocrine function in Japanese black calves at 10 months of age. The average body weight for the BB genotype (281+/-5 kg) was significantly lower (P=0.0017, ANOVA) than those for the AA (324+/-9 kg) and AB (317+/-7 kg) genotypes. Plasma concentrations of insulin and IGF-I were greater for the AA genotype than for the AB genotype, and AB and BB genotypes, respectively. There were significant differences in the triglyceride and cholesterol concentrations among the GH genotypes. The area under the basal GH concentration was significantly greater (P=0.0314) for the AA genotype than for the two other genotypes. The incremental area over the basal GH concentrations in response to intravenous GHRH injection (0.4 microg/kg BW) was significantly smaller (P=0.0005) for the BB genotype than for the two other genotypes. In addition, linear regression analysis between GH incremental area induced by GHRH and body weight demonstrated that there was a positive linear correlation (r=0.6496, P<0.002) for incremental areas less than 600 ng min/ml, but a negative correlation (r=0.6473, P<0.05) for incremental areas over 600 ng min/ml. These findings indicate that the GH genotypes of the animals could be associated with difference in the GH response in Japanese black cattle at 10 months of age. We also observed a relationship between genotype and animal performances, but other studies on more animals in different conditions must be realized to make a definite conclusion.

Effect of GroEL on the re-folding kinetics of alpha-lactalbumin.

The effect of GroEL on the re-folding kinetics of apo- and holo-alpha-lactalbumin from the acidic molten globule state has been investigated by stopped-flow fluorescence measurements. GroEL retards the re-folding of apo-alpha-lactalbumin by interacting with the molten globule state of the protein. The binding constant was estimated to be in the order of 10(5) M-1 by analyzing the kinetic data quantitatively and was found to be much weaker than the binding between GroEL and disulfide-bond reduced alpha-lactalbumin, whose binding constant is in the order of 10(7) M-1. Our present results, together with the previous results, suggest that the state recognized by GroEL is not unique and that the binding strength varies with the state of a target protein. The binding between GroEL and the molten globule state of apo-alpha-lactalbumin becomes stronger with an increasing salt concentration; the binding constant is increased tenfold (from 10(5) to 10(6) M-1) by an increase in salt concentration from 0.05 to 0.25 M. The study of the effect of GroEL on the re-folding kinetics of holo-alpha-lactalbumin, which is represented by a bi-phasic process, shows that the slow phase is affected by GroEL in the same manner as observed in the apo-alpha-lactalbumin re-folding but that the fast phase is not affected by GroEL at all. This indicates that the binding rate of GroEL is faster than the slow phase but slower than the fast phase of the re-folding, and the bi-molecular rate constant of GroEL binding to the molten globule state of alpha-lactalbumin was estimated to be in the order of 10(6) M-1S-1.

Dominant forces in the recognition of a transient folding intermediate of alpha-lactalbumin by GroEL.

GroEL is known to retard the refolding of apo-alpha-lactalbumin by interacting with the molten globule state of the protein. In order to investigate the dominant forces in this interaction, the GroEL-affected kinetic refolding of apo-alpha-lactalbumin from its acidic molten globule state was studied at different temperatures and in the presence of different kinds of monovalent cations at a fixed temperature (25 degrees C), by stopped-flow fluorescence measurements. The binding constant between GroEL and alpha-lactalbumin in the molten globule state was evaluated quantitatively from the kinetic refolding curves in the absence and presence of GroEL. The binding was found to be entropy-driven at room temperature and the heat capacity change for the binding was found to be largely negative (-3.6 kJ mol-1.K-1), indicating that GroEL binds to alpha-lactalbumin through hydrophobic interactions. The study of the effect of different monovalent cations at various ionic strengths shows that the binding is strengthened by electrostatic screening by ions, demonstrating the importance of electrostatic interactions. The relationship of these results with a putative target recognition site of GroEL will be discussed.

Detection of p53 gene mutations in fine-needle aspiration biopsied breast cancer specimens: correlations with nuclear p53 accumulations and tumor DNA aneuploidy patterns.

Using the polymerase chain reaction and a single strand conformation polymorphism (PCR-SSCP) analysis, p53 gene mutations have been examined preoperatively in aspirated biopsy specimens from 22 breast cancers. In eight (36%) of the studied cases, abnormal bands indicating mutations were detected and were more frequently present in common invasive breast carcinomas. Eight of the breast cancer cases were found to be positive for mutations: direct DNA sequencing confirmed eight mutations and revealed G to A and A to G nucleotide changes in five (63%) and two (25%) cases, respectively. The mutations that were localized at the CpG site of the gene were seen in three cases. Additionally, an immunohistochemical investigation of the presence of the p53 protein and a DNA flow-cytometrical analysis of the 22 resected breast cancers were also performed. Nuclear p53 protein accumulations and a DNA aneuploidy pattern were detected in 11 (50%) cases and in 16 (73%) cases, respectively, and both significantly correlated with p53 gene mutations (P < 0.01 and P < 0.001, respectively; Fisher's exact test). In contrast, in five cases of a breast cancer with a lower histologic grade, no p53 gene mutations, nuclear p53 protein accumulations, or DNA aneuploidy patterns were detected. These results thus suggest that p53 gene mutations, nuclear accumulations of the p53 protein, and a DNA aneuploidy pattern are events that occur with close relationship in the progression of a breast cancer, and that p53 abnormalities appear to correlate with a high grade of the malignancy. Therefore, the detection of p53 gene mutations in aspirated biopsy specimens of breast cancers may be helpful for an accurate and rapid cytological diagnosis, which reflects the prognosis.

Osseous tissue reaction around hydroxyapatite block implanted into proximal metaphysis of tibia of rat with collagen-induced arthritis.

This study was conducted to investigate the influence of osteoporosis on new bone formation around a hydroxyapatite (HA) block implanted into the proximal metaphysis of the tibia of rats with collagen-induced arthritis (CIA). Ten rats were immunized with an emulsion of bovine type II collagen and Freund's complete adjuvant (arthritis group). Another 10 rats, which were not immunized were used as the control group. Seventeen days after immunization, HA block was implanted into the proximal metaphysis of the tibia. Four weeks after implantation, all rats were killed. The serum level of tetrate-resistant acid phosphatase (TRAP), bone mineral density (BMD) in the proximal metaphysis of the tibia and the affinity index in the arthritis group were 28.0+/-3.5 IU/ml, 130.3+/-28.7 mg/cm2 and 77.6+/-10.8%, respectively, and those in the control group were 24.6+/-5.5 IU/ml, 175.9+/-30.5 mg/cm2 and 56.3+/-14.8%. The serum level of TRAP was higher (P < 0.05) and BMD was lower (P < 0.005) in the arthritis group. The amount of new bone formation around the HA block was larger (affinity index, P < 0.05) in the arthritis group than in the control group. These findings suggest that bone formation around HA block might be enhanced even in conditions associated with highly activated bone resorption and bone formation, such as arthritis.

Correlation of heat shock protein 70 expression with estrogen receptor levels in invasive human breast cancer.

The authors studied the role of 70-Kd heat shock protein (HSP70) in the progression of breast cancer by examining the correlation between the expression of HSP70 and epidermal growth factor receptor, c-erbB-2, p53, and estrogen receptor in 124 cases of invasive primary human breast cancers. Positivity of an anti-HSP70 monoclonal antibody, C92, was closely associated with the elevation of estrogen receptor (P < .008), whereas it inversely correlated with the expression of p53 (P < .01). In addition, the expression of HSP70 correlated inversely with the expression of epidermal growth factor receptor, although the correlation was not statistically significant (P = .06). These results suggest that the expression of HSP70 plays a role in the progression of human breast cancer.

Hydrogen-exchange kinetics of reduced alpha-lactalbumin bound to the chaperonin GroEL.

alpha-Lactalbumin in which all the disulfide bonds are fully reduced (RLA) is known to bind strongly to the chaperonin GroEL. Although RLA is more unfolded than the native state and the molten globule state of alpha-lactalbumin, the CD spectrum of RLA in the far-UV region shows that RLA is not fully unfolded but has an appreciable amount of secondary structure. To investigate whether the secondary structure elements present in RLA are responsible for the recognition of RLA by GroEL or not, we have examined the hydrogen-exchange kinetics of RLA in the presence and absence of GroEL. Our results show that the hydrogen-exchange kinetics of RLA bound to GroEL is identical to that of free RLA. This implies that the secondary structure elements in RLA are not important for the recognition by GroEL, but the unstructured parts of RLA that are not relevant to the stability of the secondary structure provide strong recognition sites of RLA.

Neoadjuvant intraarterial high-dose chemotherapy and autologous peripheral blood stem cell transplantation for advanced breast cancer.

Eight locally advanced breast cancer patients were treated with neoadjuvant intraarterial high-dose chemotherapy (epirubicin) plus MPA combined with autologous PBSCT. All patients completed the scheduled treatment, and there were no toxic deaths. Patients were treated with an escalating dose of epirubicin (370-480 mg) and cyclophosphamide (0-6000 mg). The rate of clinical response was 100%. The rate of good histologic response was 87.5% in the main tumor and 75% in diseased lymph nodes. The 2-year survival rate was 100%. Six patients were disease-free at the time of writing. This treatment resulted in higher rates of clinical and histologic response when compared with standard-dose intraarterial chemotherapy.

Neoadjuvant intra-arterial infusion chemotherapy combined with hormonal therapy for locally advanced breast cancer.

To determine the efficacy of combined neoadjuvant intra-arterial infusion chemotherapy and hormonal therapy for treating locally advanced breast cancer, we compared the outcomes of patients with or without this therapy, and also assessed histologic response. Ninety-four patients with locally advanced breast cancer (stage IIIa, 56; stage IIIb, 38). Nineteen stage IIIa and 17 stage IIIb patients received intra-arterial plus hormonal therapy while 37 stage IIIa and 21 stage IIIb patients with similar ages and follow-up durations did not. Treated patients received intra-arterial epirubicin plus oral medroxy-progesterone. Five-year disease-free survival rates were 77.5% for intra-arterially treated and 33.0% for other patients in stage IIIa, and 70.5% for intra-arterially treated and 38.1% for other patients in stage IIIb. Five-year overall survival rates were 94.4% for intra-arterially treated and 61.7% for other patients in stage IIIa, and 90.9% for intra-arterially treated and 56.3% for other patients in stage IIIb. Ten-year overall survival rates in stage IIIb were 90.9% for treated and 22.5% for other group patents. All differences were statistically significant (p<0.05). Good histologic response to intra-arterial therapy was seen in 75% of the primary tumors and 71% of involved lymph nodes. Neoadjuvant intra-arterial therapy with hormonal therapy yielded better survival rates than no intra-arterial therapy or our previous intra-arterial regimen.

Five years experience of cardiopulmonary resuscitation in a children's hospital.

The emergency call for resuscitation in a children's hospital is reported. Forty-seven resuscitation attempts via the emergency call were made in 43 patients over the past 5 years; 24 out of 43 patients had heart diseases. Cardiac patients were more likely to die within a few days after their resuscitation. The patients, who had previously been in cardiac arrest, lost their lives more often. These results implied that it was very crucial to prevent cardiac arrest especially for cardiac patients in order to save lives. Among the causes of emergency calls, complications with the endotracheal tubes were most common (13) and the airway obstructions followed (11). Summation of two causes, the airway problems, accounted for more than half of the series. Sixteen out of all emergency calls occurred on weekends, and all endotracheal tube troubles broke out during a night shift or on a holiday, that is, the lives of those patients were threatened especially when fewer staff were on duty. Those accidents were embarrassing for us because we believe that all patients must have been under our surveillance all day. Some hospitals have a successful resuscitation rate, organizing a cardiopulmonary resuscitation (CPR) team. However, we obtained better results (about 30%) without a team. It should be borne in mind that it is more desirable to prevent cardiac or respiratory arrests initially rather than save the patients in emergencies.

Distribution of 1,25-dihydroxyvitamin D3[22-oxa] in vivo receptor binding in adult and developing skin.

Because of the therapeutic potential of oxacalcitriol (OCT, 22-oxa-dihydroxyvitamin D3), in vivo studies were conducted in adult and neonatal rats to identify the nuclear receptor sites of action in different tissues of the skin. Results were compared with those for 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and oestradiol from previous studies. Autoradiograms were prepared from the dorsal skin of adult rats and the skin of the leg and head regions of neonatal rats 1 or 2 h after the injection of 3H-OCT. Specific nuclear concentrations of radioactivity, eliminated by competition with unlabelled OCT or 1,25(OH)2D3, were found in cells of the epidermis, outer hair sheath, hair bulb and sebaceous glands, but were absent or low in most fibroblasts of the dermis and hypodermis. The strongest nuclear binding of OCT was conspicuous in outer hair sheaths, where it was 1.5 to 3.2 times higher than in keratinocytes of the epidermis. The distribution of nuclear receptors for OCT was similar to that for 1,25(OH)2D3 but in part dissimilar to that for oestradiol. Oestradiol binding was found in the epidermis and hair sheaths, and also predominantly in fibroblasts of the dermis and hair dermal papillae. The results suggest genomic regulatory effects of OCT, similar to the effects of vitamin D, on proliferation, differentiation and activity of keratinocytes, growth and maintenance of hair, and proliferation and secretion of sebaceous glands. This may be utilized therapeutically, since OCT has a lower calcaemic effect than 1,25(OH)2D3.

Ultra-high-angle double-crystal X-ray diffractometry (U-HADOX) for determining a change in the lattice spacing: theory.

Advantages of high-angle double-crystal X-ray diffractometry (HADOX) have been re-examined. It is found that, by extending the Bragg angle theta up to 89.99 degrees, the accuracy of a change in the lattice spacing to one part in 10(9)-10(10) can be attained in proportion to tan theta. In such a case, the dispersion-free condition is so serious that the spacing of the two crystals should be equal within one part in 10(6). Therefore, this method is appropriate for determining the thermal expansion coefficient in a limited temperature range. To cover a wide temperature range, the temperature of the reference crystal must be adjusted according to the temperature of the specimen crystal; the lattice spacing as a function of temperature can be determined by integrating the temperature derivative of the spacing.

Quantitative regional cerebral flow measured by Tc-99M HMPAO SPECT in mood disorder.

Depressed (n = 14) and remitted (n = 9) patients with mood disorder, patients with depressive disorder not otherwise specified (NOS; n = 10) and normal subjects (n = 8) underwent non-invasive and quantitative measurement of cerebral blood flow using HMPAO and SPECT in a resting state. The mean and regional cerebral blood flow (CBF) in twelve ROIs were compared among the four groups and correlations between CBF and the depressive symptoms were studies. The CBF was computed using graphical analysis on the SPECT console after a bolus injection of Tc-99m HMPAO and radionuclide angiography. The depressed group had significantly lower mCBF in the bilateral hemisphere and rCBF in all except one of the ROIs than the NOS and normal group. Significant negative correlations were found between the Hamilton scale for depression and rCBF in the bilateral lower frontal cortex after correcting for age in the mood disorder. Parallel analysis using both the quantitative and semiquantitative methods revealed that the former provided more global reduction of CBF in mood disorder. These results indicate that mean and regional CBF measured by this non-invasive method contributes to the objective evaluation of depressive symptoms. Negative correlations between HRSD and rCBF in the frontal regions indicate that frontal hypoactivity is closely related to depressive symptoms.

Extraction of manganese(II), iron(II), cobalt(II), nickel(II), copper(II), zinc(II), and cadmium(II) into 1,2-dichloroethane with 4,7-diphenyl-1, 10-phenanthroline and perchlorate.

The extraction of the ion-association complexes formed by Mn(II), Fe(II), Co(II), Ni(II), Cu(II), Zn(II) and Cd(II)-4,7-diphenyl-1, 10-phenanthroline (BP) chelates and perchlorate ions into 1,2-dichloroethane has been investigated. Extraction equilibrium for Mn(II), Cu(II), Zn(II) and Cd(II) is reached within 1 hr, but equilibration for Fe(II), Co(II) and Ni(II) is very slow; the equilibration rate depends on the structure of the chelating agent, the nature of the organic solvent, and pH. In the extraction equilibrium of Co(II) the rate-determining step seems to be the complexation of hydrated Co(II) by BP in the aqueous phase.

Status of endogenous avian RNA tumor virus in Marek's disease lymphoblastoid cell lines and susceptibility of those lines to exogenous RNA tumor viruses.

Three lymphoblastoid cell lines from Marek's disease (MD) tumors, two MD virus (MDV) producer lines (MSB-1 and HPRS-1), and a nonproducer line (RPL-1) were studied for the expression of avian leukosis sarcoma (ALS) viruses. The MSB-1 line was free of all known endogenous expressions, including replicating virus (RAV-O), group-specific (gs) antigens, and chick helper factor (chf). The RPL-1 and HPRS-1 were positive for gs antigens and chf. The RPL-1 and MSB-1 lines showed no evidence of an exogenous DNA provirus by nucleic acid hybridization (HPRS-1 line was not tested for that DNA). All three lymphoblastoid cell lines were susceptible to exogenous infection with both sarcoma and leukosis viruses of subgroup A but varied in susceptibility to subgroups B and C. All were resistant to subgroups D and E.

Intravenous single and repeated dose toxicity studies of cimadronate (YM175), a novel bisphosphonate, in beagle dogs.

Cimadronate (YM175) is a novel bisphosphonate with potent inhibitory activity on bone resorption under development for the treatment of tumor-induced hypercalcemia, metastatic bone disease and osteoporosis. We conducted intravenous single and repeated dose toxicity studies of cimadronate in beagle dogs. In the single dose study, animals received a single dose of 0.3, 1, 3 or 10 mg/kg of cimadronate and the animals were observed for at least 14 days. At 10 mg/kg, both the male and female dog showed toxic signs such as vomiting, decreased locomotor activities and hypothermia and were killed in extremis within a week after dosing. In the 30-day study, animals received cimadronate at a dosage of 0 (vehicle), 0.03, 0.1, 0.3 or 1 mg/kg/day. At 0.03 mg/kg/day or more, histological findings indicated an increased amount of primary spongiosa in the rib and ilium. At 1 mg/kg/day, degenerative nephropathy, aggregation of spermatozoa and glandular hypoplasia of the prostate gland were observed. On day 16 of dosing one male animal died of acute renal failure. In the 26-week study, animals received cimadronate once weekly at a dosage of 0 (vehicle), 0.31, 0.62, or 1.25 mg/kg. Histopathological examination showed an increased amount of primary spongiosa in the rib at all dosage levels. In addition, similar findings were observed in the lumbar vertebrae at 1.25 mg/kg/week. Histopathological changes in the kidney and male reproductive organs were not observed.

Intravenous single and repeated dose toxicity studies of cimadronate (YM175), a novel bisphosphonate, in rats.

Cimadronate (YM175) is a novel bisphosphonate with potent inhibitory activity on bone resorption under development for the treatment of tumor-induced hypercalcemia, metastatic bone disease and osteoporosis. We conducted toxicity studies of cimadronate intravenously, single dose, 30-day repeated dose and 26-week weekly dose in F344 rats. In the single dose study, cimadronate was administered to rats and the animals were observed for 14 days. Major toxic symptoms were decreased motility and piloerection and LD50 values were 23 mg/kg for males and 21 mg/kg for females. In the 30-day study, the animals received cimadronate at doses of 0, 0.16, 0.31, 0.62 or 1.25 mg/kg/day. At 0.16 mg/kg/day or more, an increased amount of primary spongiosa was observed in the femur. At 0.62 mg/kg/day or more, renal and testicular/epididymal toxicity were observed. After a 30-day recovery period, the finding in the kidney disappeared, but the findings remained in the bone, testis and epididymis. In the 26-week weekly dose study, animals received cimadronate at doses of 0, 0.31, 0.62 and 1.25 mg/kg/week. At 0.31 mg/kg/week or more, an increased amount of primary spongiosa was seen in the femur. Renal and testicular/epididymal toxicity, however, were not observed.