Patients with Hodgkin's disease can develop paraneoplastic cerebellar ataxia because of the generation of autoantibodies against mGluR1 (mGluR1-Abs). Yet, the pathophysiological mechanisms underlying their motor coordination deficits remain to be elucidated. Here, we show that application of IgG purified from the patients' serum to cerebellar slices of mice acutely reduces the basal activity of Purkinje cells, whereas application to the flocculus of mice in vivo evokes acute disturbances in the performance of their compensatory eye movements. In addition, the mGluR1-Abs block induction of long-term depression in cultured mouse Purkinje cells, whereas the cerebellar motor learning behavior of the patients is affected in that they show impaired adaptation of their saccadic eye movements. Finally, postmortem analysis of the cerebellum of a paraneoplastic cerebellar ataxia patient showed that the number of Purkinje cells was significantly reduced by approximately two thirds compared with three controls. We conclude that autoantibodies against mGluR1 can cause cerebellar motor coordination deficits caused by a combination of rapid effects on both acute and plastic responses of Purkinje cells and chronic degenerative effects.

Gemtuzumab ozogamicin (CMA-676), a calicheamicin-conjugated humanized anti-CD33 mouse monoclonal antibody, has recently been introduced clinically as a promising drug for the treatment of patients with acute myeloid leukemia (AML), more than 90% of which express CD33 antigen. However, our recent study suggested that CMA-676 was excreted by a multidrug-resistance (MDR) mechanism in P-glycoprotein (P-gp)-expressing leukemia cell lines. We analyzed the in vitro effects of CMA-676 on leukemia cells from 27 AML patients in relation to the amount of P-gp, MDR-associated protein 1 (MRP1), CD33 and CD34, using a multi-laser-equipped flow cytometer. The cytocidal effect of CMA-676, estimated by the amount of hypodiploid portion on cell cycle, was inversely related to the amount of P-gp estimated by MRK16 monoclonal antibody (P = 0.004), and to the P-gp function assessed by intracellular rhodamine-123 accumulation in the presence of PSC833 or MS209 as a MDR modifier (P = 0.0004 and P = 0.002, respectively). In addition, these MDR modifiers reversed CMA-676 resistance in P-gp-expressing CD33+ leukemia cells (P = 0.001 with PSC833 and P = 0.0007 with MS209). In CD33 + AML cells from 13 patients, CMA-676 was less effective on CD33 + CD34+ than CD33 + CD34− cells (P = 0.002). PSC833 partially restored the effect of CMA-676 in CD33 + CD34+ cells. These results suggest that the combined use of CMA-676 and a MDR modifier will be more effective on CD33+ AML with P-gp-related MDR.

Neurological and psychiatric disorders are a burden on social and economic resources. Therefore, maintaining brain health and preventing these disorders are important. While the physiological functions of the brain are well studied, few studies have focused on keeping the brain healthy from a neuroscientific viewpoint. We propose a magnetic resonance imaging (MRI)-based quotient for monitoring brain health, the Brain Healthcare Quotient (BHQ), which is based on the volume of gray matter (GM) and the fractional anisotropy (FA) of white matter (WM). We recruited 144 healthy adults to acquire structural neuroimaging data, including T1-weighted images and diffusion tensor images, and data associated with both physical (BMI, blood pressure, and daily time use) and social (subjective socioeconomic status, subjective well-being, post-materialism and Epicureanism) factors. We confirmed that the BHQ was sensitive to an age-related decline in GM volume and WM integrity. Further analysis revealed that the BHQ was critically affected by both physical and social factors. We believe that our BHQ is a simple yet highly sensitive, valid measure for brain health research that will bridge the needs of the scientific community and society and help us lead better lives in which we stay healthy, active, and sharp.

The catalytic and signaling activities of RET, a receptor-type tyrosine kinase, are regulated by the autophosphorylation of several tyrosine residues in the cytoplasmic region of RET. Some studies have revealed a few possible autophosphorylation sites of RET by [ 32 P]phosphopeptide mapping or by using specific anti-phosphotyrosine antibodies. To ultimately identify these and other autophosphorylation sites of RET, we performed mass spectrometry analysis of an originally prepared RET recombinant protein. , and Tyr 900 phosphorylation in both catalytic kinase activities and cell growth. The significance of the identified autophosphorylation sites in various protein-tyrosine kinases registered in a data base is discussed in this paper.Activation of receptor-type or nonreceptor-type protein tyrosine kinases (PTKs) 1 plays a pivotal role in signal transduction in cells. The catalytic activity of PTKs is known to be regulated either positively or negatively by phosphorylation/dephosphorylation at specified tyrosine residues. RET is a proto-oncogene that encodes a receptor-type PTK with a cadherin-related motif and a cysteine-rich domain in the extracellular domain (1-3). It is known that rearrangement of RET is the major cause of papillary thyroid carcinoma (4) and that germ line single-point mutations of RET cause multiple endocrine neoplasia 2A (MEN2A), MEN2B, familial medullary thyroid carcinoma, and Hirschsprung's disease (5-10). The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs), including GDNF, neurturin, artemin, and persephin, are involved in the survival and differentiation of neurons via activation of . Unlike most other receptor-type PTKs, RET is not activated via direct binding of GFLs but is activated by the formation of a multicomponent receptor complex that includes glycosylphosphatidylinositol-anchored cell surface proteins called GFR␣s, which bind GFLs directly. Four members of the family of GFR␣s (GFR␣1 to -4) have been identified, and it has been shown that they bind GFLs with high affinity. GDNF, neurturin, artemin, and persephin use GFR␣1, GFR␣2, GFR␣3, and GFR␣4, respectively, as preferred ligand-binding receptors (11)(12)(13)(14). RET can activate various signaling pathways, including extracellular signal-regulated kinase, phosphatidylinositol 3-kinase/AKT, p38 mitogen-activated protein kinase, and c-Jun N-terminal kinase pathways, responsible for cell survival or differentiation (15-18). Upon ligand binding, RET forms dimers and is phosphorylated at a specific tyrosine residue(s) in intracellular domains. RET has been shown to be alternatively spliced to produce three isoforms (short, middle, and long isoforms) that differ in C-terminal residues (19,20). RET short and middle isoforms contain 16 tyrosine residues in their intracellular domains, and RET long isoforms have two additional tyrosines in the C-terminal tail. Among these tyrosines, Tyr 905 , Tyr 1015 , Tyr 1062 , and Tyr 1096 are thought to be phosphorylated to become binding sites for GRB7/GRB10, phospholipa...

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Across cultures, social relationships are often thought of, described, and acted out in terms of physical space (e.g. “close friends” “high lord”). Does this cognitive mapping of social concepts arise from shared brain resources for processing social and physical relationships? Using fMRI, we found that the tasks of evaluating social compatibility and of evaluating physical distances engage a common brain substrate in the parietal cortex. The present study shows the possibility of an analytic brain mechanism to process and represent complex networks of social relationships. Given parietal cortex's known role in constructing egocentric maps of physical space, our present findings may help to explain the linguistic, psychological and behavioural links between social and physical space.

Information on spatial distributions of soil water content and mechanical strength is fundamental to hydrogeomorphological studies in mountainous watersheds. For simultaneous measurements of soil water content, θ, and penetration resistance, Nc, of soil mantles on natural hillslopes, we developed a new type of combined penetrometer–moisture probe (CPMP). The new CPMP has a robust configuration to reduce the frequency of moisture probe breakdowns during penetration into gravelly and rocky natural soils, and it has a penetration depth of up to 552 cm, which is about four to 14 times greater than the maximum measurable depth of any previous CPMP developed for agricultural soils. Laboratory calibrations and field validations showed that the CPMP succeeded in producing vertical distributions for θ and Nc similar to those measured with conventional methods. The CPMP provided less time‐consuming and less destructive measurements of θ profiles than conventional methods that require excavation of deep trenches. Because θ profiles consider the stratified characteristics of soil mantles as well as the depths of groundwater tables, the CPMP was more effective than the conventional cone penetrometer for surveying the hydrogeomorphological structure of soil mantles. The CPMP was successful in determining the spatial distributions of θ and Nc in a headwater basin underlain by weathered granitic bedrock. From a direct comparison between two θ and Nc values measured on two different days at nearby points and the same depth, it was shown that Nc tended to decrease when θ increased by more than 0.15.

This paper studies the possibility of applying a gas mixture containing C-C4FS in the gas insu lation of power equipment. Environmental aspects such as global warming potential, ozone depletion potential, recycling loss and toxicity are discussed. Insulation characteristics of gas mixtures such as c-C4FslNz, c-C4Fg/air, and c-C4FsfCOz are examined experimentally under a quasi-homogeneous or an inhomogeneous electric field condition. Most of the characteristics are compared with those of SF6/Nz, which is now widely studied as the most plausible alter native to pure SF6 for gas insulation. The experimental results, together with the discussion, suggest that gas mixtures containing C-C4FS are possible substitutes for SF6 and SF6/N2•