Human P301L-Mutant Tau Expression in Mouse Entorhinal-Hippocampal Network Causes Tau Aggregation and Presynaptic Pathology but No Cognitive Deficits

Accumulation of hyperphosphorylated tau in the entorhinal cortex (EC) is one of the earliest pathological hallmarks in patients with Alzheimer’s disease (AD). It can occur before significant Aβ deposition and appears to “spread” into anatomically connected brain regions. To determine whether this early-stage pathology is sufficient to cause disease progression and cognitive decline in experimental models, we overexpressed mutant human tau (hTauP301L) predominantly in layer II/III neurons of the mouse EC. Cognitive functions remained normal in mice at 4, 8, 12 and 16 months of age, despite early and extensive tau accumulation in the EC. Perforant path (PP) axon terminals within the dentate gyrus (DG) contained abnormal conformations of tau even in young EC-hTau mice, and phosphorylated tau increased with age in both the EC and PP. In old mice, ultrastructural alterations in presynaptic terminals were observed at PP-to-granule cell synapses. Phosphorylated tau was more abundant in presynaptic than postsynaptic elements. Human and pathological tau was also detected within hippocampal neurons of this mouse model. Thus, hTauP301L accumulation predominantly in the EC and related presynaptic pathology in hippocampal circuits was not sufficient to cause robust cognitive deficits within the age range analyzed here.     

Identification of the coding region for the putidaredoxin reductase gene from the plasmid of Pseudomonas putida

The first 12 NH₂-terminal amino acids of the Pseudomonas putida putidaredoxin reductase were shown to be Met-Asn-Ala-Asn-Asp-Asn-Val-Val-Ile-Val-Gly-Thr. Comparison of these data with the DNA sequence of the BamHI-HindIII 197-base fragment derived from the PstI 2.2-kb fragment obtained from the P. putida plasmid showed that the putidaredoxin reductase gene was downstream from the cytochrome P-450 gene and the intergenic region had the 24-nucleotide sequence TAAACACATGGGAGTGCGTGCTAA. The Shine-Dalgarno sequence GGAG was detected in this region. The initiating triplet for the reductase gene was GTG, which normally codes for valine, but in the initiating codon position codes for methionine. From the amino acid sequence and X-ray data comparisons with other flavoproteins, what appears to be the AMP binding region of the FAD can be recognized in the NH₂-terminal portion of the reductase involving residues 5–35.This article was presented during the proceedings of the International Conference on Macromolecular Structure and Function, held at the National Defence Medical College, Tokorozawa, Japan, December 1985.     

Mitogenic Activity of Cytoplasmic Membranes Isolated from L-Forms of Staphylococcus aureus

Cytoplasmic membranes of L-forms of Staphylococcus aureus exerted a strong mitogenic effect on splenocytes of athymic nude mice as well as normal mice, while a cytoplasmic fraction of the same bacteria did not show definite mitogenicity. The mitogenic principle(s) of the membrane fraction was resistant to treatment with trypsin and was heat stable (at 100 C for 10 min). The active principle(s) in the insoluble residue of the membrane fraction digested with trypsin was not extracted with cold acetone, but could be solubilized by extraction with a cold chloroform-methanol mixture (2:1, v/v). The mitogenic principle(s) in the extract was fractionated by silicic acid column chromatography. Among five fractions separated by chromatography, fractions eluted with chloroform-methanol mixtures (1:1 and 1:20, v/v) were found to be strongly mitogenic. The cytoplasmic membranes of the L-forms also exerted a definite mitogenic effect on guinea pig splenocytes, but not on the thymocytes.     

Coordinates transformation and learning control for visually-guided voluntary movement with iteration: A Newton-like method in a function space

In order to control visually-guided voluntary movements, the central nervous system (CNS) must solve the following three computational problems at different levels: (1) determination of a desired trajectory in the visual coordinates, (2) transformation of the coordinates of the desired trajectory to the body coordinates and (3) generation of motor command. In this paper, the second and the third problems are treated at computational, representational and hardware levels of Marr. We first study the problems at the computational level, and then propose an iterative learning scheme as a possible algorithm. This is a trial and error type learning such as repetitive training of golf swing. The amount of motor command needed to coordinate activities of many muscles is not determined at once, but in a step-wise, trial and error fashion in the course of a set of repetitions. Actually, the motor command in the (n+1)-th iteration is a sum of the motor command in then-th iteration plus two modification terms which are, respectively, proportional to acceleration and speed errors between the desired trajectory and the realized trajectory in then-th iteration. We mathematically formulate this iterative learning control as a Newton-like method in functional spaces and prove its convergence under appropriate mathematical conditions with use of dynamical system theory and functional analysis. Computer simulations of this iterative learning control of a robotic manipulator in the body or visual coordinates are shown. Finally, we propose that areas 2, 5, and 7 of the sensory association cortex are possible sites of this learning control. Further we propose neural network model which acquires transformation matrices from acceleration or velocity to motor command, which are used in these schemes.     

Solution Radioactivated by Hadron Radiation Can Increase Sister Chromatid Exchanges

When energetic particles irradiate matter, it becomes activated by nuclear reactions. Radioactivation induced cellular effects are not clearly understood, but it could be a part of bystander effects. This investigation is aimed at understanding the biological effects from radioactivation in solution induced by hadron radiation. Water or phosphate buffered saline was activated by being exposed to hadron radiation including protons, carbon- and iron-ions. 1 mL of radioactivated solution was transferred to flasks with Chinese hamster ovary (CHO) cells cultured in 5 mL of complete media. The induction of sister chromatid exchanges (SCE) was used to observe any increase in DNA damage responses. The energy spectrum and the half-lives of the radioactivation were analyzed by NaI scintillation detector in order to identify generated radionuclides. In the radioactivated solution, 511 keV gamma-rays were observed, and their half-lives were approximately 2 min, 10 min, and 20 min. They respectively correspond to the beta+ decay of ¹⁵O, ¹³N, and ¹¹C. The SCE frequencies in CHO cells increased depending on the amount of radioactivation in the solution. These were suppressed with a 2-hour delayed solution transfer or pretreatment with dimethyl sulfoxide (DMSO). Our results suggest that the SCE induction by radioactivated solution was mediated by free radicals produced by the annihilated gamma-rays. Since the SCE induction and DMSO modulation are also reported in radiation-induced bystander effects, our results imply that radioactivation of the solution may have some contribution to the bystander effects from hadron radiation. Further investigations are required to assess if radioactivation effects would attribute an additional level of cancer risk of the hadron radiation therapy itself.     

Evolutionarily stable seasonal timing for insects with competition for renewable resource

Summary I study the evolutionarily stable seasonal patterns of hatching and pupation for herbivorous insects that engage in exploitative competition for a renewable resource. A longer larval feeding period enhances female fecundity, but also causes a higher mortality by predation and parasitism. Previously, it was shown that the evolutionarily stable population exhibits asynchronous starting and ending of the larval feeding period in a model in which larval growth rate decreases with the total larval biomass in the population due presumably to interference competition. Here I study the case in which resource availability changes not only with environmental seasonality but with the depletion by the feeding of larvae. I find that if the impact of the herbivory is strong, both hatching and pupation should occur asynchronously in the evolutionarily stable population. And if the favourable season for the host plant is short the ESS population may include synchronous timing of pupation. If the timing of hatching and pupation occurs asynchronously, in the first day of each interval some fraction of the population hatch or pupate, respectively and the rest do so gradually over the interval. In addition, if the environmental variable changes as a symmetric function of time, the length of the period in which hatching occurs tends to be much shorter than the period in which pupation occurs.