Effects of the length ratio between the contractile element and the series elastic element on an explosive muscular performance.

Effects of the length ratio between the contractile element (CE) and the series elastic element (SEE) on the behavior of the muscle tendon complex were investigated during stretch-shortening cycles. A computer simulation model of the Hill-type muscle tendon complex was constructed. The proximal end of the CE was affixed to a point in the gravitational field, and a massless supporting object was affixed to the distal end of the SEE. A mass was held on the supporting object. Initially, the muscle tendon complex was fixed at a certain length, and the CE was activated at 100%. Through this process, the CE contracted as much as the SEE was stretched. Thereafter, the supporting object was released, which caused the muscle tendon complex to propel the mass upward, simulating a stretch-shortening cycle. The length ratio between the CE and the SEE, the size of the mass and the initial length of the CE were sequentially changed. As a result, it was found that a higher performance is obtained with a longer SEE when the mass is small, while with a shorter SEE when the mass is large.     

A helper factor needed for the generation of mouse cytolytic T lymphocytes is made by tumor cell lines, cloned T cells, and spleen cells exposed to a variety of stimuli

A helper factor termed cytolytic T lymphocyte helper factor (CHF) that is needed for the generation of allospecific mouse cytolytic T lymphocytes (CTL) in vitro was produced by mouse spleen cells 3 to 4 days after the time when interleukin 2 (IL 2) had reached its maximal production. These kinetics were observed by stimulation of immune spleen cells with allogeneic tumor or spleen cells, with Sendai or influenza viral peptides, with virus infected cells, or with concanavalin A (Con A). CHF produced by rat spleen cells was able to help in the generation of mouse CTL, indicating that this cytokine was not restricted genetically. CHF could also be made by WEHI-3 and EL4 cell lines, as well as cloned cytolytic and helper T cells. The production of CHF by WEHI-3 cells argues that CHF is not IL 2. In addition, if CHF was not present early in the in vitro stimulation no CTL were generated, suggesting that CHF participated in the activation of CTL precursors. The addition of IL 2-containing conditioned medium to the CHF assay resulted in no substantial CTL generation, although significant cellular proliferation was observed. In contrast, CHF-containing conditioned medium allowed the generation of CTL in the absence of the same level of proliferation.     

Genetic analysis of the chromosome of alkaliphilic Bacillus halodurans C-125

Seventeen Sse8387I linking clones isolated from the chromosome of Bacillus halodurans C-125 for the purpose of constructing a physical map were sequenced and analyzed by comparison with the BSORF database and the nonredundant protein databank. The orientations of Sse8387I or AscI linking clones serving to join adjacent fragments were determined by southern blot analysis using specific DNA probes. One-third of the open reading frames (ORFs) identified in the Sse8387I linking clones showed no significant similarity to any protein so far reported. The ORFs showing significant similarities to those of Bacillus subtilis were mapped in the chromosome of strain C-125, and the locations of the putative genes on the map were not well conserved between B. halodurans C-125 and B. subtilis. Received: March 26, 1999 / Accepted: April 27, 1999     

Discovery of novel scaffolds for γ-secretase modulators without an arylimidazole moiety

Gamma-secretase modulators (GSMs) selectively inhibit the production of amyloid-β 42 (Aβ42) and may therefore be useful in the management of Alzheimer’s disease. Most heterocyclic GSMs that are not derived from nonsteroidal anti-inflammatory drugs contain an arylimidazole moiety that potentially inhibits cytochrome P450 (CYP) activity. Here, we discovered imidazopyridine derivatives that represent a new class of scaffold for GSMs, which do not have a strongly basic end group such as arylimidazole. High-throughput screening identified 2-methyl-8-[(2-methylbenzyl)oxy]-3-(pyridin-4-yl)imidazo[1,2-a]pyridine (3a), which inhibited the cellular production of Aβ42 (IC₅₀?=?7.1?µM) without changing total production of Aβ. Structural optimization of this series of compounds identified 5-[8-(benzyloxy)-2-methylimidazo[1,2-a]pyridin-3-yl]-2-ethylisoindolin-1-one (3m) as a potent inhibitor of Aβ42 (IC₅₀?=?0.39?µM) but not CYP3A4. Further, 3m demonstrated a sustained pharmacokinetic profile in mice and sufficiently penetrated the brain.     

Novel Defense by Metallothionein Induction Against Cognitive Decline: From Amyloid β<Subscript>1–42</Subscript>-Induced Excess Zn<Superscript>2+</Superscript> to Functional Zn<Superscript>2+</Superscript> Deficiency

The role of metallothioneins (MTs) in cognitive decline associated with intracellular Zn²⁺ dysregulation remains unclear. Here, we report that hippocampal MT induction defends cognitive decline, which was induced by amyloid β_1–42 (Aβ_1–42)-mediated excess Zn²⁺ and functional Zn²⁺ deficiency. Excess increase in intracellular Zn²⁺, which was induced by local injection of Aβ_1–42 into the dentate granule cell layer, attenuated in vivo perforant pathway LTP, while the attenuation was rescued by preinjection of MT inducers into the same region. Intraperitoneal injection of dexamethasone, which increased hippocampal MT proteins and blocked Aβ_1–42-mediated Zn²⁺ uptake, but not Aβ_1–42 uptake, into dentate granule cells, also rescued Aβ_1–42-induced impairment of memory via attenuated LTP. The present study indicates that hippocampal MT induction blocks rapid excess increase in intracellular Zn²⁺ in dentate granule cells, which originates in Zn²⁺ released from Aβ_1–42, followed by rescuing Aβ_1–42-induced cognitive decline. Furthermore, LTP was vulnerable to Aβ_1–42 in the aged dentate gyrus, consistent with enhanced Aβ_1–42-mediated Zn²⁺ uptake into aged dentate granule cells, suggesting that Aβ_1–42-induced cognitive decline, which is caused by excess intracellular Zn²⁺, can more frequently occur along with aging. On the other hand, attenuated LTP under functional Zn²⁺ deficiency in dentate granule cells was also rescued by MT induction. Hippocampal MT induction may rescue cognitive decline under lack of cellular transient changes in functional Zn²⁺ concentration, while its induction is an attractive defense strategy against Aβ_1–42-induced cognitive decline.     

No wisdom in the crowd: genome annotation in the era of big data – current status and future prospects

Science and engineering rely on the accumulation and dissemination of knowledge to make discoveries and create new designs. Discovery‐driven genome research rests on knowledge passed on via gene annotations. In response to the deluge of sequencing big data, standard annotation practice employs automated procedures that rely on majority rules. We argue this hinders progress through the generation and propagation of errors, leading investigators into blind alleys. More subtly, this inductive process discourages the discovery of novelty, which remains essential in biological research and reflects the nature of biology itself. Annotation systems, rather than being repositories of facts, should be tools that support multiple modes of inference. By combining deduction, induction and abduction, investigators can generate hypotheses when accurate knowledge is extracted from model databases. A key stance is to depart from ‘the sequence tells the structure tells the function’ fallacy, placing function first. We illustrate our approach with examples of critical or unexpected pathways, using MicroScope to demonstrate how tools can be implemented following the principles we advocate. We end with a challenge to the reader.     

Electrophysiology and kinesiology for health and disease.

This paper summarizes my Basmajian keynote presentation at the 2004 International Society of Electrophysiology and Kinesiology Conference. I dedicate this paper to Dr. Herbert A. deVries, the mentor of my research career. The following topics will be covered from the standpoint of Electrophysiology and Kinesiology for health and disease: (1) electromechanical manifestations of neuromuscular fatigue and muscle soreness, (2) cardiac depolarization-repolarization characteristics of normal and patients, (3) etiology of obesity and diabetes and autonomic nervous system, and (4) functional electrical stimulation for health and disease, respectively.     

Occurrence of both a-type and o-type cytochromes as the functional terminal oxidases in Rhodopseudomonas spheroides

1. 1. The functional terminal oxidase of the light-anaerobically grown Rhodopseudomonas spheroides cells was found to be the o-type cytochrome, whereas that of the dark-aerobically grown cells was the a-type cytochrome. When the dark-aerobically grown cells were further incubated under a semianaerobic condition in the dark, the content of the o-type cytochrome was increased in these cells, while the synthesis of the a-type cytochrome appeared to be repressed. In Rhodospirillum rubrum cells, grown either aerobically in the dark or anaerobically in the light, cytochrome o was the sole functional terminal oxidase.

2. 2. Reactions with the a-type and o-type cytochromes from Rhodopseudomonas spheroides and also with the o-type cytochrome from Rhodospirillum rubrum were compared using reduced yeast cytochrome c as substrate. The reaction with the a-type cytochrome was far less sensitive to NaN₃ and hydroxylamine than those with the o-type cytochromes, whereas all the reactions were inhibited by KCN in apparently the same manner.