Distinct cellular pathways select germline-encoded and somatically mutated antibodies into immunological memory

One component of memory in the antibody system is long-lived memory B cells selected for the expression of somatically mutated, high-affinity antibodies in the T cell–dependent germinal center (GC) reaction. A puzzling observation has been that the memory B cell compartment also contains cells expressing unmutated, low-affinity antibodies. Using conditional Bcl6 ablation, we demonstrate that these cells are generated through proliferative expansion early after immunization in a T cell–dependent but GC-independent manner. They soon become resting and long-lived and display a novel distinct gene expression signature which distinguishes memory B cells from other classes of B cells. GC-independent memory B cells are later joined by somatically mutated GC descendants at roughly equal proportions and these two types of memory cells efficiently generate adoptive secondary antibody responses. Deletion of T follicular helper (Tfh) cells significantly reduces the generation of mutated, but not unmutated, memory cells early on in the response. Thus, B cell memory is generated along two fundamentally distinct cellular differentiation pathways. One pathway is dedicated to the generation of high-affinity somatic antibody mutants, whereas the other preserves germ line antibody specificities and may prepare the organism for rapid responses to antigenic variants of the invading pathogen

Nuclear factor (erythroid derived 2)-like 2 activation increases exercise endurance capacity via redox modulation in skeletal muscles

Sulforaphane (SFN) plays an important role in preventing oxidative stress by activating the nuclear factor (erythroid derived 2)-like 2 (Nrf2) signalling pathway. SFN may improve exercise endurance capacity by counteracting oxidative stress-induced damage during exercise. We assessed running ability based on an exhaustive treadmill test (progressive-continuous all-out) and examined the expression of markers for oxidative stress and muscle damage. Twelve- to 13-week-old Male wild-type mice (Nrf2+/+) and Nrf2-null mice (Nrf2−/−) on C57BL/6J background were intraperitoneally injected with SFN or vehicle prior to the test. The running distance of SFN-injected Nrf2+/+ mice was significantly greater compared with that of uninjected mice. Enhanced running capacity was accompanied by upregulation of Nrf2 signalling and downstream genes. Marker of oxidative stress in SFN-injected Nrf2+/+ mice were lower than those in uninjected mice following the test. SFN produced greater protection against muscle damage during exhaustive exercise conditions in Nrf2+/+ mice than in Nrf2−/− mice. SFN-induced Nrf2 upregulation, and its antioxidative effects, might play critical roles in attenuating muscle fatigue via reduction of oxidative stress caused by exhaustive exercise. This in turn leads to enhanced exercise endurance capacity. These results provide new insights into SFN-induced upregulation of Nrf2 and its role in improving exercise performance

Apelin Deficiency Accelerates the Progression of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons. Recent studies have implicated that chronic hypoxia and insufficient vascular endothelial growth factor (VEGF)-dependent neuroprotection may lead to the degeneration of motor neurons in ALS. Expression of apelin, an endogenous ligand for the G protein-coupled receptor APJ, is regulated by hypoxia. In addition, recent reports suggest that apelin protects neurons against glutamate-induced excitotoxicity. Here, we examined whether apelin is an endogenous neuroprotective factor using SOD1G93A mouse model of ALS. In mouse CNS tissues, the highest expressions of both apelin and APJ mRNAs were detected in spinal cord. APJ immunoreactivity was observed in neuronal cell bodies located in gray matter of spinal cord. Although apelin mRNA expression in the spinal cord of wild-type mice was not changed from 4 to 18 weeks age, that of SOD1G93A mice was reduced along with the paralytic phenotype. In addition, double mutant apelin-deficient and SOD1G93A displayed the disease phenotypes earlier than SOD1G93A littermates. Immunohistochemical observation revealed that the number of motor neurons was decreased and microglia were activated in the spinal cord of the double mutant mice, indicating that apelin deficiency pathologically accelerated the progression of ALS. Furthermore, we showed that apelin enhanced the protective effect of VEGF on H2O2-induced neuronal death in primary neurons. These results suggest that apelin/APJ system in the spinal cord has a neuroprotective effect against the pathogenesis of ALS

アタラシイ ニホンゴ ノウリョク シケン ノ タメノ ゴイ ヒョウ サクセイ ニ ムケテ

日本語能力試験の実施機関である国際交流基金と日本国際教育支援協会は「日本語能力試験の改善に関する検討会」を2005年に発足させたが、2009年からの新試験開始を目指して各分科会は日々調査研究を重ねている。本稿は、分科会の一つである出題基準分科会漢字表・語彙表部会が行っている語彙表作成作業の2007年9月現在の中間報告である。 部会の活動は、この2年間で4つの段階を経た。作成方針と選別方針を決定し、データベースに関する調査および整備をする第一段階、語彙の選別をする第二段階、語彙の再選別及び記述方法の検討をする第三段階、語彙の再選別と初出級の検討をする第四段階である。実際にどのようなデータベースを使い、どのような検討を重ね、どのような選別作業をしたのか。本稿ではそれぞれの段階ごとに具体的な例を挙げながら報告をする。また、それとともに今後考えていかなければならない課題についても言及する。The Japan Foundation and Japan Educational Exchanges and Services inaugurated an "Examination Committee on Improving Japanese Language Proficiency Test" in 2005, and have been conducting research on the New Test to be incorporated in 2009. There are various revisions to be made. This is an interim report as of September 2007, on the working of vocabulary list which has been made by the kanji and vocabulary list subdivision of the Test Content Specifications division. The activities of the subdivision have been divided into four stages during these two years. The first stage is for decisions on the policy for composition and selection, and research on the database. The second stage is for the selection of vocabulary. The third stage is for discussion on the re-selection and description of vocabulary. The forth stage is for re-selection of vocabulary and for each level to be decided

Electrical Connections between Persistent Left Superior Vena Cava and Left Atrium during Catheter Ablation for Atrial Tachycardia

A 74-year-old man presented with palpitation and 12-lead ECG exhibited atrial premature contraction (APC) at general check-up. Holter ECG demonstrated narrow QRS tachycardia with a rate of 160/min and more than 31,000/day atrial premature beats. The P wave morphology of atrial premature beats showed negative in II, III, aVF and biphasic in V1. Venography was performed and disclosed persistent left superior vena cava (LSVC) draining into the right atrium via the markedly dilated coronary sinus (CS). Electrogram recordings from LSVC and CS were obtained with an electrode catheter via the left subclavian vein. At the level where a ventricular potential disappeared, the intra-LSVC potentials began to show a discrete second sharp potential after local left atrial signals. Double potentials were obtained within the LSVC from the lower left atrium (LA) to the higher LA. A proximal-to-distal activation sequence of the second components was observed. The interval between the 1st and 2nd component ranged from 8 to 22 msec between the proximal LSVC and distal LSVC. The double potentials resulted in fusion at the lower part of the LSVC, indicating the presence of an electrical connection between the LSVC and lower LA

APJ expression in the lumbar spinal cord of WT mice.

<p>Representative pictures of ventral horn show double immunostaining for APJ and NeuN (A–C) or GFAP (D–F) in the lumbar spinal cord. Scale bar = 200 µm (upper panels), 100 µm (lower panels).</p

Effect of apelin deficiency on disease progression of ALS mice.

<p>(A) Motor signs (hind limb tremors) were measured as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0023968#pone-0023968-g003" target="_blank">Fig. 3B</a>. (B) Rotarod performance of SOD1^G93A littermates (open circles) and KO-SOD1^G93A (closed circles) mice was measured as described in the methods for 180 s. (C) The number of motorneurons was decreased in the lumbar spinal cord of KO-SOD1 ^G93A mice at 14 weeks-old (n = 3). Data represent mean ± SEM. *<i>p</i><0.05 vs. SOD1 ^G93A mice.</p