The mitogen-activated protein kinase (MAPK) cascades, in which the major components are MAPK, MAPK kinase (MAPKK), and MAPKK kinase (MAPKKK), are conserved eukaryotic signaling pathways (2, 7, 14, 46). The general function of the MAPK cascades is to link a variety of extracellular stimuli to nuclear responses, i.e., the modulation of gene expression (45). MAPK is activated by dual phosphorylation on threonine and tyrosine residues catalyzed by MAPKK, and MAPKK is activated by serine/threonine phosphorylation catalyzed by MAPKKK. In mammals, at least three MAPK cascades have been identified. The MAPKs in each pathway are ERK (extracellular signal-regulated kinase), JNK/SAPK (cJun N-terminal kinase/stress-activated protein kinase), and p38. The ERK cascade is mostly responsive to mitogenic and differentiation stimuli, whereas the JNK and p38 cascades are strongly activated by proinflammatory cytokines, such as interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF-␣), and extracellular stresses, such as UV irradiation and osmotic shock (4,23,29,36).In the ERK cascade, Raf (Raf-1, A-Raf, and B-Raf), MEK (MEK1 and MEK2), and ERK (ERK1 and ERK2) correspond to MAPKKK, MAPKK, and MAPK, respectively (36). The p38 cascade contains p38␣/CSBP/RK/Mxi2 (12,25,37,56) and p38␤ (18) as MAPKs and MKK3 (9) and MKK6 (6,13,32,35,42) as MAPKKs, while in the JNK cascade the MAPKs are JNK1, JNK2, and JNK3 (also known as SAPK␥, SAPK␣, and SAPK␤, respectively) (8,11,19,22,31), and the MAPKKs are SEK1/MKK4/JNKK1 (9,26, 38) and MKK7/JNKK2 (33,44,48). The specificity of the MAPKKKs involved in the JNK and p38 cascades is less clear. For instance, the TAK1 (52), ASK1 (16), and MLK3 (43) MAPKKKs can activate both the JNK and p38 cascades, while the MEKK1 (28, 50, 53) and MEKK4 (10) MAPKKKs selectively activate the JNK cascade.The identification of numerous components of the MAPK cascades as described above suggests that there are a number of these distinct signaling pathways in cells. Furthermore, studies of JNK3-deficient mice (54) indicate the existence of a JNK3-specific cascade that cannot be complemented by the other JNK family members, even though JNK1, JNK2, and JNK3 exhibit over 80% identity, and these JNKs seem to be

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There is little evidence for multisession repetitive transcranial magnetic stimulation (rTMS) on pain relief in patients with neuropathic pain (NP), although single-session rTMS was suggested to provide transient pain relief in NP patients. We aimed to assess the efficacy and safety of 10 daily rTMS in NP patients. We conducted a randomized, double-blind, sham-controlled, crossover study at 7 centers. Seventy NP patients were randomly assigned to 2 groups. A series of 10 daily 5-Hz rTMS (500 pulses/session) of primary motor cortex (M1) or sham stimulation was applied to each patient with a follow-up of 17days. The primary outcome was short-term pain relief assessed using a visual analogue scale (VAS). The secondary outcomes were short-term change in the short form of the McGill pain questionnaire (SF-MPQ), cumulative changes in the following scores (VAS, SF-MPQ, the Patient Global Impression of Change scale [PGIC], and the Beck Depression Inventory [BDI]), and the incidence of adverse events. Analysis was by intention to treat. This trial is registered with the University hospital Medical Information Network Clinical Trials Registry. Sixty-four NP patients were included in the intention-to-treat analysis. The real rTMS, compared with the sham, showed significant short-term improvements in VAS and SF-MPQ scores without a carry-over effect. PGIC scores were significantly better in real rTMS compared with sham during the period with daily rTMS. There were no significant cumulative improvements in VAS, SF-MPQ, and BDI. No serious adverse events were observed. Our findings demonstrate that daily high-frequency rTMS of M1 is tolerable and transiently provides modest pain relief in NP patients.

Replication of influenza viral genomic RNA (vRNA) is catalyzed by viral RNA-dependent RNA polymerase (vRdRP). Complementary RNA (cRNA) is first copied from vRNA, and progeny vRNAs are then amplified from the cRNA. Although vRdRP and viral RNA are minimal requirements, efficient cell-free replication could not be reproduced using only these viral factors. Using a biochemical complementation assay system, we found a novel activity in the nuclear extracts of uninfected cells, designated IREF-2, that allows robust unprimed vRNA synthesis from a cRNA template. IREF-2 was shown to consist of host-derived proteins, pp32 and APRIL. IREF-2 interacts with a free form of vRdRP and preferentially upregulates vRNA synthesis rather than cRNA synthesis. Knockdown experiments indicated that IREF-2 is involved in in vivo viral replication. On the basis of these results and those of previous studies, a plausible role(s) for IREF-2 during the initiation processes of vRNA replication is discussed.DOI: http://dx.doi.org/10.7554/eLife.08939.001

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