T790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.
The shoot apical meristem (SAM) is a group of stem cells that are responsible for plant development. Mutations in rice SHOOTLESS2 (SHL2), SHL4/SHOOT ORGANIZATION2 (SHO2), and SHO1 cause complete deletion or abnormal formation of the SAM. In this study we showed that defects in SAM formation in shl mutants are associated with the loss of expression of the homeodomainleucine zipper (HD-ZIPIII) family genes. Rice SHL2, SHL4/SHO2, and SHO1 encoded orthologues of Arabidopsis RNA-dependent RNA polymerase 6, ARGONAUTE (AGO) 7, and DICER-like 4, respectively, whose mutations affect leaf development through the trans-acting siRNA (ta-siRNA) pathway. This suggested that the ta-siRNA pathway regulates the critical step of SAM formation during rice embryogenesis. The gain-of-function experiment by the ectopic expression of SHL4 resulted in reduced accumulation of an microRNA, miR166, and partial adaxialization of leaves, supporting a role for the ta-siRNA pathway in the maintenance of leaf polarity as previously reported in maize. Analysis of the spatiotemporal expression patterns of HD-ZIPIII and miR166 in wild-type and shl mutant embryos suggested that the loss of HD-ZIPIII expression in the SAM region of the developing embryo is the result of ectopic expression of miR166. Our analysis of shl mutants demonstrated that HD-ZIPIII expression regulated by miR166 is sensitive to the ta-siRNA pathway during SAM formation in rice embryogenesis.embryogenesis ͉ shoot apical meristem ͉ shootless ͉ shoot organization I n multicellular organisms, precise control of the spatial and temporal expression of developmental regulatory genes is essential. Recent studies have revealed the existence of a posttranscriptional mechanism of regulation of these genes through small RNAs (1, 2). Among the various types of small RNA molecules, microRNAs (miRNAs) control the expression of developmental regulatory molecules in both plants and animals, and their target sequences are often conserved between species. Recently, it has been shown that repeat-associated siRNAs and trans-acting siRNAs (ta-siRNAs) are also involved in the regulation of development (1, 3-5). However, the downstream developmental and genetic events that are regulated by these small RNAs are poorly understood.The shoot apical meristem (SAM) is a center of morphogenesis in plants and the developmental origin of most of the aboveground parts of the plant, including the leaves, stems, and axillary buds (6). Embryonic SAM formation is the initial process that establishes stem cells, providing an appropriate local environment for the maintenance of the stem cells, and ensures postembryonic development of the shoot architecture. Thus, understanding the mechanism of embryonic SAM formation is a priority issue in the developmental biology in plants, and doing so provides a unique system to study the mechanism of stem cell establishment. In rice, shootless (shl) mutants were originally identified as embryonic mutants that completely lack a SAM (7). In most shl mutants, the scutellum and ra...
Intramuscular injection of nerve growth factor (NGF) is known to induce deep-tissue mechanical hyperalgesia. In this study it was hypothesised that daily intramuscular injections of NGF produce a progressive manifestation of soreness, mechanical hyperalgesia, and temporal summation of pain. In a double-blind placebo-controlled design, 12 healthy subjects were injected on 3 days with NGF into the tibialis anterior muscle and with isotonic saline on the contralateral side. Assessments were performed before and after the injections on days 0, 1, and 2, and repeated on days 3, 6, and 10. The self-perceived muscle soreness was assessed on a Likert scale. Computer-controlled pressure algometry was used to assess the pressure pain thresholds (PPTs). Temporal summation of pain after repeated pressure stimulations was assessed by computer-controlled pressure algometry. The pain distribution following painful pressure stimulation was also recorded. Compared with baseline and isotonic saline, the NGF injections caused (P<0.05): (1) progressively increasing soreness scores from 3 hours after the first injection until day 2, after which it remained increased; (2) decreased PPTs at days 1 to 3; (3) facilitated temporal summation of pressure pain at days 1 to 10; and (4) enlarged pressure-induced pain area after the injection on day 1 to day 6. The daily injections of NGF produced a progressive manifestation of muscle soreness, mechanical hyperalgesia, temporal summation of pressure pain, and pressure-induced pain distribution. These data illustrate that the prolonged NGF application affects peripheral and central mechanisms and may reflect process in musculoskeletal pain conditions.
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