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Background: The immunomodulatory drug lenalidomide, which is now widely used for the treatment of multiple myeloma (MM), exerts pharmacological action through the ubiquitin-dependent degradation of IKZF1 and subsequent down-regulation of interferon regulatory factor 4 (IRF4), a critical factor for the survival of MM cells. IKZF1 acts principally as a tumour suppressor via transcriptional repression of oncogenes in normal lymphoid lineages. In contrast, IKZF1 activates IRF4 and other oncogenes in MM cells, suggesting the involvement of unknown co-factors in switching the IKZF1 complex from a transcriptional repressor to an activator. The transactivating components of the IKZF1 complex might promote lenalidomide resistance by residing on regulatory regions of the IRF4 gene to maintain its transcription after IKZF1 degradation., Methods: To identify unknown components of the IKZF1 complex, we analyzed the genome-wide binding of IKZF1 in MM cells using chromatin immunoprecipitation-sequencing (ChIP-seq) and screened for the co-occupancy of IKZF1 with other DNA-binding factors on the myeloma genome using the ChIP-Atlas platform., Results: We found that c-FOS, a member of the activator protein-1 (AP-1) family, is an integral component of the IKZF1 complex and is primarily responsible for the activator function of the complex in MM cells. The genome-wide screening revealed the co-occupancy of c-FOS with IKZF1 on the regulatory regions of IKZF1-target genes, including IRF4 and SLAMF7, in MM cells but not normal bone marrow progenitors, pre-B cells or mature T-lymphocytes. c-FOS and IKZF1 bound to the same consensus sequence as the IKZF1 complex through direct protein-protein interactions. The complex also includes c-JUN and IKZF3 but not IRF4. Treatment of MM cells with short-hairpin RNA against FOS or a selective AP-1 inhibitor significantly enhanced the anti-MM activity of lenalidomide in vitro and in two murine MM models. Furthermore, an AP-1 inhibitor mitigated the lenalidomide resistance of MM cells., Conclusions: C-FOS determines lenalidomide sensitivity and mediates drug resistance in MM cells as a co-factor of IKZF1 and thus, could be a novel therapeutic target for further improvement of the prognosis of MM patients., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Premise of the Study: Timing of budburst ( D BB ) may be related to the functional traits and distributions of woody species in temperate regions. Although many previous studies have investigated D BB in a number of temperate species, it has seldom been linked to multiple plant trait relationships., Methods: D BB and plant traits were investigated for 24 woody species for 2 years in a warm-temperate secondary forest in Japan. Particular attention was paid to differences in trait relationships between coexisting deciduous and evergreen broad-leaved species., Key Results: D BB was correlated with plant traits in deciduous but not evergreen broad-leaved species; D BB was later for deciduous species with greater leaf mass, leaf area, vessel diameter, and leaf nitrogen content per unit mass. In addition, D BB was later for species with more northern distributions in deciduous and evergreen species., Conclusions: Clear differences in the trait relationships between deciduous and evergreen broad-leaved species might be caused by different selection pressures on D BB ; selection is expected to be more severe in deciduous species. Overall, the continuous variable of vessel diameter might be used as a simple and effective trait to predict D BB of deciduous species regardless of wood anatomy; however, no such traits were detected as effective predictors of D BB in evergreen species at this study site. In addition, D BB was earlier for the species of more southern distributions, suggesting that such species benefit more from warming., (© 2017 Botanical Society of America.)

Premise of the Study: Leaf life span (LLS) has long been hypothesized to plastically increase with decreasing nitrogen (N) supply from soil to maximize N retention, carbon assimilation, and fitness; however, accumulating evidence shows no consistent trend. The apparent inconsistencies are explained by a recent model that assumes LLS has a hump-shaped quadratic response to the N-supply gradient. The available evidence mostly originates from comparisons of LLS at only two levels of N availability, and the hypothesis remains unanswered., Methods: We investigated LLS of two asteraceous forbs ( Adenocaulon himalaicum and Xanthium canadense ) experimentally grown at eight levels of N supply, which covered a range of N supply in their natural habitats. We additionally conducted a literature search to retrieve studies reporting LLS response along an N-supply gradient., Key Results: The LLS of neither species showed a hump-shaped response along the N-supply gradient. Past studies examining the LLS of an aquatic forb and terrestrial shrubs and trees along the N-supply gradient (more than four levels of N supply) also refuted the hypothesis., Conclusions: The LLS of a single species exhibited neither an increase nor a hump-shaped response to decreased N supply in a variety of life forms. Comparisons at only a few N levels are misleading with regard to LLS response to N supply., (© 2017 Botanical Society of America.)

Premise of the Study: Differences in leaf size are expected to be coordinated with various shoot traits and branching intensity because these relationships will influence light capture efficiency, water use, and biomechanics. Previous studies have mainly focused on interspecific patterns of these trait relationships, but not on intraspecific patterns at the geographic scale. We investigated intraspecific variation in shoot traits and branching intensity of Fagus crenata in Japan., Methods: Allometric relationships between the traits of current-year shoots and branching intensity per branch unit of 1-m length on the main axis (BI) and its coordination with latitude were investigated using trees from 10 provenances in a common garden., Key Results: Individual trees originating from lower latitudes have smaller leaves with greater leaf mass per area and nitrogen content per area, greater Huber value (stem cross-sectional area per total leaf area [ATL]) of current-year shoots, and greater BI. Notably, the slope of the log-log relationship between BI and ATL was close to -1.0 across the trees from different source sites, implying that branching in this species occurs to control leaf area., Conclusions: Shoot traits and branching intensity were apparently coordinated with leaf size to control leaf area deployment in this species. Such patterns probably reflect differences in competition for hydraulic conductance among nearby shoots within crowns, as a consequence of different meteorological conditions across the source sites., (© 2015 Botanical Society of America, Inc.)

Aims: Life-threatening arrhythmias are a major problem in chronic heart failure (CHF). The aim of the present study was to investigate the mechanism underlying the low proarrhythmic potential of amiodarone in a model of pacing-induced heart failure., Methods and Results: Heart failure was induced in 35 female rabbits by rapid ventricular pacing, resulting in a significant decrease of ejection fraction. Thirty-four rabbits were sham-operated. In 17 of 35 CHF-rabbits and 20 of 34 'sham'-rabbits, amiodarone (50 mg/kg/day) was fed for 6 weeks. Eight monophasic action potentials and a simultaneously recorded 12-lead electrocardiogram showed prolongation of QT-interval and action potential duration (APD(90)) in all failing hearts (P< 0.05). Amiodarone pre-treatment led to a prolongation of APD(90) (+19 ms) as compared with sham-controlled hearts but showed only a marginal effect on APD(90) in failing hearts. Infusion of sotalol (50-100 µM) led to a significant prolongation of APD(90) in sham and a further prolongation of APD(90) in failing hearts [+55 ms (50 µM); +70 ms (100 µM); P< 0.01 as compared with sham hearts]. Sotalol led to a triangular action potential configuration in sham and failing hearts, whereas amiodarone did not cause triangularization but caused a rapid phase-III repolarization. Moreover, amiodarone did not increase dispersion of repolarization either in sham or in failing hearts. Infusion of sotalol led to a significant increase in dispersion of repolarization in sham (+29 ms) and a further increase in failing hearts (+67 ms; P< 0.05)., Conclusion: Chronic amiodarone results in a rapid phase-III-repolarization and does not increase dispersion of repolarization. These electrophysiological findings are present in healthy hearts and are preserved in heart failure. This contributes to the low proarrhythmic potential of amiodarone in heart failure.

The purpose of this study was to investigate the anatomical morphology and measurement of the medial patellofemoral ligament (MPFL), especially the femoral attachment. A total of 20 knee specimens were dissected and the total length, width, thickness, inclination, as well as the attachment points of the MPFL were measured. The MPFL was well-developed in seven knees, moderate in ten knees and wispy in three knees. Total length of the MPFL was 58.8 +/- 4.7 mm. The width and thickness was 12.0 +/- 3.1 mm and 0.44 +/- 0.19 mm at the middle point. The long axis of the MPFL inclined at 15.9 +/- 5.6 degrees proximally. The center of the patellar attachment was located at 27 +/- 10% from the upper end of the patella in the longitudinal patellar height. The femoral attachment was superoposterior to the medial femoral epicondyle and just distal to the adductor tubercle. The center of the anterior edge of the femoral attachment was 9.5 +/- 1.8 mm proximally and 5.0 +/- 1.7 mm posteriorly from the center of the medial femoral epicondyle. The femoral attachment was located at 61 +/- 4% of anteroposterior length of the medial femoral condyle from the anterior edge.

This study investigated the results of augmented repair for avulsion-tear type medial patellofemoral ligament (MPFL) injury performed on a total of five knees with initial acute lateral patellar dislocation. Augmented repair was performed using a medial retinaculum slip on all five knees. The average follow-up was 5.9 years. The results were evaluated with the Insall, Aglietti, and Tria grading system. Three knees were classified as excellent, one knee as good, and one knee as fair. The mean Kujala score at follow-up was 97.6 points. Augmented repair of the injured MPFL for avulsion-type MPFL injury may be considered as one good option to prevent subsequent dislocation and subluxation.

The relative effects of light and tree height on the architecture of leader crowns (i.e., the leading section of the main trunk, 100 cm in length) and current-year shoots for a canopy species, Fagus crenata, occupying both the ridge top and the valley bottom in a cool-temperate forest in Japan were investigated. For leader crowns, the number of current-year shoots and leaves increased with increasing tree height, whereas the mean length of current-year shoots increased with increasing relative photon flux density (PFD). The leader crown area decreased, and the depth and leaf area index of leader crowns increased, with increasing relative PFD. The mass of current-year shoots increased with relative PFD. However, this total mass was allocated differently between stems and leaves depending on tree height, such that the relative allocation to stems increased with increasing tree height. Furthermore, stem structures within current-year shoots also changed with height, such that taller trees produced thicker and shorter stems of the same volume. In contrast, leaf structure and leaf biomass allocations changed with relative PFD. Specific leaf area decreased with increasing relative PFD. In addition, leaf number increased more rapidly with increasing individual leaf mass for trees exposed to greater relative PFD. Consequently, the total leaf area supported by a stem of a given diameter decreased with increasing tree height and relative PFD. Thus, the architecture of leader crowns and current-year shoots were related differently to light and tree height, which are considered important for efficient light capture and the growth of small and tall trees in different environments.