Prostate tumors develop resistance to androgen deprivation therapy (ADT) by multiple mechanisms, one of which is to express constitutively active androgen receptor (AR) splice variants lacking the ...ligand-binding domain. AR splice variant 7 (AR-V7, also termed AR3) is the most abundantly expressed variant that drives prostate tumor progression under ADT conditions. However, the molecular mechanism by which AR-V7 is generated remains unclear. In this manuscript, we demonstrated that RNA splicing of AR-V7 in response to ADT was closely associated with AR gene transcription initiation and elongation rates. Enhanced AR gene transcription by ADT provides a prerequisite condition that further increases the interactions between AR pre-mRNA and splicing factors. Under ADT conditions, recruitment of several RNA splicing factors to the 3' splicing site for AR-V7 was increased. We identified two RNA splicing enhancers and their binding proteins (U2AF65 and ASF/SF2) that had critical roles in splicing AR pre-mRNA into AR-V7. These data indicate that ADT-induced AR gene transcription rate and splicing factor recruitment to AR pre-mRNA contribute to the enhanced AR-V7 levels in prostate cancer cells.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The Drosophila wing was proposed to be a taste organ more than 35 years ago, but there has been remarkably little study of its role in chemoreception. We carry out a differential RNA-seq analysis of ...a row of sensilla on the anterior wing margin and find expression of many genes associated with pheromone and chemical perception. To ask whether these sensilla might receive pheromonal input, we devised a dye-transfer paradigm and found that large, hydrophobic molecules comparable to pheromones can be transferred from one fly to the wing margin of another. One gene, Ionotropic receptor (IR)52a, is coexpressed in neurons of these sensilla with fruitless, a marker of sexual circuitry; IR52a is also expressed in legs. Mutation of IR52a and optogenetic silencing of IR52a+ neurons decrease levels of male sexual behavior. Optogenetic activation of IR52a+ neurons induces males to show courtship toward other males and, remarkably, toward females of another species. Surprisingly, IR52a is also required in females for normal sexual behavior. Optogenetic activation of IR52a+ neurons in mated females induces copulation, which normally occurs at very low levels. Unlike other chemoreceptors that act in males to inhibit male-male interactions and promote male-female interactions, IR52a acts in both males and females, and can promote male-male as well as male-female interactions. Moreover, IR52a+ neurons can override the circuitry that normally suppresses sexual behavior toward unproductive targets. Circuit mapping and Ca2+ imaging using the trans-Tango system reveals second-order projections of IR52a+ neurons in the subesophageal zone (SEZ), some of which are sexually dimorphic. Optogenetic activation of IR52a+ neurons in the wing activates second-order projections in the SEZ. Taken together, this study provides a molecular description of the chemosensory sensilla of a greatly understudied taste organ and defines a gene that regulates the sexual circuitry of the fly.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
Background
TCS (topical corticosteroids) are the first‐line drug in the treatment of oral lichen planus (OLP). However, the value of topical calcineurin inhibitors (TCI) including tacrolimus, ...pimecrolimus and ciclosporin for OLP is still controversial.
Objectives
To compare the efficacy and safety of TCI vs. TCS for OLP.
Methods
The authors searched PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science and four Chinese databases from 1950 to May 2018. The randomized controlled trials comparing TCI and TCS for OLP reported at least one of the following outcomes: improvement of clinical signs and/or symptoms, relapse, blood levels of TCI and adverse events.
Results
Twenty‐one trials involving 965 patients were included in the analysis. For the treatment of OLP (3–8 weeks), TCI including tacrolimus, pimecrolimus and ciclosporin were similar to TCS in efficacy. Tacrolimus–TCS resulted in similar outcomes, with relapse at 3 weeks to 6 months. Blood levels of TCI were usually undetectable. In addition, tacrolimus showed a statistically higher incidence of local adverse events than TCS for short‐term treatment. A few systemic adverse events occurred in the tacrolimus and ciclosporin groups, but they were not serious.
Conclusions
The evidence for tacrolimus (n = 12), pimecrolimus (n = 3) and ciclosporin (n = 6) demonstrated that treatment with TCI may be an alternative approach when OLP does not respond to the standard protocols. Tacrolimus 0·1% should be the first drug of choice when selecting TCI for short‐term treatment in recalcitrant OLP. Further well‐designed trials are warranted to evaluate the long‐term efficacy and safety of TCI.
What's already known about this topic?
The main topical drug for oral lichen planus (OLP) is topical corticosteroids (TCS).
Patients with OLP who are not responsive to TCS or are at risk of adverse events from TCS need other alternative drugs.
Topical calcineurin inhibitors (TCI), including tacrolimus, pimecrolimus and ciclosporin, have become a hot topic in a variety of mucocutaneous immune‐mediated diseases.
What does this study add?
TCI including tacrolimus, pimecrolimus and ciclosporin were similar to TCS in efficacy for the short‐term treatment of OLP.
The local adverse events of tacrolimus were higher than with TCS. A few systemic adverse events were reported with TCI, but they were all tolerable and not serious.
The limited evidence for pimecrolimus (three trials) and ciclosporin (six trials) requires further studies to evaluate the short‐term and long‐term efficacy and safety of TCI compared with TCS.
Linked Comment: Thongprasom. Br J Dermatol 2019; 181:1120.
Plain language summary available online
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Using observational data and phase 5 of the Coupled Model Intercomparison Project (CMIP5) model outputs the preindustrial (PI) control run of the Community Climate System Model, version 4 (CCSM4) and ...historical simulations of 17 CMIP5 models, Indian Ocean dipoles (IODs) with a peak in fall are categorized into three types. The first type is closely related to the development phase of El Niño/La Niña. The second type evolves from the basinwide warming (cooling) in the tropical Indian Ocean (IO), usually occurring in the year following El Niño (La Niña). The third type is independent of El Niño and La Niña. The dominant trigger condition for the first (third) type of IOD is the anomalous Walker circulation (anomalous cross-equatorial flow); the anomalous zonal sea surface temperature (SST) gradient in the tropical IO is the trigger condition for the second type. The occurrence of anomalous ocean Rossby waves during the forming stage of IO basinwide mode and their effect on SST in the southwestern IO during winter and spring are critical for early development of the second type of IOD. Although most models simulate a stronger El Niño–Southern Oscillation and IOD compared to the observations, this does not influence the phase-locking and classification of the IOD peaking in the fall.
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BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
AbstractA new framework for bridge-deflection estimation through inclinometer data is presented in this paper. Whether the structure is damaged or not, deflection could be precisely estimated via the ...finite-element model (FEM) combined with the partial least-square regression (PLSR) method. In addition, damage localization is achieved at the same time. First, the deflection of a damaged structure is equivalent to that of an undamaged structure but subjected to special virtual loads. Second, the basis functions used in regression are calculated by the FEM of the undamaged structure rather than pure mathematical derivations. Third, the PLSR model is built on the basis of these basis functions and measured inclination data. By solving the PLSR equation, all the nodal inclinations and corresponding nodal loads of the structure could be obtained despite a limited number of measured nodes. Finally, the rotation-displacement transfer matrix is derived to reconstruct deflection from estimated inclinations, and the changes in nodal loads are served as damage indicators. To verify its effectiveness, numerical simulations considering various damage scenarios and different noise levels are performed. The results indicate that the proposed method is quite accurate and reliable in deflection estimation, and it could provide rough damage localization as well, which reveals a great potential in the field of structural health monitoring.
Chip formation during dry turning of Ti6Al4V alloy has been examined in association with dynamic cutting force measurements under different cutting speeds, feed rates and depths of cut. Both ...continuous and segmented chip formation processes were observed in one cut under conditions of low cutting speed and large feed rate. The slipping angle in the segmented chip was 55°, which was higher than that in the continuous chip (38°). A cyclic force was produced during the formation of segmented chips and the force frequency was the same as the chip segmentation frequency. The peak of the cyclic force when producing segmented chips was 1.18 times that producing the continuous chip.
The undeformed surface length in the segmented chip was found to increase linearly with the feed rate but was independent of cutting speed and depth of cut. The cyclic force frequency increased linearly with cutting speed and decreased inversely with feed rate. The cutting force increased with the feed rate and depth of cut at constant cutting speed due to the large volume of material being removed. The increase in cutting force with increasing cutting speed from 10 to 16 and 57 to 75
m/min was attributed to the strain rate hardening at low and high strain rates, respectively. The decrease in cutting force with increasing cutting speed outside these speed ranges was due to the thermal softening of the material. The amplitude variation of the high-frequency cyclic force associated with the segmented chip formation increased with increasing depth of cut and feed rate, and decreased with increasing cutting speed from 57
m/min except at the cutting speeds where harmonic vibration of the machine occurs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Odorant binding proteins (Obps) are remarkable in their number, diversity, and abundance, yet their role in olfactory coding remains unclear. They are widely believed to be required for transporting ...hydrophobic odorants through an aqueous lymph to odorant receptors. We construct a map of the
antenna, in which the abundant Obps are mapped to olfactory sensilla with defined functions. The results lay a foundation for an incisive analysis of Obp function. The map identifies a sensillum type that contains a single abundant
,
Surprisingly, deletion of the sole abundant
in these sensilla does not reduce the magnitude of their olfactory responses. The results suggest that this Obp is not required for odorant transport and that this sensillum does not require an abundant Obp. The results further suggest a novel role for this Obp in buffering changes in the odor environment, perhaps providing a molecular form of gain control.
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