eIF4A inhibitors suppress cell-cycle feedback response and acquired resistance to CDK4/6 inhibition in cancer

CDK4/6 inhibitors are FDA-approved drugs for estrogen receptor-positive (ER+) breast cancer and are being evaluated to treat other tumor types, including KRAS-mutant non-small cell lung cancer (NSCLC). However, their clinical utility is often limited by drug resistance. Here, we sought to better understand the resistant mechanisms and help devise potential strategies to overcome this challenge. We show that treatment with CDK4/6 inhibitors in both ER+ breast cancer and KRAS-mutant NSCLC cells induces feedback upregulation of cyclin D1, CDK4, and cyclin E1, mediating drug resistance. We demonstrate that rocaglates, which preferentially target translation of key cell-cycle regulators, effectively suppress this feedback upregulation induced by CDK4/6 inhibition. Consequently, combination treatment of CDK4/6 inhibitor palbociclib with the eukaryotic initiation factor (eIF) 4A inhibitor, CR-1-31-B, is synergistic in suppressing the growth of these cancer cells in vitro and in vivo Furthermore, ER+ breast cancer and KRAS-mutant NSCLC cells that acquired resistance to palbociclib after chronic drug exposure are also highly sensitive to this combination treatment strategy. Our findings reveal a novel strategy using eIF4A inhibitors to suppress cell-cycle feedback response and to overcome resistance to CDK4/6 inhibition in cancer.Accepted manuscrip

Regulatory feedback response mechanisms to phosphate starvation in rice

Phosphorus is a growth-limiting nutrient for plants. The growing scarcity of phosphate stocks threatens global food security. Phosphate-uptake regulation is so complex and incompletely known that attempts to improve phosphorus use efficiency have had extremely limited success. This study improves our understanding of the molecular mechanisms underlying phosphate uptake by investigating the transcriptional dynamics of two regulators: the Ubiquitin ligase PHO2 and the long non-coding RNA IPS1. Temporal measurements of RNA levels have been integrated into mechanistic mathematical models using advanced statistical techniques. Models based solely on current knowledge could not adequately explain the temporal expression profiles. Further modeling and bioinformatics analysis have led to the prediction of three regulatory features: the PHO2 protein mediates the degradation of its own transcriptional activator to maintain constant PHO2 mRNA levels; the binding affinity of the transcriptional activator of PHO2 is impaired by a phosphate-sensitive transcriptional repressor/inhibitor; and the extremely high levels of IPS1 and its rapid disappearance upon Pi re-supply are best explained by Pi-sensitive RNA protection. This work offers both new opportunities for plant phosphate research that will be essential for informing the development of phosphate efficient crop varieties, and a foundation for the development of models integrating phosphate with other stress responses

A Feedback-Response Pause Normalises Response Perseveration Deficits in Pathological Gamblers

A failure to inhibit punished responses is central to problematic gambling. We used a computerised card playing game to determine if this failure can be ameliorated by imposing a delay between feedback from the previous trial and the opportunity to play the next card. We compared two experimental conditions: No pause (Standard task) and a 5-s pause (Pause task). Community-based problematic gamblers (n = 42) were compared with a control group (n = 39). Number of cards played (and cash won/lost) and latency of response were measured. Results show that, compared to a control group, problematic gamblers perseverated longer and lost more money on the Standard task, but this deficit was abolished by the imposition of a 5-s pause. Results suggest that, by strengthening inhibitory control processes, problematic gambling on computer gaming machines can be significantly reduced by the imposition of a simple short-delay before the next bet

A General Precipitation-Limited L_X-T-R Relation Among Early-Type Galaxies

The relation between X-ray luminosity (L_X) and ambient gas temperature (T) among massive galactic systems is an important cornerstone of both observational cosmology and galaxy-evolution modeling. In the most massive galaxy clusters, the relation is determined primarily by cosmological structure formation. In less massive systems, it primarily reflects the feedback response to radiative cooling of circumgalactic gas. Here we present a simple but powerful model for the L_X-T relation as a function of physical aperture R within which those measurements are made. The model is based on the precipitation framework for AGN feedback and assumes that the circumgalactic medium is precipitation-regulated at small radii and limited by cosmological structure formation at large radii. We compare this model with many different data sets and show that it successfully reproduces the slope and upper envelope of the L_X-T-R relation over the temperature range from ~0.2 keV through >10 keV. Our findings strongly suggest that the feedback mechanisms responsible for regulating star formation in individual massive galaxies have much in common with the precipitation-triggered feedback that appears to regulate galaxy-cluster cores.Comment: Submitted to ApJ, 9 pages, 3 figures (v2 fixes a few small typos

Feedback response in the CLIC main linac to transverse and longitudinal dynamic imperfections

In the main linac of the Compact Linear Collider (CLIC), longitudinal and transverse dynamic imperfections, such as RF phase jitter, variation of bunch length and movements of elements, can result in significant luminosity loss. The responses of local trajectory feedbacks to these imperfections are studied in this paper

Increased intracellular Ca++ in the macula densa regulates tubuloglomerular feedback

Increased intracellular Ca++ in the macula densa regulates tubuloglomerular feedback.BackgroundTubuloglomerular feedback is initiated by an increase in NaCl at the macula densa lumen, which in turn increases intracellular Ca++. In the present study, we examined the role of increased intracellular Ca++ in tubuloglomerular feedback and the source of the increased Ca++. We hypothesized that an increase in intracellular Ca++ at the macula densa via the basolateral Na+/Ca++ exchanger, caused by an increase in luminal NaCl, initiates Ca++-mediated Ca++ release from intracellular stores, which is essential for tubuloglomerular feedback.MethodsRabbit afferent arterioles and attached macula densas were simultaneously microperfused in vitro. Tubuloglomerular feedback was induced by increasing macula densa Na+/Cl- from 11/10mmol/L (low) to 81/80mmol/L (high) and was measured before and after treatment.ResultsTo investigate whether elevations in intracellular Ca++ are required for tubuloglomerular feedback, the calcium ionophore A23187 or the Ca++ chelator BAPTA-AM was added to the macula densa lumen. During the control period, tubuloglomerular feedback decreased afferent arteriole diameter from 18.1 ± 1.1 μm to 15.3 ± 0.8 μm. Adding 2 × 10-6 mol/L A23187 to the low NaCl macula densa perfusate induced tubuloglomerular feedback; diameter decreased from 18.0 ± 1.0 μm to 15.4 ± 0.9 μm (N = 6; P < 0.01). After adding BAPTA-AM (25 μmol/L) to the macula densa lumen, tubuloglomerular feedback response was completely eliminated. We next studied the source of increased macula densa Ca++ in response to increased NaCl concentration. During the control period, tubuloglomerular feedback decreased afferent arteriole diameter from 18.5 ± 1.6 μm to 15.3 ± 1.2 μm (N = 6; P < 0.01). After adding the Na+/Ca++ exchanger inhibitor 2′4′-dichlorobenzamil (10 μmol/L) or KB-R7943 (30 μmol/L) to the bath, the tubuloglomerular feedback response was blocked; however, the afferent arteriole response to angiotensin II or adenosine was not altered. Next, we tested the Ca++-adenosine triphosphatase (ATPase) inhibitor thapsigargin (0.1 μmol/L), which has been reported to inhibit sarcoplasmic reticulum Ca++-ATPase activity and prevent restoration of intracellular Ca++ stores. When thapsigargin was added to the macula densa lumen, it reduced the first tubuloglomerular feedback response by 33% and completely eliminated the second and third tubuloglomerular feedback responses. In the absence of thapsigargin, there was no significant decrease in the tubuloglomerular feedback responses (N = 6). Neither the L-type Ca++ channel blocker nifedipine (25 μmol/L), nor the T-type Ca++ channel blocker pimozide (10 μmol/L), inhibited tubuloglomerular feedback when added to the macula densa lumen.ConclusionWe concluded that (1) increased intracellular Ca++ at the macula densa is required for the tubuloglomerular feedback response; (2) Na+/Ca++ exchange appears to initiate Ca++-mediated Ca++ release from intracellular stores; and (3) luminal L-type or T-type Ca++ channels are not involved in tubuloglomerular feedback

The C. elegans DSB-2 protein reveals a regulatory network that controls competence for meiotic DSB formation and promotes crossover assurance.

For most organisms, chromosome segregation during meiosis relies on deliberate induction of DNA double-strand breaks (DSBs) and repair of a subset of these DSBs as inter-homolog crossovers (COs). However, timing and levels of DSB formation must be tightly controlled to avoid jeopardizing genome integrity. Here we identify the DSB-2 protein, which is required for efficient DSB formation during C. elegans meiosis but is dispensable for later steps of meiotic recombination. DSB-2 localizes to chromatin during the time of DSB formation, and its disappearance coincides with a decline in RAD-51 foci marking early recombination intermediates and precedes appearance of COSA-1 foci marking CO-designated sites. These and other data suggest that DSB-2 and its paralog DSB-1 promote competence for DSB formation. Further, immunofluorescence analyses of wild-type gonads and various meiotic mutants reveal that association of DSB-2 with chromatin is coordinated with multiple distinct aspects of the meiotic program, including the phosphorylation state of nuclear envelope protein SUN-1 and dependence on RAD-50 to load the RAD-51 recombinase at DSB sites. Moreover, association of DSB-2 with chromatin is prolonged in mutants impaired for either DSB formation or formation of downstream CO intermediates. These and other data suggest that association of DSB-2 with chromatin is an indicator of competence for DSB formation, and that cells respond to a deficit of CO-competent recombination intermediates by prolonging the DSB-competent state. In the context of this model, we propose that formation of sufficient CO-competent intermediates engages a negative feedback response that leads to cessation of DSB formation as part of a major coordinated transition in meiotic prophase progression. The proposed negative feedback regulation of DSB formation simultaneously (1) ensures that sufficient DSBs are made to guarantee CO formation and (2) prevents excessive DSB levels that could have deleterious effects