Soluble histone H2AX is induced by DNA replication stress and sensitizes cells to undergo apoptosis

<p>Abstract</p> <p>Background</p> <p>Chromatin-associated histone H2AX is a key regulator of the cellular responses to DNA damage. However, non-nucleosomal functions of histone H2AX are poorly characterized. We have recently shown that soluble H2AX can trigger apoptosis but the mechanisms leading to non-chromatin-associated H2AX are unclear. Here, we tested whether stalling of DNA replication, a common event in cancer cells and the underlying mechanism of various chemotherapeutic agents, can trigger increased soluble H2AX.</p> <p>Results</p> <p>Transient overexpression of H2AX was found to lead to a detectable fraction of soluble H2AX and was associated with increased apoptosis. This effect was enhanced by the induction of DNA replication stress using the DNA polymerase α inhibitor aphidicolin. Cells manipulated to stably express H2AX did not contain soluble H2AX, however, short-term treatment with aphidicolin (1 h) resulted in detectable amounts of H2AX in the soluble nuclear fraction and enhanced apoptosis. Similarly, soluble endogenous H2AX was detected under these conditions. We found that excessive soluble H2AX causes chromatin aggregation and inhibition of ongoing gene transcription as evidenced by the redistribution and/or loss of active RNA polymerase II as well as the transcriptional co-activators CBP and p300.</p> <p>Conclusion</p> <p>Taken together, these results show that DNA replication stress rapidly leads to increased soluble H2AX and that non-chromatin-associated H2AX can sensitize cells to undergo apoptosis. Our findings encourage further studies to explore H2AX and the cellular pathways that control its expression as anti-cancer drug targets.</p

Proposed Lessons for Improved Home Lighting for Home Economics Extension Program in Taiwan

Home Management, Equipment, and Family Economic

The Breathing, Thinking, Functioning clinical model: a proposal to facilitate evidence-based breathlessness management in chronic respiratory disease.

Refractory breathlessness is a highly prevalent and distressing symptom in advanced chronic respiratory disease. Its intensity is not reliably predicted by the severity of lung pathology, with unhelpful emotions and behaviours inadvertently exacerbating and perpetuating the problem. Improved symptom management is possible if clinicians choose appropriate non-pharmacological approaches, but these require engagement and commitment from both patients and clinicians. The Breathing Thinking Functioning clinical model is a proposal, developed from current evidence, that has the potential to facilitate effective symptom control, by providing a rationale and focus for treatment

Composition constraints of the TRAPPIST-1 planets from their formation

We study the formation of the TRAPPIST-1 (T1) planets starting shortly after Moon-sized bodies form just exterior to the ice line. Our model includes mass growth from pebble accretion and mergers, fragmentation, type-I migration, and eccentricity and inclination dampening from gas drag. We follow the composition evolution of the planets fed by a dust condensation code that tracks how various dust species condense out of the disc as it cools. We use the final planet compositions to calculate the resulting radii of the planets using a new planet interior structure code and explore various interior structure models. Our model reproduces the broader architecture of the T1 system and constrains the initial water mass fraction of the early embryos and the final relative abundances of the major refractory elements. We find that the inner two planets likely experienced giant impacts and fragments from collisions between planetary embryos often seed the small planets that subsequently grow through pebble accretion. Using our composition constraints we find solutions for a two-layer model, a planet comprised of only a core and mantle, that match observed bulk densities for the two inner planets b and c. This, along with the high number of giant impacts the inner planets experienced, is consistent with recent observations that these planets are likely dessicated. However, two-layer models seem unlikely for most of the remaining outer planets which suggests that these planets have a primordial hydrosphere. Our composition constraints also indicate that no planets are consistent with a core-free interior structure.Comment: 15 pages, 8 figures, 4 tables, and an appendix. Accepted for publication in MNRA

Germline genetic variation and predicting immune checkpoint inhibitor induced toxicity

Immune checkpoint inhibitor (ICI) therapy has revolutionised the treatment of various cancer types. ICIs reinstate T-cell function to elicit an anti-cancer immune response. The resulting immune response can however have off-target effects which manifest as autoimmune type serious immune-related adverse events (irAE) in ~10–55% of patients treated. It is currently challenging to predict both who will experience irAEs and to what severity. Identification of patients at high risk of serious irAE would revolutionise patient care. While the pathogenesis driving irAE development is still unclear, host genetic factors are proposed to be key determinants of these events. This review presents current evidence supporting the role of the host genome in determining risk of irAE. We summarise the spectrum and timing of irAEs following treatment with ICIs and describe currently reported germline genetic variation associated with expression of immuno-modulatory factors within the cancer immunity cycle, development of autoimmune disease and irAE occurrence. We propose that germline genetic determinants of host immune function and autoimmune diseases could also explain risk of irAE development. We also endorse genome-wide association studies of patients being treated with ICIs to identify genetic variants that can be used in polygenic risk scores to predict risk of irAE

miR824/AGAMOUS-LIKE16 Module Integrates Recurring Environmental Heat Stress Changes to Fine-Tune Poststress Development

Plant development is continually fine-tuned based on environmental factors. How environmental perturbations are integrated into the developmental programs and how poststress adaptation is regulated remains an important topic to dissect. Vegetative to reproductive phase change is a very important developmental transition that is complexly regulated based on endogenous and exogenous cues. Proper timing of flowering is vital for reproductive success. It has been shown previously that AGAMOUS LIKE 16 (AGL16), a MADS-box transcription factor negatively regulates flowering time transition through FLOWERING LOCUS T (FT), a central downstream floral integrator. AGL16 itself is negatively regulated by the microRNA miR824. Here we present a comprehensive molecular analysis of miR824/AGL16 module changes in response to mild and recurring heat stress. We show that miR824 accumulates gradually in response to heat due to the combination of transient transcriptional induction and posttranscriptional stability. miR824 induction requires heat shock cis-elements and activity of the HSFA1 family and HSFA2 transcription factors. Parallel to miR824 induction, its target AGL16 is decreased, implying direct causality. AGL16 posttranscriptional repression during heat stress, however, is more complex, comprising of a miRNA-independent, and a miR824-dependent pathway. We also show that AGL16 expression is leaf vein-specific and overlaps with miR824 (and FT) expression. AGL16 downregulation in response to heat leads to a mild derepression of FT. Finally, we present evidence showing that heat stress regulation of miR824/AGL16 is conserved within Brassicaceae. In conclusion, due to the enhanced post-transcriptional stability of miR824, stable repression of AGL16 is achieved following heat stress. This may serve to fine-tune FT levels and alter flowering time transition. Stress-induced miR824, therefore, can act as a "posttranscriptional memory factor" to extend the acute impact of environmental fluctuations in the poststress period

Direct Regulation of BK Channels by Phosphatidylinositol 4,5-Bisphosphate as a Novel Signaling Pathway

Large conductance, calcium- and voltage-gated potassium (BK) channels are ubiquitous and critical for neuronal function, immunity, and smooth muscle contractility. BK channels are thought to be regulated by phosphatidylinositol 4,5-bisphosphate (PIP2) only through phospholipase C (PLC)–generated PIP2 metabolites that target Ca2+ stores and protein kinase C and, eventually, the BK channel. Here, we report that PIP2 activates BK channels independently of PIP2 metabolites. PIP2 enhances Ca2+-driven gating and alters both open and closed channel distributions without affecting voltage gating and unitary conductance. Recovery from activation was strongly dependent on PIP2 acyl chain length, with channels exposed to water-soluble diC4 and diC8 showing much faster recovery than those exposed to PIP2 (diC16). The PIP2–channel interaction requires negative charge and the inositol moiety in the phospholipid headgroup, and the sequence RKK in the S6–S7 cytosolic linker of the BK channel-forming (cbv1) subunit. PIP2-induced activation is drastically potentiated by accessory β1 (but not β4) channel subunits. Moreover, PIP2 robustly activates BK channels in vascular myocytes, where β1 subunits are abundantly expressed, but not in skeletal myocytes, where these subunits are barely detectable. These data demonstrate that the final PIP2 effect is determined by channel accessory subunits, and such mechanism is subunit specific. In HEK293 cells, cotransfection of cbv1+β1 and PI4-kinaseIIα robustly activates BK channels, suggesting a role for endogenous PIP2 in modulating channel activity. Indeed, in membrane patches excised from vascular myocytes, BK channel activity runs down and Mg-ATP recovers it, this recovery being abolished by PIP2 antibodies applied to the cytosolic membrane surface. Moreover, in intact arterial myocytes under physiological conditions, PLC inhibition on top of blockade of downstream signaling leads to drastic BK channel activation. Finally, pharmacological treatment that raises PIP2 levels and activates BK channels dilates de-endothelized arteries that regulate cerebral blood flow. These data indicate that endogenous PIP2 directly activates vascular myocyte BK channels to control vascular tone

pi^0 -> gamma gamma*, omega -> pi^0 gamma*, and rho -> pi gamma* decays in nuclear medium

We calculate the medium modification of the pi-omega-rho vertex and analyze its significance for the pi^0 -> gamma gamma*, omega -> pi^0 gamma*, and rho -> pi gamma* decays in nuclear matter. We use a relativistic hadronic approach at zero temperature and in the leading-density limit, and consider decays of particles at rest with respect to the medium. It is shown that for the pi^0 -> gamma gamma* the effects of the Delta isobar cancel almost exactly the effects of the nucleon ph excitations, such that the net medium effect is small. On the contrary, for the decays omega -> pi^0 gamma* and rho -> pi gamma* we find a sizeable increase of the partial widths at virtualities of the photon in the range 0.3-0.6 GeV. The effect has direct significance for the calculation of dilepton yields from the Dalitz decays in relativistic heavy-ion collisions.Comment: 9 pages, 3 figure