Control of steroid receptor dynamics and function by genomic actions of the cochaperones p23 and Bag-1L

Molecular chaperones encompass a group of unrelated proteins that facilitate the correct assembly and disassembly of other macromolecular structures of which they themselves do not remain a part. Chaperones associate with a large and diverse set of cofactors termed cochaperones that regulate their function and specificity. Chaperones and cochaperones regulate the activity of several classes of signaling molecules, including steroid receptors. Upon binding ligand, steroid receptors interact with discrete nucleotide sequences within the nucleus to control the expression of diverse physiological and developmental genes. Molecular chaperones and cochaperones are typically known to provide the correct conformation for ligand binding by the steroid receptors. While this contribution is widely accepted, recent studies have reported that they further modulate steroid receptor action outside ligand binding. Specifically, they are thought to contribute to receptor turnover, transport of the receptor to different subcellular localizations, recycling of the receptor on chromatin and stabilization of receptor DNA binding. In addition to these combined effects with molecular chaperones, cochaperones have additional functions that are independent of molecular chaperones, some of which impact steroid receptor action. Two well-studied examples are the cochaperones p23 and Bag-1L, which have been identified as modulators of steroid receptor activity in the nucleus. Understanding details of their regulatory action will provide new therapeutic opportunities for controlling steroid receptor action independent of the widespread effects of molecular chaperones

Determination of polynuclear aromatic compounds in composted municipal refuse and compost-amended soils by a simple clean-up procedure

3 pages, 1 figure, 2 tables, 21 references.A rapid and reproducible procedure suitable for the analysis of polycyclic aromatic compounds (PACs) in sludges and soil samples has been developed. The PACs are isolated by ultrasonic extraction with methyl chloride, redissolution of the crude extract in isooctane and clean-up of the PAC-containing fraction by chromatography on alumina micro-columns. After separation and quantitative determination of the various PACS by capillary gas chromatography/mass spectrometry, more than 50 PAC compounds which cover a wide range of concentrations were detected in the sludge samples. The most abundant compounds were mono-, di- and trimethyl derivatives of naphthalene, phenanthrene, fluorene, dibenzethiophene and naphthothiophene. No accumulation of PAC in an agricultural soil after an experiment of compost application over three years was observed.Peer Reviewe

Principal 2-bundles and their gauge 2-groups

In this paper we introduce principal 2-bundles and show how they are classified by non-abelian Cech cohomology. Moreover, we show that their gauge 2-groups can be described by 2-group-valued functors, much like in classical bundle theory. Using this, we show that, under some mild requirements, these gauge 2-groups possess a natural smooth structure. In the last section we provide some explicit examples.Comment: 40 pages; v3: completely revised and extended, classification corrected, name changed, to appear in Forum Mat

The potential of lasmiditan in migraine

Lasmiditan, a highly selective 5-hydroxytryptamine receptor 1F (5-HT1F) agonist, is the first drug in its class and is lacking triptan-like vasoactive properties. The US Food and Drug Administration (FDA) has recently approved lasmiditan for the acute treatment of migraine in adults based on positive results of two pivotal phase III trials, which showed a significant difference to placebo in the proportion of patients achieving total migraine freedom within 2h. More patients with lasmiditan achieved headache freedom and, in addition, freedom from the most bothersome symptom, that is, photophobia, than with placebo. Treatmentrelated side effects seem to be related to the rapid penetration of the drug into the brain and include dizziness, paresthesia and drowsiness, mostly of mild to moderate intensity. Interim results from an ongoing long-term phase III trial suggest a decrease in the frequency of adverse events after multiple lasmiditan use. Lasmiditan is a promising acute anti-migraine therapy, in particular for patients with cardiovascular risk factors, contraindications, or unwanted side effects to triptans

Invariants of Lie algebras extended over commutative algebras without unit

We establish results about the second cohomology with coefficients in the trivial module, symmetric invariant bilinear forms and derivations of a Lie algebra extended over a commutative associative algebra without unit. These results provide a simple unified approach to a number of questions treated earlier in completely separated ways: periodization of semisimple Lie algebras (Anna Larsson), derivation algebras, with prescribed semisimple part, of nilpotent Lie algebras (Benoist), and presentations of affine Kac-Moody algebras.Comment: v3: added a footnote on p.10 about a wrong derivation of the correct statemen

IER2-induced senescence drives melanoma invasion through osteopontin

Expression of the immediate-early response gene IER2 has been associated with the progression of several types of cancer, but its functional role is poorly understood. We found that increased IER2 expression in human melanoma is associated with shorter overall survival, and subsequently investigated the mechanisms through which IER2 exerts this effect. In experimental melanoma models, sustained expression of IER2 induced senescence in a subset of melanoma cells in a p53/MAPK/AKT-dependent manner. The senescent cells produced a characteristic secretome that included high levels of the extracellular phosphoglycoprotein osteopontin. Nuclear localization of the IER2 protein was critical for both the induction of senescence and osteopontin secretion. Osteopontin secreted by IER2-expressing senescent cells strongly stimulated the migration and invasion of non-senescent melanoma cells. Consistently, we observed coordinate expression of IER2, p53/p21, and osteopontin in primary human melanomas and metastases, highlighting the pathophysiological relevance of IER2-mediated senescence in melanoma progression. Together, our study reveals that sustained IER2 expression drives melanoma invasion and progression through stimulating osteopontin secretion via the stochastic induction of senescence

Search for the exotic Ξ−−(1860)\Xi^{--}(1860) Resonance in 340GeV/c Σ−\Sigma^--Nucleus Interactions

We report on a high statistics search for the $\Xi^{--}(1860)$ resonance in $\Sigma^-$-nucleus collisions at 340GeV/c. No evidence for this resonance is found in our data sample which contains 676000 $\Xi^-$ candidates above background. For the decay channel $\Xi^{--}(1860) \to \Xi^-\pi^-$ and the kinematic range 0.15$<x_F<$0.9 we find a 3$\sigma$ upper limit for the production cross section of 3.1 and 3.5 $\mu$b per nucleon for reactions with carbon and copper, respectively.Comment: 5 pages, 4 figures, modification of ref. 43 and 4

Identification of an Imidazopyridine-based Compound as an Oral Selective Estrogen Receptor Degrader for Breast Cancer Therapy.

UNLABELLED: The pro-oncogenic activities of estrogen receptor alpha (ERα) drive breast cancer pathogenesis. Endocrine therapies that impair the production of estrogen or the action of the ERα are therefore used to prevent primary disease metastasis. Although recent successes with ERα degraders have been reported, there is still the need to develop further ERα antagonists with additional properties for breast cancer therapy. We have previously described a benzothiazole compound A4B17 that inhibits the proliferation of androgen receptor-positive prostate cancer cells by disrupting the interaction of the cochaperone BAG1 with the AR. A4B17 was also found to inhibit the proliferation of estrogen receptor-positive (ER+) breast cancer cells. Using a scaffold hopping approach, we report here a group of small molecules with imidazopyridine scaffolds that are more potent and efficacious than A4B17. The prototype molecule X15695 efficiently degraded ERα and attenuated estrogen-mediated target gene expression as well as transactivation by the AR. X15695 also disrupted key cellular protein-protein interactions such as BAG1-mortalin (GRP75) interaction as well as wild-type p53-mortalin or mutant p53-BAG2 interactions. These activities together reactivated p53 and resulted in cell-cycle block and the induction of apoptosis. When administered orally to in vivo tumor xenograft models, X15695 potently inhibited the growth of breast tumor cells but less efficiently the growth of prostate tumor cells. We therefore identify X15695 as an oral selective ER degrader and propose further development of this compound for therapy of ER+ breast cancers. SIGNIFICANCE: An imidazopyridine that selectively degrades ERα and is orally bioavailable has been identified for the development of ER+ breast cancer therapeutics. This compound also activates wild-type p53 and disrupts the gain-of-function tumorigenic activity of mutant p53, resulting in cell-cycle arrest and the induction of apoptosis

Weather sensitivity in migraineurs

The scientific evidence for weather being a trigger factor for migraine attacks is inconclusive. We investigated the association between weather components and the onset and severity of attacks. Headache diaries of 20 migraineurs were analyzed retrospectively and correlated in 4-h intervals to atmospheric air pressure, temperature, and relative air humidity in Berlin (Germany) for a period of 12 consecutive months. Absolute values and relative changes within the preceding 24 h were analyzed. Migraine attacks started most frequently at 4 a.m. and reached the highest intensity between 4 and 8 a.m. A highly significant association between meteorological variables and the occurrence of migraine attacks was found in six patients. The onset of an attack as well as high headache intensity was associated with lower temperature and higher humidity. Our data indicate that a subgroup of migraineurs is highly sensitive to changes of certain weather components

Causal structures and causal boundaries

We give an up-to-date perspective with a general overview of the theory of causal properties, the derived causal structures, their classification and applications, and the definition and construction of causal boundaries and of causal symmetries, mostly for Lorentzian manifolds but also in more abstract settings.Comment: Final version. To appear in Classical and Quantum Gravit