AXL modulates extracellular matrix protein expression and is essential for invasion and metastasis in endometrial cancer

The receptor tyrosine kinase AXL promotes migration, invasion, and metastasis. Here, we evaluated the role of AXL in endometrial cancer. High immunohistochemical expression of AXL was found in 76% (63/83) of advanced-stage, and 77% (82/107) of high-grade specimens and correlated with worse survival in uterine serous cancer patients. In vitro, genetic silencing of AXL inhibited migration and invasion but had no effect on proliferation of ARK1 endometrial cancer cells. AXL-deficient cells showed significantly decreased expression of phospho-AKT as well as uPA, MMP-1, MMP-2, MMP-3, and MMP-9. In a xenograft model of human uterine serous carcinoma with AXL-deficient ARK1 cells, there was significantly less tumor burden than xenografts with control ARK1 cells. Together, these findings underscore the therapeutic potentials of AXL as a candidate target for treatment of metastatic endometrial cancer

Formation of Super-Earths

Super-Earths are the most abundant planets known to date and are characterized by having sizes between that of Earth and Neptune, typical orbital periods of less than 100 days and gaseous envelopes that are often massive enough to significantly contribute to the planet's overall radius. Furthermore, super-Earths regularly appear in tightly-packed multiple-planet systems, but resonant configurations in such systems are rare. This chapters summarizes current super-Earth formation theories. It starts from the formation of rocky cores and subsequent accretion of gaseous envelopes. We follow the thermal evolution of newly formed super-Earths and discuss their atmospheric mass loss due to disk dispersal, photoevaporation, core-cooling and collisions. We conclude with a comparison of observations and theoretical predictions, highlighting that even super-Earths that appear as barren rocky cores today likely formed with primordial hydrogen and helium envelopes and discuss some paths forward for the future.Comment: Invited review accepted for publication in the 'Handbook of Exoplanets,' Planet Formation section, Springer Reference Works, Juan Antonio Belmonte and Hans Deeg, Ed

Induction of \u3cem\u3eIL19\u3c/em\u3e Expression through JNK and cGAS-STING Modulates DNA Damage–Induced Cytokine Production

Cytokine production is a critical component of cell-extrinsic responses to DNA damage and cellular senescence. Here, we demonstrated that expression of the gene encoding interleukin-19 (IL-19) was enhanced by DNA damage through pathways mediated by c-Jun amino-terminal kinase (JNK) and cGAS-STING and that IL19 expression was required for the subsequent production of the cytokines IL-1, IL-6, and IL-8. IL19 expression was stimulated by diverse cellular stresses, including inhibition of the DNA replication checkpoint kinase ATR (ataxia telangiectasia and Rad3-related protein), oncogene expression, replicative exhaustion, oxidative stress, and DNA double-strand breaks. Unlike the production of IL-6 and IL-8, IL19 expression was not affected by abrogation of signaling by the IL-1 receptor (IL-1R) or the mitogen-activated protein kinase p38. Instead, the DNA damage–induced production of IL-1, IL-6, and IL-8 was substantially reduced by suppression of IL19 expression. The signaling pathways required to stimulate IL19 expression selectively depended on the type of DNA-damaging agent. Reactive oxygen species and the ASK1-JNK pathway were critical for responses to ionizing radiation (IR), whereas the cGAS-STING pathway stimulated IL19 expression in response to either IR or ATR inhibition. Whereas induction of IL1, IL6, and IL8 by IR depended on IL19 expression, the cGAS-STING–dependent induction of the immune checkpoint gene PDL1 after IR and ATR inhibition was independent of IL19. Together, these results suggest that IL-19 production by diverse pathways forms a distinct cytokine regulatory arm of the response to DNA damage

Enhanced insulin sensitivity associated with provision of mono and polyunsaturated fatty acids in skeletal muscle cells involves counter modulation of PP2A

International audienceAims/Hypothesis: Reduced skeletal muscle insulin sensitivity is a feature associated with sustained exposure to excess saturated fatty acids (SFA), whereas mono and polyunsaturated fatty acids (MUFA and PUFA) not only improve insulin sensitivity but blunt SFA-induced insulin resistance. The mechanisms by which MUFAs and PUFAs institute these favourable changes remain unclear, but may involve stimulating insulin signalling by counter-modulation/repression of protein phosphatase 2A (PP2A). This study investigated the effects of oleic acid (OA; a MUFA), linoleic acid (LOA; a PUFA) and palmitate (PA; a SFA) in cultured myotubes and determined whether changes in insulin signalling can be attributed to PP2A regulation. Principal Findings: We treated cultured skeletal myotubes with unsaturated and saturated fatty acids and evaluated insulin signalling, phosphorylation and methylation status of the catalytic subunit of PP2A. Unlike PA, sustained incubation of rat or human myotubes with OA or LOA significantly enhanced Akt-and ERK1/2-directed insulin signalling. This was not due to heightened upstream IRS1 or PI3K signalling nor to changes in expression of proteins involved in proximal insulin signalling, but was associated with reduced dephosphorylation/inactivation of Akt and ERK1/2. Consistent with this, PA reduced PP2Ac demethylation and tyrosine 307 phosphorylation-events associated with PP2A activation. In contrast, OA and LOA strongly opposed these PA-induced changes in PP2Ac thus exerting a repressive effect on PP2A.Conclusions/Interpretation: Beneficial gains in insulin sensitivity and the ability of unsaturated fatty acids to oppose palmitate-induced insulin resistance in muscle cells may partly be accounted for by counter-modulation of PP2A

Dual Chromatin and Cytoskeletal Remodeling by SETD2

Posttranslational modifications (PTMs) of tubulin specify microtubules for specialized cellular functions and comprise what is termed a "tubulin code." PTMs of histones comprise an analogous "histone code," although the "readers, writers, and erasers" of the cytoskeleton and epigenome have heretofore been distinct. We show that methylation is a PTM of dynamic microtubules and that the histone methyltransferase SET-domain-containing 2 (SETD2), which is responsible for H3 lysine 36 trimethylation (H3K36me3) of histones, also methylates α-tubulin at lysine 40, the same lysine that is marked by acetylation on microtubules. Methylation of microtubules occurs during mitosis and cytokinesis and can be ablated by SETD2 deletion, which causes mitotic spindle and cytokinesis defects, micronuclei, and polyploidy. These data now identify SETD2 as a dual-function methyltransferase for both chromatin and the cytoskeleton and show a requirement for methylation in maintenance of genomic stability and the integrity of both the tubulin and histone codes

Structure and Evolution of Nearby Stars with Planets. I. Short-Period Systems

Using the Yale stellar evolution code, we have calculated theoretical models for nearby stars with planetary-mass companions in short-period nearly circular orbits: 51 Pegasi, Tau Bootis, Upsilon Andromedae, Rho Cancri, and Rho Coronae Borealis. We present tables listing key stellar parameters such as mass, radius, age, and size of the convective envelope as a function of the observable parameters (luminosity, effective temperature, and metallicity), as well as the unknown helium fraction. For each star we construct best models based on recently published spectroscopic data and the present understanding of galactic chemical evolution. We discuss our results in the context of planet formation theory, and, in particular, tidal dissipation effects and stellar metallicity enhancements.Comment: 48 pages including 13 tables and 5 figures, to appear in Ap

Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser.

G-protein-coupled receptors (GPCRs) signal primarily through G proteins or arrestins. Arrestin binding to GPCRs blocks G protein interaction and redirects signalling to numerous G-protein-independent pathways. Here we report the crystal structure of a constitutively active form of human rhodopsin bound to a pre-activated form of the mouse visual arrestin, determined by serial femtosecond X-ray laser crystallography. Together with extensive biochemical and mutagenesis data, the structure reveals an overall architecture of the rhodopsin-arrestin assembly in which rhodopsin uses distinct structural elements, including transmembrane helix 7 and helix 8, to recruit arrestin. Correspondingly, arrestin adopts the pre-activated conformation, with a ∼20° rotation between the amino and carboxy domains, which opens up a cleft in arrestin to accommodate a short helix formed by the second intracellular loop of rhodopsin. This structure provides a basis for understanding GPCR-mediated arrestin-biased signalling and demonstrates the power of X-ray lasers for advancing the frontiers of structural biology

Mutations in the Gene DNAJC5 Cause Autosomal Dominant Kufs Disease in a Proportion of Cases: Study of the Parry Family and 8 Other Families

Background: The Neuronal Ceroid Lipofuscinoses (NCL) comprise at least nine progressive neurodegenerative genetic disorders. Kufs disease, an adult-onset form of NCL may be recessively or dominantly inherited. Our study aimed to identify genetic mutations associated with autosomal dominant Kufs disease (ADKD). Methodology and Principal Findings We have studied the family first reported with this phenotype in the 1970s, the Parry family. The proband had progressive psychiatric manifestations, seizures and cognitive decline starting in her mid 20s. Similarly affected relatives were observed in seven generations. Several of the affected individuals had post-mortem neuropathological brain study confirmatory for NCL disease. We conducted whole exome sequencing of three affected family members and identified a pLeu116del mutation in the gene DNAJC5, which segregated with the disease phenotype. An additional eight unrelated affected individuals with documented autosomal dominant or sporadic inheritance were studied. All had diagnostic confirmation with neuropathological studies of brain tissue. Among them we identified an additional individual with a p.Leu115Arg mutation in DNAJC5. In addition, a pAsn477Ser change in the neighboring gene PRPF6, a gene previously found to be associated with retinitis pigmentosa, segregated with the ADKD phenotype. Interestingly, two individuals of the Parry family did report visual impairment. Conclusions: Our study confirmed the recently reported association of DNAJC5 mutations with ADKD in two out of nine well-defined families. Sequence changes in PRPF6 have not been identified in other unrelated cases. The association of vision impairment with the expected PRPF6 dysfunction remains possible but would need further clinical studies in order to confirm the co-segregation of the visual impairment with this sequence change