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During the epoch of reionization, neutral gas in the early Universe was ionized by hard ultraviolet radiation emitted by young stars in the first galaxies. To do so, ionizing ultraviolet photons must escape from the host galaxy. We present Hubble Space Telescope observations of the gravitationally lensed post-reionization galaxy PSZ1-ARC G311.6602–18.4624 (nicknamed the “Sunburst Arc”), revealing bright, multiply imaged ionizing photon escape from a compact star-forming region through a narrow channel in an optically thick gas. The gravitational lensing magnification shows how ionizing photons escape this galaxy, contributing to the reionization of the Universe. The multiple sight lines to the source probe absorption by intergalactic neutral hydrogen on a scale of less than a few hundred parsecs.

The use of recombinant growth factors has led to improved hematopoietic function after chemotherapy, but hematologic and immune complications still occur after chemotherapy which can be life-threatening. Here we show that pan-SHIPi compounds can induce endogenous G-CSF and TPO production in vivo and can also increase host survival after a lethal fungal challenge. In addition, we show that consistent with their ability to induce G-CSF, pan-SHIPi compounds can promote increased granulopoiesis in normal mice and speed recovery of neutrophil counts after chemotherapy. We also report the identification of a novel SHIP1-selective inhibitor, A32, that also increases steady state production of both G-CSF and TPO. These findings indicate small molecule inhibitors of SHIP1 can promote hematologic recovery after myeloablative chemotherapy and are a unique means to induce endogenous production of multiple growth factors that promote hematologic recovery.

Membrane-anchored and soluble inositol phospholipid species are critical mediators of intracellular cell signaling cascades. Alterations in their normal production or degradation are implicated in the pathology of a number of disorders including cancer and pro-inflammatory conditions. The SH2-containing 5′ inositol phosphatases, SHIP1 and SHIP2, play a fundamental role in these processes by depleting PI(3,4,5)P3, but also by producing PI(3,4)P2 at the inner leaflet of the plasma membrane. With the intent of targeting SHIP1 or SHIP2 selectively, or both paralogs simultaneously, small molecule inhibitors and agonists have been developed and tested in vitro and in vivo over the last decade in various disease models. These studies have shown promising results in various pre-clinical models of disease including cancer and tumor immunotherapy. In this review the potential use of SHIP inhibitors in cancer is discussed with particular attention to the molecular structure, binding site and efficacy of these SHIP inhibitors.

The SH2-containing inositol polyphosphate 5-phosphatase 1 (SHIP1) enzyme opposes the activity of PI3K and therefore is of interest in the treatment of inflammatory disorders. Recent results also indicate that SHIP1 promotes phagolysosomal degradation of lipids by microglia, suggesting that the enzyme may be a target for the treatment of Alzheimer’s disease. Therefore, small molecules that increase SHIP1 activity may have benefits in these areas. Recently we discovered a bis-sulfonamide that increases the enzymatic activity of SHIP1. A series of similar SHIP1 activators have been synthesized and evaluated to determine structure–activity relationships and improve in vivo stability. Some new analogs have now been found with improved potency. In addition, both the thiophene and the thiomorpholine in the parent structure can be replaced by groups without a low valent sulfur atom, which provides a way to access activators that are less prone to oxidative degradation.

Inhibition of phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase (SHIP) with small molecule inhibitors leads to apoptosis in tumor cells. Inhibitors that target both SHIP1 and SHIP2 (pan-SHIP1/2 inhibitors) may have benefits in these areas since paralog compensation is not possible when both SHIP paralogs are being inhibited. A series of tryptamine-based pan-SHIP1/2 inhibitors have been synthesized and evaluated for their ability to inhibit the SHIP paralogs. The most active compounds were also evaluated for their effects on cancer cell lines.

Humans homozygous for inactivating LRBA (lipopolysaccharide (LPS)-responsive beige-like anchor) mutations or with compound heterozygous mutations exhibit a spectrum of immune-related pathologies including inflammatory bowel disease (IBD). The cause of this pathology remains undefined. Here we show that disruption of the colon epithelial barrier in LRBA-deficient mice by dextran sulfate sodium (DSS) consumption leads to severe and uniformly lethal colitis. Analysis of bone marrow (BM) chimeras showed that susceptibility to lethal colitis is primarily due to LRBA deficiency in the immune compartment and not the gut epithelium. Further dissection of the immune defect in LRBA-deficient hosts showed that LRBA is essential for the expression of CTLA4 by Treg cells and IL22 and IL17 expression by ILC3 cells in the large intestine when the gut epithelium is compromised by DSS. We further show that SHIP1 agonism partially abrogates the severity and lethality of DSS-mediated colitis. Our findings indicate that enteropathy induced by LRBA deficiency has multiple causes and that SHIP1 agonism can partially abrogate the inflammatory milieu in the gut of LRBA-deficient hosts.

The primary productivity of four species of crustose coralline algae was measured as a function of depth (0-18 m) and irradiance on samples collected from and growing upon the windward coral reef at Lizard Island, northern Great Barrier Reef, Australia. Significantly higher productivities were measured in the field than in the laboratory. Maximum gross oxygen production in situ varied from 12.8 to 22.8 mmol $\\text{m}^{-2}\\text{h}^{-1}$; dark respiration consumed between 2.7 and 4.5 mmol $\\text{O}_{2}\\ \\text{m}^{-2}\\ \\text{h}^{-1}$. Integration of photosynthesis-irradiance models with half sine curve approximations of whole-day irradiance yielded estimated in situ net productivities of 15-132 mmol O2 m-2 d-1. When multiplied by previously determined photosynthetic quotients, in situ net carbon fixation was estimated to vary from 0.2 to 1.3 g m-2 d-1. Multiplying these rates by measured surface relief factors of 3.1 for the reef crest and 5.0 for the windward slope yielded estimated contributions to reef organic production of ∼0.9-5 g C (net) planar m-2 d-1 over the depth interval 0-18 m, given 100% cover. These data suggest that crustose coralline algae make a larger contribution to organic production on coral reefs than has been thought to this time. A curvilinear model is presented that enables their primary productivity to be estimated from measurements of in situ irradiance at the solar zenith.

2-Substituted indoles may be directly transformed to 3,3-dialkyl indolenines with trichloroacetimidate electrophiles and the Lewis acid TMSOTf. These reactions provide rapid access to complex indolenines which are present in a variety of complex natural products and medicinally relevant small molecule structures. This method provides an alternative to the use of transition metal catalysis. The indolenines are readily transformed into spiroindoline systems which are privileged scaffolds in medicinal chemistry.

Many tumors present with increased activation of the phosphatidylinositol 3-kinase (PI3K)-PtdIns( 3 , 4 , 5 )P 3 -protein kinase B (PKB/Akt) signaling pathway. It has long been thought that the lipid phosphatases SH2 domain-containing inositol-5′-phosphatase 1 (SHIP1) and SHIP2 act as tumor suppressors by counteracting with the survival signal induced by this pathway through hydrolysis or PtdIns(3/4/5)P 3 to PtdIns( 3 , 4 )P 2 . However, a growing body of evidence suggests that PtdInd( 3 , 4 )P 2 is capable of, and essential for, Akt activation, thus suggesting a potential role for SHIP1/2 enzymes as proto-oncogenes. We recently described a novel SHIP1-selective chemical inhibitor (3α-aminocholestane (3AC)) that is capable of killing malignant hematologic cells. In this study, we further investigate the biochemical consequences of 3AC treatment in multiple myeloma (MM) and demonstrate that SHIP1 inhibition arrests MM cell lines in either G0/G1 or G2/M stages of the cell cycle, leading to caspase activation and apoptosis. In addition, we show that in vivo growth of MM cells is blocked by treatment of mice with the SHIP1 inhibitor 3AC. Furthermore, we identify three novel pan-SHIP1/2 inhibitors that efficiently kill MM cells through G2/M arrest, caspase activation and apoptosis induction. Interestingly, in SHIP2-expressing breast cancer cells that lack SHIP1 expression, pan-SHIP1/2 inhibition also reduces viable cell numbers, which can be rescued by addition of exogenous PtdIns( 3 , 4 )P 2 . In conclusion, this study shows that inhibition of SHIP1 and SHIP2 may have broad clinical application in the treatment of multiple tumor types.

Ghrelin is a 28 amino acid peptide hormone that impacts a wide range of biological processes, including appetite regulation, glucose metabolism, growth hormone regulation, and cognitive function. To bind and activate its cognate receptor, ghrelin must be acylated on a serine residue in a post-translational modification performed by ghrelin O-acyltransferase (GOAT). GOAT is a membrane-bound O-acyltransferase (MBOAT) responsible for the catalysis of the addition of an octanoyl fatty acid to the third serine of desacyl ghrelin. Beyond its canonical role for ghrelin maturation in endocrine cells within the stomach, GOAT was recently reported to be overexpressed in prostate cancer (PCa) cells and detected at increased levels in the serum and urine of PCa patients. This suggests GOAT can serve as a potential route for the detection and therapeutic targeting of PCa and other diseases that exhibit GOAT overexpression. Building upon a ghrelin mimetic peptide with nanomolar affinity for GOAT, we developed an antibody-conjugate-inspired system for customizable ligand-conjugate (LC) synthesis allowing for the attachment of a wide range of cargoes. The developed synthetic scheme allows for the easy synthesis of the desired LCs and demonstrates that our ligand system tolerates an extensive palette of cargoes while maintaining nanomolar affinity against GOAT.