A sequential CH functionalization strategy for the synthesis of the marine alkaloid dictyodendrin B is reported. Our synthesis begins from commercially available 4‐bromoindole and involves six ...direct functionalizations around the heteroarene core as part of a gram‐scale strategy towards the natural product.
One by one: A sequential CH functionalization strategy for the synthesis of the marine alkaloid dictyodendrin B is reported. The synthetic route begins from commercially available 4‐bromoindole and involves six direct functionalizations around the heteroarene core as part of a gram‐scale strategy towards the natural product.
Purpose Despite recent increases in the popularity of tattooing, little is known about the prevalence and characteristics of adults who have ever been tattooed. We investigated demographic and ...behavioral correlates of ever getting tattooed in an adult population. Methods Computer-assisted telephone interviews were completed by a representative sample of 8656 men and women ages 16–64 years in Australia. Results A total of 14.5% of respondents had ever been tattooed, and 2.4% of respondents had been tattooed in the year before the interview. Men were more likely than women to report a tattoo, but the highest rates of tattooing were found among women in their 20s (29.4%). Men and women ages 20–39 were most likely to have been tattooed, as were men with lower levels of education, tradesmen, and women with live-out partners. Tattooing was also associated with risk-taking behaviours, including smoking, greater numbers of lifetime sexual partners, cannabis use (women only) and ever having depression (men only). Conclusions Tattooing has increased in popularity during the past decade. Yet tattoos still appear to be a marker for risk-taking behavior in adults.
This paper reports on fertility knowledge and intentions to have children among a national sample of students in years 10–12.
Data were from the Fifth National Survey of Australian Secondary Students ...and Sexual Health. Students identified factors that could affect fertility, if they wanted children and at what age.
Most students wanted to have children (77%). Of those who wanted children or were unsure (n=1,780), 54% were able to identify six of eight factors that could affect fertility. Male students had poorer knowledge than females. Poorer knowledge was also reported by male students who were born overseas or used marijuana and by female students who were sexually active or religious. More than half the students (59%) wanted their first child aged 25–29, while 19% wanted their first child after 30. Intentions to have children at an earlier age were associated with being religious, sexually active (females), and using marijuana (males). Students not exclusively attracted to the opposite sex were more likely to want children at an older age.
Most students typically want children in their late 20s. Many were unaware of factors that could affect their fertility and there was a mismatch between intentions and likely behaviour. These factors could be addressed as part of relationship education.
Although agricultural intensification generally has homogenizing effects on landscapes that reduce crop diversity, the specific effects of different input strategies on crop diversity are unclear. ...This study examines the effects of irrigation inputs on crop species diversity in Mexico. We assess the richness and evenness diversity of 297 crop species across 2455 municipalities while controlling for environmental and socioeconomic factors and farm structural and functional characteristics. Using a quantile regression approach, we assess relationships across conditional quantiles of low-, medium-, and high-diversity farm regions. Results show irrigation level (% cropland irrigated) is a strong positive predictor of crop species richness and evenness diversity across all quantile regions. Moreover, the quantile effects of irrigation on evenness diversity are five times greater in low-diversity rather than high-diversity regions. With implications for agricultural water policy in Mexico, this study illustrates the potential benefits of sustainable irrigation expansion in water-rich but irrigation-poor farming regions. Specifically, by enhancing crop species diversity, carefully targeted irrigation expansion can support the transition to sustainable intensification.
Dynamins are large GTPases with mechanochemical properties that are known to constrict and tubulate membranes. A recently identified mammalian dynamin-like protein (DLP1) is essential for the proper ...cellular distribution of mitochondria and the endoplasmic reticulum in cultured cells. In this study, we investigated the ability of DLP1 to remodel membranes similar to conventional dynamin. We found that the expression of a GTPase-defective mutant, DLP1-K38A, in cultured cells led to the formation of large cytoplasmic aggregates. Electron microscopy (EM) of cells expressing DLP1-K38A revealed that these aggregates were comprised of membrane tubules of a consistent diameter. High-magnification EM revealed the presence of many regular striations along individual membrane tubules, and immunogold labeling confirmed the association of DLP1 with these structures. Biochemical experiments with the use of recombinant DLP1 and labeled GTP demonstrated that DLP1-K38A binds but does not hydrolyze or release GTP. Furthermore, the affinity of DLP1-K38A for membrane is increased compared with wild-type DLP1. To test whether DLP1 could tubulate membrane in vitro, recombinant DLP1 was combined with synthetic liposomes and nucleotides. We found that DLP1 protein alone assembled into sedimentable macromolecular structures in the presence of guanosine-5'-O-(3-thio)triphosphate (GTPgammaS) but not GTP. EM of the GTPgammaS-treated DLP1 revealed clusters of stacked helical ring structures. When liposomes were included with DLP1, formation of long membrane tubules similar in size to those formed in vivo was observed. Addition of GTPgammaS greatly enhanced membrane tubule formation, suggesting the GTP-bound form of DLP1 deforms liposomes into tubules as the DLP1-K38A does in vivo. These results provide the first evidence that the dynamin family member, DLP1, is able to tubulate membranes both in living cells and in vitro. Furthermore, these findings also indicate that despite the limited homology to conventional dynamins (35%) these proteins remodel membranes in a similar manner.
The dynamin family of large GTPases has been implicated in vesicle formation from both the plasma membrane and various intracellular membrane compartments. The dynamin-like protein DLP1, recently ...identified in mammalian tissues, has been shown to be more closely related to the yeast dynamin proteins Vps1p and Dnm1p (42%) than to the mammalian dynamins (37%). Furthermore, DLP1 has been shown to associate with punctate vesicles that are in intimate contact with microtubules and the endoplasmic reticulum (ER) in mammalian cells. To define the function of DLP1, we have transiently expressed both wild-type and two mutant DLP1 proteins, tagged with green fluorescent protein, in cultured mammalian cells. Point mutations in the GTP-binding domain of DLP1 (K38A and D231N) dramatically changed its intracellular distribution from punctate vesicular structures to either an aggregated or a diffuse pattern. Strikingly, cells expressing DLP1 mutants or microinjected with DLP1 antibodies showed a marked reduction in ER fluorescence and a significant aggregation and tubulation of mitochondria by immunofluorescence microscopy. Consistent with these observations, electron microscopy of DLP1 mutant cells revealed a striking and quantitative change in the distribution and morphology of mitochondria and the ER. These data support very recent studies by other authors implicating DLP1 in the maintenance of mitochondrial morphology in both yeast and mammalian cells. Furthermore, this study provides the first evidence that a dynamin family member participates in the maintenance and distribution of the ER. How DLP1 might participate in the biogenesis of two presumably distinct organelle systems is discussed.
Triclosan, triclocarban and 4-nonylphenol are all chemicals of emerging concern found in a wide variety of consumer products that have exhibited a wide range of endocrine-disrupting effects and are ...present in increasing amounts in groundwater worldwide. Results of the present study indicate that exposure to these chemicals at critical developmental periods, whether long-term or short-term in duration, leads to significant mortality, morphologic, behavioral and transcriptomic effects in zebrafish (
. These effects range from total mortality with either long- or short-term exposure at 100 and 1000 nM of triclosan, to abnormalities in uninflated swim bladder seen with long-term exposure to triclocarban and short-term exposure to 4-nonylphenol, and cardiac edema seen with short-term 4-nonylphenol exposure. Additionally, a significant number of genes involved in neurological and cardiovascular development were differentially expressed after the exposures, as well as lipid metabolism genes and metabolic pathways after exposure to each chemical. Such changes in behavior, gene expression, and pathway abnormalities caused by these three known endocrine disruptors have the potential to impact not only the local ecosystem, but human health as well.
In this paper, a novel synthesis of tertiary amides from anionically activated aromatic trifluoromethyl groups is presented. Anionically activated trifluoromethyl groups react with secondary amines ...under aqueous conditions to afford tertiary amides. The mechanism involves initial elimination of hydrogen fluoride by an E1cB mechanism to afford an electrophilic quinone methide- or azafulvene-type intermediate that reacts with secondary amines under aqueous conditions to afford the tertiary amide in good yield (up to 99%).
Abstract Canonical Wnt signaling has been demonstrated to increase bone formation, and Wnt pathway components are being pursued as potential drug targets for osteoporosis and other metabolic bone ...diseases. Deletion of the Wnt antagonist secreted frizzled-related protein (sFRP)-1 in mice activates canonical signaling in bone and increases trabecular bone formation in aged animals. We have developed small molecules that bind to and inhibit sFRP-1 in vitro and demonstrate robust anabolic activity in an ex vivo organ culture assay. A library of over 440,000 drug-like compounds was screened for inhibitors of human sFRP-1 using a cell-based functional assay that measured activation of canonical Wnt signaling with an optimized T-cell factor (TCF)-luciferase reporter gene assay. One of the hits in this screen, a diarylsulfone sulfonamide, bound to sFRP-1 with a KD of 0.35 μM in a tryptophan fluorescence quenching assay. This compound also selectively inhibited sFRP-1 with an EC50 of 3.9 μM in the cell-based functional assay. Optimization of this high throughput screening hit for binding and functional potency as well as metabolic stability and other pharmaceutical properties led to improved lead compounds. One of these leads (WAY-316606) bound to sFRP-1 with a KD of 0.08 μM and inhibited it with an EC50 of 0.65 μM. Moreover, this compound increased total bone area in a murine calvarial organ culture assay at concentrations as low as 0.0001 μM. This work demonstrates the feasibility of developing small molecules that inhibit sFRP-1 and stimulate canonical Wnt signaling to increase bone formation.
To analyse the additional clinical value of protocol-driven and selective use of multidetector single-photon-emission tomography/computed tomography (SPECT/CT) in oncology patients undergoing ...whole-body bone scintigraphy (BS) and to analyse reporter confidence in diagnosis with and without SPECT/CT.
During a 2-year period, 2,954 whole-body BS examinations were performed in oncology patients, with 444 (15%) undergoing additional protocol-driven SPECT/CT. Retrospective evaluation of planar BS and SPECT/CT images was performed by two experienced dual-trained nuclear medicine radiologists. The BS and SPECT/CT images were graded blindly using a five-point scale designed to evaluate the likelihood of a lesion being benign or malignant. Interpretation was applied on a per-patient basis.
There was a 74.5% increase in definitive diagnostic classification and a 26.6% reduction in equivocal findings with SPECT/CT when compared to BS alone (p<0001). Of cases initially classified as “probably benign” on BS, 5.1% (10/193) were reclassified to “probably malignant” (1%) or “malignant” (4.1%) using the SPECT/CT data. The highest impact in reporter confidence was seen with SPECT/CT in the interpretation of lesions within the pelvis (34%), ribs (23%), lumbar spine (22%), and thoracic spine (21%).
Protocol-driven, selective use of SPECT/CT imaging to augment planar BS reduces equivocal findings and improves reporter confidence whilst minimising the impact on patient and reporting workflows.
•SPECT/CT in bone scintigraphy can be used selectively in a protocol-driven manner for oncology patients.•SPECT/CT reduces equivocal findings compared to planar BS imaging.•SPECT/CT significantly increases reporter confidence in the axial skeleton.•Prospective studies are required to evaluate the impact of SPECT/CT on clinical management.
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