Genetically identical explants of the New Zealand marine sponge
Mycale hentscheli were cultured in two different habitats at 7 m depth using subsurface mesh arrays to determine the effect of ...environment on survival, growth and biosynthesis of the biologically active secondary metabolites, mycalamide A, pateamine and peloruside A. Two 27 cm
3 explants were excised from each of 10 wild donor sponges at Capsize Point, Pelorus Sound. One explant from each donor sponge was grown in arrays next to the wild donor sponge population for 250 days, while the second explant from each donor was translocated and grown at 7 m at Mahanga Bay, Wellington Harbour for 214 days. Growth rate measured by surface area and survival of explants was monitored in situ using a digital video camera. Explant surface area correlated positively with blotted wet weight (
r
2
=
0.93). The mean concentration of each of the three compounds was determined analytically from
1H NMR spectra of replicate 30-g samples from each of 10 donor sponges at the start of the trial, and compared to mean concentrations in donors and explants at the end of the trial. Phenomenal growth rates were achieved for explants both at Capsize Point (3365
±
812%, 95% CI) and Mahanga Bay (2749
±
1136%, 95% CI). Explant survival was high: 100% at Capsize Point and 90% at Mahanga Bay. Wild donor sponges regressed in size and experienced 40% mortality by the end of the trial. Mycalamide A was present in relatively high concentrations in donors and explants throughout the trial. Pateamine was more variable among individuals and was present at lower concentrations in Capsize explants at the end of the trial. Peloruside A was highly variable among wild donor sponges. Only 50% of donors contained detectable concentrations of peloruside A, and only those sponges and their explants grown in their native environment at Capsize Point continued to biosynthesise peloruside A. No explants at Mahanga Bay contained peloruside A after 214 days in culture, indicating the production of this compound may be environmentally controlled. Our results demonstrate that in-sea aquaculture of
M. hentscheli is a viable method for supply of mycalamide A, pateamine and peloruside A, and that environmental conditions may be critical for the biosynthesis of peloruside A. Furthermore, results show the potential to establish cultivars to maximize peloruside A yield.
Epithelial ovarian cancer (EOC) has few modifiable risk factors. There is evidence that some antihypertensive medicines may have cancer preventive and/or therapeutic actions; therefore, we assessed ...the associations between use of different antihypertensive medicines and risk of specific EOC histotypes.
Our nested case-control study of linked administrative health data included 6070 Australian women aged over 50 years diagnosed with EOC from 2004 to 2013, and 30,337 matched controls. We used multivariable conditional logistic regression to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) for the association between ever use of each antihypertensive medicine group, including beta-adrenergic blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, diuretics, and alpha blockers, and the risk of EOC overall and separately for the serous, endometrioid, mucinous, clear cell and other histotypes.
We found that most antihypertensive medicines were not associated with risk of EOC. However, women who used calcium channel blockers had a reduced risk of serous EOC (OR= 0.89, 95 % CI:0.81,0.98) and use of combination thiazide and potassium-sparing diuretics was associated with an increased risk of endometroid EOC (OR= 2.09, 95 % CI:1.15,3.82).
Our results provide little support for a chemo-preventive role for most antihypertensives, however, the histotype-specific associations we found warrant further investigation.
•Most antihypertensive medicines were not associated with ovarian cancer risk.•Use of calcium channel blockers were associated with decreased risk of serous ovarian cancers.•Thiazide/potassium-sparing diuretics doubled the risk of endometrioid ovarian cancer.
Identify environmental correlates for tropical tree diversity and composition. Borneo, Southeast Asia. A GIS-environmental database with 5 arc minute (c. 10 x 10 km) resolution was combined with tree ...inventory data. Tree diversity, phylogenetic diversity (PD) and the two main compositional gradients were determined for 46 tree inventories. Akaike's information criterion and a data jackknifing procedure were used to select 50 explanatory models for diversity and composition gradients. The average of these models was used as our final diversity and compositional model. We applied Moran's I to detect spatial autocorrelation of residuals. Tree diversity, PD and the two main compositional gradients in Borneo were all significantly correlated with the environment. Tree diversity correlated negatively with elevation, soil depth, soil coarseness (texture) and organic carbon content, whereas it correlated positively with soil C:N ratio, soil pH, moisture storage capacity and annual rainfall. Tree PD was correlated positively with elevation and temperature seasonality and was largely determined by gymnosperms. However, angiosperm PD also correlated positive with elevation. Compositional patterns were strongly correlated with elevation but soil texture, cation-exchange-capacity, C:N ratio, C and N content and drainage were also important next to rainfall seasonality and El Niño Southern Oscillation drought impact. Although elevation is the most important correlate for diversity and compositional gradients in Borneo, significant additional variability is explained by soil characteristics (texture, carbon content, pH, depth, drainage and nutrient status) and climate (annual rainfall, rainfall seasonality and droughts). The identified environmental correlates for diversity and composition gradients correspond to those found in other tropical regions of the world. Differences between the regions are mainly formed by differences in the relative importance of the environmental variables in explaining diversity and compositional gradients.
Two experiments investigated the effects of perspective and visualization on motivation to engage in health‐related behaviors. Participants visualized themselves donating blood (Experiment 1) or ...quitting smoking (Experiment 2) from either the first‐person (own) or third‐person (observer's) perspective. Subsequently, motivation to engage in the visualized behavior was assessed. Contrary to previous findings showing the benefits of taking a third‐person perspective on behaviors not related to health, visualizing using the first‐person perspective had greater effects on motivation than visualizing using the third‐person perspective. Indeed, visualizing using the third‐person perspective was no more effective than not visualizing anything (Experiment 2). The theoretical implications and potential applications of these findings are discussed.
Hereditary haemorrhagic telangiectasia (HHT) is a genetically heterogeneous disorder caused by mutations in the genes
,
, and
Yet the genetic cause remains unknown for some families even after ...exhaustive exome analysis. We hypothesised that non-coding regions of the known HHT genes may harbour variants that disrupt splicing in these cases.
DNA from 35 individuals with clinical findings of HHT and 2 healthy controls from 13 families underwent whole genome sequencing. Additionally, 87 unrelated cases suspected to have HHT were evaluated using a custom designed next-generation sequencing panel to capture the coding and non-coding regions of
,
and
. Individuals from both groups had tested negative previously for a mutation in the coding region of known HHT genes. Samples were sequenced on a HiSeq2500 instrument and data were analysed to identify novel and rare variants.
Eight cases had a novel non-coding
variant that disrupted splicing. One family had an
intron 9:chromosome 3 translocation, the first reported case of a translocation causing HHT. The other seven cases had a variant located within a ~300 bp CT-rich 'hotspot' region of
intron 9 that disrupted splicing.
Despite the difficulty of interpreting deep intronic variants, our study highlights the importance of non-coding regions in the disease mechanism of HHT, particularly the CT-rich hotspot region of
intron 9. The addition of this region to HHT molecular diagnostic testing algorithms will improve clinical sensitivity.
We have developed a wide-field time-resolved imaging system to image quantitatively both the fluorescence lifetime and the rotational correlation time of a fluorophore. Using a polarization-resolved ...imager, we simultaneously image orthogonal polarization components of the fluorescence emission onto a time-gated intensified CCD. We demonstrate imaging of solvent viscosity variations through the rotational correlation time of fluorescein in a multiwell plate and apply this technique to probe the microviscosity in live cells.
Gram-positive bacteria assemble a multilayered cell wall that provides tensile strength to the cell. The cell wall is composed of glycan strands cross-linked by nonribosomally synthesized peptide ...stems. Herein, we modify the peptide stems of the Gram-positive bacterium
with noncanonical electrophilic d-amino acids, which when in proximity to adjacent stem peptides form novel covalent 5,3-cross-links. Approximately 20% of canonical cell-wall cross-links can be replaced with synthetic cross-links. While a low level of synthetic cross-link formation does not affect
growth and phenotype, at higher levels cell growth is perturbed and bacteria elongate. A comparison of the accumulation of synthetic cross-links over time in Gram-negative and Gram-positive bacteria highlights key differences between them. The ability to perturb cell-wall architecture with synthetic building blocks provides a novel approach to studying the adaptability, elasticity, and porosity of bacterial cell walls.
In an investigation of the factors leading to geographic structuring among Adélie Penguin (Pygoscelis adeliae) populations, we studied the size and overlap of colony-specific foraging areas within an ...isolated cluster of colonies. The study area, in the southwestern Ross Sea, included one large and three smaller colonies, ranging in size from 3900 to 135 000 nesting pairs, clustered on Ross and Beaufort Islands. We used triangulation of radio signals from transmitters attached to breeding penguins to determine foraging locations and to define colony-specific foraging areas during the chick-provisioning period of four breeding seasons, 1997-2000. Colony populations (nesting pairs) were determined using aerial photography just after egg-laying; reproductive success was estimated by comparing ground counts of chicks fledged to the number of breeding pairs apparent in aerial photos. Foraging-trip duration, meal size, and adult body mass were estimated using RFID (radio frequency identification) tags and an automated reader and weighbridge. Chick growth was assessed by weekly weighing. We related the following variables to colony size: foraging distance, area, and duration; reproductive success; chick meal size and growth rate; and seasonal variation in adult body mass. We found that penguins foraged closest to their respective colonies, particularly at the smaller colonies. However, as the season progressed, foraging distance, duration, and area increased noticeably, especially at the largest colony. The foraging areas of the smaller colonies overlapped broadly, but very little foraging area overlap existed between the large colony and the smaller colonies, even though the foraging area of the large colony was well within range of the smaller colonies. Instead, the foraging areas of the smaller colonies shifted as that of the large colony grew. Colony size was not related to chick meal size, chick growth, or parental body mass. This differed from the year previous to the study, when foraging trips of the large colony were very long, parents lost mass, and chick meals were smaller. In light of existing data on prey abundance in neritic waters in Antarctica suggesting that krill are relatively evenly distributed and in high abundance in the Southern Ross Sea, we conclude that penguins depleted or changed the availability of their prey, that the degree of alteration was a function of colony size, and that the large colony affected the location (and perhaps ultimately the size) of foraging areas for the smaller colonies. It appears, therefore, that foraging dynamics play a role in the geographic structuring of colonies in this species.
Because nonopioid analgesics are much sought after, we computationally docked more than 301 million virtual molecules against a validated pain target, the α
-adrenergic receptor (α
AR), seeking new α
...AR agonists chemotypes that lack the sedation conferred by known α
AR drugs, such as dexmedetomidine. We identified 17 ligands with potencies as low as 12 nanomolar, many with partial agonism and preferential G
and G
signaling. Experimental structures of α
AR complexed with two of these agonists confirmed the docking predictions and templated further optimization. Several compounds, including the initial docking hit '9087 mean effective concentration (EC
) of 52 nanomolar and two analogs, '7075 and PS75 (EC
4.1 and 4.8 nanomolar), exerted on-target analgesic activity in multiple in vivo pain models without sedation. These newly discovered agonists are interesting as therapeutic leads that lack the liabilities of opioids and the sedation of dexmedetomidine.
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