The control of potentially mutagenic impurities in pharmaceutical products is of key importance in assessing carcinogenic risk to humans. The recent discovery of nitrosamine impurities in several ...marketed pharmaceuticals has increased interest in their mutagenic and carcinogenic potential. This chemical class is considered part of a ‘cohort of concern’, indicating that standard control protocols, such as the use of a threshold of toxicological concern (TTC), cannot be applied. Whilst some nitrosamines are known to be exceptionally potent carcinogens, it's not clear whether this is a property of all members of the class. To investigate the mutagenic and carcinogenic potential of nitrosamines, data was extracted from published literature to augment that already present in the Vitic and Lhasa Carcinogenicity Databases. This data was analysed to assess the application of the ICH M7 guideline to nitrosamine impurities, with respect to the predictivity of the Ames test for carcinogenic potential and the distribution of carcinogenic potency. It was found that 18% of nitrosamines were considered non-carcinogenic. Nitrosamines showed a greater correlation between mutagenicity and carcinogenicity compared to non-nitrosamine compounds. Whilst nitrosamines, in general, are more potent carcinogens than non-nitrosamines, there is a significant overlap between the two distributions of TD50s for each class.
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•Nitrosamines are carcinogenic impurities which have been found in marketed drugs.•Carcinogenicity data must be reviewed regarding their potential acceptable intakes.•The Ames test is a reliable predictor of nitrosamine carcinogenicity.•While they are potent carcinogens, they cover a broad distribution of TD50 values.
The discovery of carcinogenic nitrosamine impurities above the safe limits in pharmaceuticals has led to an urgent need to develop methods for extending structure–activity relationship (SAR) analyses ...from relatively limited datasets, while the level of confidence required in that SAR indicates that there is significant value in investigating the effect of individual substructural features in a statistically robust manner. This is a challenging exercise to perform on a small dataset, since in practice, compounds contain a mixture of different features, which may confound both expert SAR and statistical quantitative structure–activity relationship (QSAR) methods. Isolating the effects of a single structural feature is made difficult due to the confounding effects of other functionality as well as issues relating to determining statistical significance in cases of concurrent statistical tests of a large number of potential variables with a small dataset; a naïve QSAR model does not predict any features to be significant after correction for multiple testing. We propose a variation on Bayesian multiple linear regression to estimate the effects of each feature simultaneously yet independently, taking into account the combinations of features present in the dataset and reducing the impact of multiple testing, showing that some features have a statistically significant impact. This method can be used to provide statistically robust validation of expert SAR approaches to the differences in potency between different structural groupings of nitrosamines. Structural features that lead to the highest and lowest carcinogenic potency can be isolated using this method, and novel nitrosamine compounds can be assigned into potency categories with high accuracy.
Small-Pitch HgCdTe Photodetectors Tennant, W. E.; Gulbransen, D. J.; Roll, A. ...
Journal of electronic materials,
08/2014, Letnik:
43, Številka:
8
Journal Article, Conference Proceeding
Recenzirano
Odprti dostop
If we can make wavelength-sized detectors, we approach the limit at which smaller detectors have no further advantage for imaging focal plane arrays with practical (f/1-2) optics. Of course, this ...must be accomplished without compromising performance—a challenge for 5-
μ
m devices for which the perimeter, the currents of which depend on passivation quality, is very large compared with the area of the device. This paper describes the development of small LWIR HgCdTe detectors and compares dark current performance with that of larger basic devices, as described by “Rule 07”, a well-known rule of thumb which gives the HgCdTe dark-current density characteristics of the best reported diodes as a function of device cut-off wavelength and operating temperature. Low cross-talk requires a fully-depleted absorber layer sufficiently thick to provide adequate quantum efficiency (QE). Preliminary results show dark-current densities are more than a factor of ten below the Rule 07 trend line. With these dark-current densities, the measured ∼40% non-anti-reflection-coated QE in the 8–10
μ
m region is more than adequate to achieve background-limited performance with the margin under tactical backgrounds for the fast (f/1), diffraction-limited optics required for the small pixels.
Identifying the sources of variation in mating interactions between males and females is important because this variation influences the strength and/or the direction of sexual selection that ...populations experience. While the origins and effects of variation in male attractiveness and ornamentation have received much scrutiny, the causes and consequences of intraspecific variation in females have been relatively overlooked. We used cytogenetic cloning techniques developed for Drosophila melanogaster to create "hemiclonal" males and females with whom we directly observed sexual interaction between individuals of different known genetic backgrounds and measured subsequent reproductive outcomes. Using this approach, we were able to quantify the genetic contribution of each mate to the observed phenotypic variation in biologically important traits including mating speed, copulation duration, and subsequent offspring production, as well as measure the magnitude and direction of intersexual genetic correlation between female choosiness and male attractiveness.
We found significant additive genetic variation contributing to mating speed that can be attributed to male genetic identity, female genetic identity, but not their interaction. Furthermore we found that phenotypic variation in copulation duration had a significant male-associated genetic component. Female genetic identity and the interaction between male and female genetic identity accounted for a substantial amount of the observed phenotypic variation in egg size. Although previous research predicts a trade-off between egg size and fecundity, this was not evident in our results. We found a strong negative genetic correlation between female choosiness and male attractiveness, a result that suggests a potentially important role for sexually antagonistic alleles in sexual selection processes in our population.
These results further our understanding of sexual selection because they identify that genetic identity plays a significant role in phenotypic variation in female behaviour and fecundity. This variation may be potentially due to ongoing sexual conflict found between the sexes for interacting phenotypes. Our unexpected observation of a negative correlation between female choosiness and male attractiveness highlights the need for more explicit theoretical models of genetic covariance to investigate the coevolution of female choosiness and male attractiveness.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mutagenicity data is a core component of the safety assessment data required by regulatory agencies for acceptance of new drug compounds, with the OECD-471 bacterial reverse mutation (Ames) assay ...most widely used as a primary screen to assess drug impurities for potential mutagenic risk. N-Nitrosamines are highly potent mutagenic carcinogens in rodent bioassays and their recent detection as impurities in pharmaceutical products has sparked increased interest in their safety assessment. Previous literature reports indicated that the Ames test might not be sensitive enough to detect the mutagenic potential of N-nitrosamines in order to accurately predict a risk of carcinogenicity. To explore this hypothesis, public Ames and rodent carcinogenicity data pertaining to the N-nitrosamine class of compounds was collated for analysis. Here we present how variations to the OECD 471-compliant Ames test, including strain, metabolic activation, solvent type and pre-incubation/plate incorporation methods, may impact the predictive performance for carcinogenicity. An understanding of optimal conditions for testing of N-nitrosamines may improve both the accuracy and confidence in the ability of the Ames test to identify potential carcinogens.
•Assessment of the ability of the Ames test to predict carcinogenicity of N-nitrosamines using an expert-curated database.•Protocol variations to the OECD 471-compliant Ames test may impact its ability to predict carcinogenic potential.•An in-depth review of strain, metabolic activation, solvent type and pre-incubation/plate incorporation method data.•Limitations of historical studies to be addressed before a standard Ames protocol for N-nitrosamines can be recommended.
The yeast prion PSI+ is a self-propagating amyloidogenic isoform of the translation termination factor Sup35. Overproduction of the chaperone protein Hsp104 results in loss of PSI+. Here we ...demonstrate that this effect is decreased by deletion of either the gene coding for one of the major yeast ubiquitin-conjugating enzymes, Ubc4, or the gene coding for the ubiquitin-recycling enzyme, Ubp6. The effect of ubc4Δ on PSI+ loss was increased by depletion of the Hsp70 chaperone Ssb but was not influenced by depletion of Ubp6. This indicates that Ubc4 affects PSI+ loss via a pathway that is the same as the one affected by Ubp6 but not by Ssb. In the presence of Rnq1 protein, ubc4Δ also facilitates spontaneous de novo formation of PSI+. This stimulation is independent of PIN+, the prion isoform of Rnq1. Numerous attempts failed to detect ubiquitinated Sup35 in the yeast extracts. While ubc4Δ and other alterations of ubiquitin system used in this work cause slight induction of some Hsps, these changes are insufficient to explain their effect on PSI+. However, ubc4Δ increases the proportion of the Hsp70 chaperone Ssa bound to Sup35, suggesting that misfolded Sup35 is either more abundant or more accessible to the chaperones in the absence of Ubc4. The proportion of PSI+ cells containing large aggregated Sup35 structures is also increased by ubc4Δ. We propose that UPS alterations induce an adaptive response, resulting in accumulation of the large “aggresome”-like aggregates that promote de novo prion generation and prion recovery from the chaperone treatment.
The amyloidogenic pathway leading to the production and deposition of Aβ peptides, major constituents of Alzheimer disease senile plaques, is linked to neuronal metal homeostasis. The amyloid ...precursor protein binds copper and zinc in its extracellular domain, and the Aβ peptides also bind copper, zinc, and iron. The first step in the generation of Aβ is cleavage of amyloid precursor protein by the aspartic protease BACE1. Here we show that BACE1 interacts with CCS (the copper chaperone for superoxide dismutase-1 (SOD1)) through domain I and the proteins co-immunoprecipitate from rat brain extracts. We have also been able to visualize the co-transport of membranous BACE1 and soluble CCS through axons. BACE1 expression reduces the activity of SOD1 in cells consistent with direct competition for available CCS as overexpression of CCS restores SOD1 activity. Finally, we demonstrate that the twenty-four residue C-terminal domain of BACE1 binds a single Cu(I) atom with high affinity through cysteine residues.
Shallow-etch mesa isolation (SEMI) of graded-bandgap “W”-structured type II superlattice (GGW) infrared photodiodes provides a powerful means for reducing excess dark currents due to surface and bulk ...junction related processes, and it is particularly well suited for focal-plane array fabrication. In the
n
-on-
p
GGW photodiode structure the energy gap is increased in a series of steps from that of the lightly
p
-type infrared-absorbing region to a value typically two to three times larger. The wider gap levels off about 10 nm short of the doping-defined junction, and continues for another 0.25
μ
m into the heavily
n
-doped cathode before the structure is terminated by an
n
+
-doped InAs top cap layer. The increased bandgap in the high-field region near the junction helps to strongly suppress both bulk tunneling and generation–recombination (G–R) current by imposing a much larger tunneling barrier and exponentially lowering the intrinsic carrier concentration. The SEMI approach takes further advantage of the graded structure by exposing only the widest-gap layers on etched surfaces. This lowers surface recombination and trap-assisted tunneling in much the same way as the GGW suppresses these processes in the bulk. Using SEMI, individual photodiodes are defined using a shallow etch that typically terminates only 10 nm to 20 nm past the junction, which is sufficient to isolate neighboring pixels while leaving the narrow-gap absorber layer buried 100 nm to 200 nm below the surface. This provides for separate optimization of the photodiode’s electrical and optical area. The area of the junction can be reduced to a fraction of that of the pixel, lowering bulk junction current, while maintaining 100% optical fill factor with the undisturbed absorber layer. Finally, with the elimination of deep, high-aspect-ratio trenches, SEMI simplifies array fabrication. We report herein results from SEMI-processed GGW devices, including large-area discrete photodiodes, mini-arrays, and a focal-plane array. Current–voltage data show strong suppression of side-wall leakage relative to that for more deeply etched devices, as well as scaling of dark current with junction area without loss of quantum efficiency.
Strained-layer superlattices (SLS) based on type II InAs/Ga(In)Sb materials are a rapidly maturing technology and are theoretically predicted to exceed the dark-current performance of ...state-of-the-art HgCdTe. A substantial effort is underway at Teledyne Imaging Sensors in the development of SLS materials for infrared focal-plane arrays. In this paper, we describe state-of-the-art materials, device research and characterization, along with testing results for long-wavelength infrared SLS devices based on double-heterostructure and
p
+
-B-
n
architectures, having
n
-on-
p
and
p
-on-
n
polarities, respectively. Detector materials exhibited excellent morphological and crystalline characteristics, and electro-optical characterization demonstrated performance comparable to the state of the art.
We review recent advances in the HgCdTe material quality and detector performance achieved at Teledyne using molecular beam epitaxy growth and the double-layer planar hetero-junction (DLPH) detector ...architecture. By using an un-doped, fully depleted absorber, Teledyne’s DLPH architecture can be extended for use in high operating temperatures and other applications. We assess the potential achievable performance for long wavelength infrared (LWIR) hetero-junction
p
-lightly-doped
n
or
p
-intrinsic-
n
(p-i-n) detectors based on recently reported results for 10.7
μ
m cutoff 1 K × 1 K focal plane arrays (FPAs) tested at temperatures down to 30 K. Variable temperature dark current measurements show that any Shockley–Read–Hall currents in the depletion region of these devices have lifetimes that are reproducibly greater than 100 ms. Under the assumption of comparable lifetimes at higher temperatures, it is predicted that fully-depleted background radiation-limited performance can be expected for 10-
μ
m cutoff detectors from room temperature to well below liquid nitrogen temperatures, with room-temperature dark current nearly 400 times lower than predicted by Rule 07. The hetero-junction p-i-n diode is shown to have numerous other significant potential advantages including minimal or no passivation requirements for pBn-like processing, low 1/
f
noise, compatibility with small pixel pitch while maintaining high modulation transfer function, low crosstalk and good quantum efficiency. By appropriate design of the FPA dewar shielding, analysis shows that dark current can theoretically be further reduced below the thermal equilibrium radiative limit. Modeling shows that background radiation-limited LWIR HgCdTe operating with
f
/1 optics has the potential to operate within √2 of background-limited performance at 215 K. By reducing the background radiation by 2/3 using novel shielding methods, operation with a single-stage thermo-electric-cooler may be possible. If the background radiation can be reduced by 90%, then room-temperature operation is possible.
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