Role of Static Displacements in Stabilizing Body Centered Cubic High Entropy Alloys.

The configurational entropy of high entropy alloys (HEAs) plays little role in the stabilization of one particular crystal structure over another. We show that disorder-induced atomic displacements help stabilize body centered cubic (bcc) structure HEAs with average valences <4.7. These disorder-induced atomic displacements mimic the temperature-induced vibrations that stabilize the bcc structure of group IV elemental metals at high temperatures. The static displacements are significantly larger than for face centered cubic HEAs, approaching values associated with the Lindemann criterion for melting. Chemical disorder in high entropy alloys have a previously unidentified, nonentropic energy contribution that stabilizes a particular crystalline ground state.

Curie-Weiss behavior of liquid structure and ideal glass state.

We present the results of a structural study of metallic alloy liquids from high temperature through the glass transition. We use high energy X-ray scattering and electro-static levitation in combination with molecular dynamics simulation and show that the height of the first peak of the structure function, S(Q) - 1, follows the Curie-Weiss law. The structural coherence length is proportional to the height of the first peak, and we suggest that its increase with cooling may be related to the rapid increase in viscosity. The Curie temperature is negative, implying an analogy with spin-glass. The Curie-Weiss behavior provides a pathway to an ideal glass state, a state with long-range correlation without lattice periodicity, which is characterized by highly diverse local structures, reminiscent of spin-glass.

Predictive multiphase evolution in Al-containing high-entropy alloys.

The ability to predict and understand phases in high-entropy alloys (HEAs) is still being debated, and primarily true predictive capabilities derive from the known thermodynamics of materials. The present work demonstrates that prior work using high-throughput first-principles calculations may be further utilized to provide direct insight into the temperature- and composition-dependent phase evolution in HEAs, particularly Al-containing HEAs with a strengthening multiphase microstructure. Using a simple model with parameters derived from first-principles calculations, we reproduce the major features associated with Al-containing phases, demonstrating a generalizable approach for exploring potential phase evolution where little experimental data exists. Neutron scattering, in situ microscopy, and calorimetry measurements suggest that our high-throughput Monte Carlo technique captures both qualitative and quantitative features for both intermetallic phase formation and microstructure evolution at lower temperatures. This study provides a simple approach to guide HEA development, including ordered multi-phase HEAs, which may prove valuable for structural applications.

DNA damage emergency: cellular garbage disposal to the rescue?

The proteasome is a cellular machine found in the cytosol, nucleus and on chromatin that performs much of the proteolysis in eukaryotic cells. Recent reports show it is enriched at sites of double-stranded DNA breaks (DSBs) in mammalian cells. What is it doing there? This review will address three possibilities suggested by recent reports: in degrading proteins after their ubiquitination at and eviction from chromatin; as a deubiquitinase, specific to the antagonism of ubiquitin conjugates generated as part of the signalling of a DSB; and as a functional component of DNA repair mechanism itself. These findings add complexity to the proteasome as a potential therapeutic target in cancer treatment.

The origin of viscosity as seen through atomic level stress correlation function.

The atomic level origin of viscosity and of various relaxation times is of primary interest in the field of supercooled liquids and the glass transition. Previously, by starting from the Green-Kubo expression for viscosity and by decomposing it into correlation functions between local atomic level stresses, we showed that there is a connection between shear stress waves and viscosity, and that the range of propagation of shear waves is also the range that is relevant for viscosity. Here, the behavior of the atomic level stress correlation function at different temperatures is discussed in more detail. The comparison of different time scales of the system shows that the long time decay of the stress correlation function (τ(S)) is approximately three times shorter than the long time decay of the intermediate self-scattering function (τ(α)), while the the Maxwell relaxation time (τ(M)) is approximately five times shorter than τ(α). It is demonstrated how different timescales of the stress correlation function contribute to the Maxwell relaxation time. Finally, we discuss the non-trivial role of periodic boundary conditions.

The Forkhead Box M1 protein regulates BRIP1 expression and DNA damage repair in epirubicin treatment.

FOXM1 is implicated in genotoxic drug resistance but its role and mechanism of action remain unclear. Here, we establish that γH2AX foci, indicative of DNA double-strand breaks (DSBs), accumulate in a time-dependent manner in the drug-sensitive MCF-7 cells but not in the resistant counterparts in response to epirubicin. We find that FOXM1 expression is associated with epirubicin sensitivity and DSB repair. Ectopic expression of FOXM1 can increase cell viability and abrogate DSBs sustained by MCF-7 cells following epirubicin, owing to an enhancement in repair efficiency. Conversely, alkaline comet and γH2AX foci formation assays show that Foxm1-null cells are hypersensitive to DNA damage, epirubicin and γ-irradiation. Furthermore, we find that FOXM1 is required for DNA repair by homologous recombination (HR) but not non-homologous end joining (NHEJ), using HeLa cell lines harbouring an integrated direct repeat green fluorescent protein reporter for DSB repair. We also identify BRIP1 as a direct transcription target of FOXM1 by promoter analysis and chromatin-immunoprecipitation assay. In agreement, depletion of FOXM1 expression by small interfering RNA downregulates BRIP1 expression at the protein and mRNA levels in MCF-7 and the epirubicin-resistant MCF-7 Epi(R) cells. Remarkably, the requirement for FOXM1 for DSB repair can be circumvented by reintroduction of BRIP1, suggesting that BRIP1 is an important target of FOXM1 in DSB repair. Indeed, like FOXM1, BRIP1 is needed for HR. These data suggest that FOXM1 regulates BRIP1 expression to modulate epirubicin-induced DNA damage repair and drug resistance.

Size effects and stochastic behavior of nanoindentation pop in.

A statistical model for pop in initiated at preexisting dislocations during nanoindentation is developed to explain size-dependent pop-in stresses. To verify theoretical predictions of this model, experiments were performed on single-crystal Mo, utilizing indenter radii that vary by over 3 orders of magnitude. The stress where plastic deformation begins ranges from the theoretical strength in small volumes, to 1 order of magnitude lower in larger volumes. An intermediate regime shows wide variability in the stress to initiate plastic deformation. Our theory accurately reproduces the experimental cumulative probability distributions, and predicts a scaling behavior that matches experimental behavior.

Viscosity, shear waves, and atomic-level stress-stress correlations.

The Green-Kubo equation relates the macroscopic stress-stress correlation function to a liquid's viscosity. The concept of the atomic-level stresses allows the macroscopic stress-stress correlation function in the equation to be expressed in terms of the space-time correlations among the atomic-level stresses. Molecular dynamics studies show surprisingly long spatial extension of stress-stress correlations and also longitudinal and transverse waves propagating in liquids over ranges which could exceed the system size. The results reveal that the range of propagation of shear waves corresponds to the range of distances relevant for viscosity. Thus our results show that viscosity is a fundamentally nonlocal quantity. We also show that the periodic boundary conditions play a nontrivial role in molecular dynamics simulations, effectively masking the long-range nature of viscosity.

Ginzburg-Landau-type multiphase field model for competing fcc and bcc nucleation.

We address crystal nucleation and fcc-bcc phase selection in alloys using a multiphase field model that relies on Ginzburg-Landau free energies of the liquid-fcc, liquid-bcc, and fcc-bcc subsystems, and determine the properties of the nuclei as a function of composition, temperature, and structure. With a realistic choice for the free energy of the fcc-bcc interface, the model predicts well the fcc-bcc phase-selection boundary in the Fe-Ni system.

Atomic bond fluctuations and crossover to potential-energy-landscape-influenced regime in supercooled liquid.

The ideas related to potential-energy landscape and cooperativity of atomic rearrangements are widely discussed in the research field of glass transition. The crossover transition from high-temperature regime to potential-energy-landscape-influenced regime was extensively studied using the concept of inherent structure. However, the interpretation of this crossover behavior in terms of microscopic changes in real structures is still lacking. In this paper we present several observations on the crossover behavior on real structures. We compare fluctuations in the global properties (total number of bonds, total potential energy, pressure) versus fluctuations in the local properties (coordination number, atomic potential energy, local atomic pressure) by means of molecular dynamics simulations. We then show that the total and local fluctuations in the number of atomic bonds in the system depend on temperature differently above and below the temperature of crossover to the landscape-influenced regime. Similarly, the ratio between the global and local fluctuations in the potential energy and pressure changes in the vicinity of the crossover temperature, whereas the change is less distinct than in the case of the bond fluctuations. Our results indicate that local fluctuations become more correlated below the crossover temperature, most likely via the interaction through the dynamic shear elastic field.

Regional variability in age-related loss of neurons from the primary visual cortex and medial prefrontal cortex of male and female rats.

During aging, changes in the structure of the cerebral cortex of the rat have been seen, but potential changes in neuron number remain largely unexplored. In the present study, stereological methods were used to examine neuron number in the medial prefrontal cortex and primary visual cortex of young adult (85-90 days of age) and aged (19-22 months old) male and female rats in order to investigate any age-related losses. Possible sex differences in aging were also examined since sexually dimorphic patterns of aging have been seen in other measures. An age-related loss of neurons (18-20%), which was mirrored in volume losses, was found to occur in the primary visual cortex in both sexes in all layers except IV. Males, but not females, also lost neurons (15%) from layer V/VI of the ventral medial prefrontal cortex and showed an overall decrease in volume of this region. In contrast, dorsal medial prefrontal cortex showed no age-related changes. The effects of aging clearly differ among regions of the rat brain and to some degree, between the sexes.

Biallelic mutation of MSH2 in primary human cells is associated with sensitivity to irradiation and altered RAD51 foci kinetics.

BACKGROUND: Reports of differential mutagen sensitivity conferred by a defect in the mismatch repair (MMR) pathway are inconsistent in their conclusions. Previous studies have investigated cells established from immortalised human colorectal tumour lines or cells from animal models. METHODS: We examined primary human MSH2-deficient neonatal cells, bearing a biallelic truncating mutation in MSH2, for viability and chromosomal damage after exposure to DNA-damaging agents. RESULTS: MSH2-deficient cells exhibit no response to interstrand DNA cross-linking agents but do show reduced viability in response to irradiation. They also show increased chromosome damage and exhibit altered RAD51 foci kinetics after irradiation exposure, indicating defective homologous recombinational repair. DISCUSSION: The cellular features and sensitivity of MSH2-deficient primary human cells are broadly in agreement with observations of primary murine cells lacking the same gene. The data therefore support the view that the murine model recapitulates early features of MMR deficiency in humans, and implies that the variable data reported for MMR-deficient immortalised human cells may be due to further genetic or epigenetic lesions. We suggest caution in the use of radiotherapy for treatment of malignancies in individuals with functional loss of MSH2.

Neuron number decreases in the rat ventral, but not dorsal, medial prefrontal cortex between adolescence and adulthood.

Neuroimaging studies have established that there are losses in the volume of gray matter in certain cortical regions between adolescence and adulthood, with changes in the prefrontal cortex being particularly dramatic. Previous work from our laboratory has demonstrated that cell death can occur as late as the fourth postnatal week in the rat cerebral cortex. The present study examined the possibility that neuronal loss may occur between adolescence and adulthood in the rat prefrontal cortex. Rats of both sexes were examined during adolescence (at day 35) and young adulthood (at day 90). The volume, neuronal number, and glial number of the medial prefrontal cortex (mPFC) were quantified using unbiased stereological techniques. Neurons were lost from the ventral, but not dorsal, mPFC between adolescence and adulthood, suggesting a late wave of apoptosis that was region-specific. This was accompanied by a decrease in the volume of the female ventral mPFC. In contrast to neuron number, the number of glial cells was stable in the ventral mPFC and increased between adolescence and adulthood in the dorsal mPFC. Sex-specific developmental changes in neuron number, glial number, and volume resulted in sex differences in adults that were not seen during adolescence. The loss of neurons at this time may make the peri-adolescent prefrontal cortex particularly susceptible to the influence of environmental factors.

Influence of buried hydrogen-bonding groups within monolayer films on gas-surface energy exchange and accommodation.

Self-assembled monolayers (SAMs) of carbonyl-containing alkanethiols on gold are employed to explore the influence of hydrogen-bonding interactions on gas-surface energy exchange and accommodation. H-bonding, COOH-terminated SAMs are found to produce more impulsive scattering and less thermal accommodation than non-H-bonding, COOCH3-terminated monolayers. For carbamate-functionalized SAMs of the form Au/S(CH2)16OCONH(CH2)(n-1)CH3, impulsive scattering decreases and accommodation increases as the H-bonding group is positioned farther below the terminal CH3.

Genes, genetics, and epigenetics: a correspondence.

Over the past months, as this special issue took shape, the Editors of Science have monitored an exchange of seven letters initiated by three queries from M. Bacon. These queries concern the popular definitions of "genes," "genetics," and "epigenetics." Below, we reprint excerpts from these letters, referring interested readers to www.sciencemag.org/cgi/content/full/293/5532/1103/DC1 for the complete text and additional references.

Mouse ST6Gal sialyltransferase gene expression during mammary gland lactation.

The sialyltransferase ST6Gal mediates the biosynthetic addition of sialic acid, via an alpha2,6 linkage, to the nonreducing end of terminal lactosamine structures. Transcription of the murine ST6Gal gene, Siat1, is regulated by the selective use of multiple promoters in a tissue- and development-specific manner. Here we report that Siat1 mRNA expression is dramatically elevated in lactating (relative to virgin) mouse mammary gland. The predominant ST6Gal mRNA species expressed in lactating mammary gland is a heretofore undocumented isoform containing a unique 5'-untranslated region originating from the mouse Siat1 genetic region, now defined as Exon L, residing 549-bp 5' of the previously characterized Exon X(2). Thus, the novel ST6Gal mRNA form initiates transcription from the region designated as p4 and incorporates the unique sequence from Exon L in 5'-juxtaposition to commonly shared sequences encoded on Exon I to Exon VI. In contrast, cells derived from virgin mammary tissue expressed only the housekeeping mRNA form derived from p3, with Exon O sequence preceding Exons I-VI. The Exon L-containing, p4 class of mRNA was also not detected in a survey of eight other mouse tissues. Previous reports have indicated a strong correlation between mammary cancers and elevated ST6Gal expression in rats and in human patients. However, we uncovered neither elevated expression of ST6Gal mRNA nor appearance of p4 class in mouse breast carcinomas experimentally induced by transformation with the polyoma-middle T oncogene. A number of established breast carcinoma cell lines were also examined, with ST6Gal mRNA and activity generally low. Moreover, with the exception of the Shionogi cell line, p4 class of ST6Gal mRNA was not expressed in any of the mouse breast carcinoma specimens examined. Taken together, our data indicate that murine ST6Gal induction during lactation is achieved by de novo recruitment of a normally silent promoter. Furthermore, the data provide no support for elevated Siat1 expression on the mRNA level in association with murine mammary gland carcinogenesis. With the single exception of the Shionogi cell line, the p3 class remains the predominant ST6Gal mRNA expressed in all other murine mammary carcinoma cells examined.

A comparison of African American and White American veteran MMPI-2 profiles.

The present study compared a matched sample of 180 African American and 180 White American veterans who completed the MMPI-2 as a part of their evaluation while receiving inpatient psychiatric treatment. Findings indicated no significant multivariate or univariate effects associated with race on the basic validity and clinical scales, a significant multivariate effect but no significant univariate effects associated with race across the supplementary scales. Overall the two groups had very similar mean profiles across the basic validity, clinical, and supplementary scales. Comparison of the two groups on the content scales yielded a significant multivariate and significant univariate effects with African Americans scoring higher on the FRS, BIZ, CYN, and ASP scales. Because the two groups differed in terms of frequency and type of drug abuse, follow-up 2 x 2 univariate analyses of variance were conducted for the FRS, BIZ, CYN, and ASP content scales comparing participants classified in terms of presence or absence of a primary or secondary drug abuse diagnosis by race. A significant main effect associated with drug abuse was obtained for ASP. Results are discussed and considered in light of earlier research on the MMPI-2 and race. Content scale differences are also discussed in terms of possible differences in worldview.

The Sp1 transcription factor regulates cell type-specific transcription of MUC1.

Because the MUC1 mucin is highly expressed in breast and other carcinomas, interest is focused on the MUC1 promoter, particularly in the context of the delivery of genes to carcinomas. Earlier in vitro studies showed that the region between -152 and -66 of the MUC1 promoter is required for transcriptional activity in MUC1-expressing cells. Experiments reported here showed that sequences -119/-62 within this region are able to modulate transcription of the heterologous constitutively active herpes simplex virus thymidine kinase promoter in a pattern consistent with MUC1 expression. Band-shift experiments showed that although several factors (including Sp1 and Sp3) bind to these sequences, the element important in directing this MUC1 pattern of expression was an Sp1 GC box at -97. The data also show that the positioning or phase of the GC box was crucial for directing expression. The importance of the Sp1 transcription factor was confirmed by demonstrating that overexpression of Sp1 in MUC1-nonexpressing cells increased, not only the expression of a reporter gene driven by the 1.4-kb MUC1 promoter, but also the expression of MUC1 from the endogenous gene. Together, these data define an important role for Sp1 in the cell type-specific transcription of MUC1.

Up-regulation of MUC1 in mammary tumors generated in a double-transgenic mouse expressing human MUC1 cDNA, under the control of 1.4-kb 5' MUC1 promoter sequence and the middle T oncogene, expressed from the MMTV promoter.

In this study we examined the regulation of expression of the human MUC1 gene in vivo, by developing MUC1 transgenic mice. The data showed that epithelial-specific expression of MUC1 can be directed by just 1.4 kb of 5' flanking sequence using MUC1 cDNA as a reporter gene in vivo. Furthermore, high levels of MUC1 expression were seen in the lactating mammary gland and in spontaneous mammary tumors generated by crossing the MUC1 transgenics with mice transgenic for the polyoma middle T oncogene under the control of the mouse mammary tumor virus promoter. This pattern of expression in epithelial tissues is comparable to the expression of MUC1 in humans and also to the expression pattern in another transgenic mouse line developed with a 10.6-kb genomic MUC1 fragment. This study confirmed that MUC1 is a compact gene and demonstrated that the 1.4-kb 5' sequence not only directs epithelial-specific expression of MUC1 in vivo but also contains the elements governing the up-regulation observed during lactation and in malignancy.