Unique Role of Refractory Ta Alloying in Enhancing the Figure of Merit of NbFeSb Thermoelectric Materials

NbFeSb‐based half‐Heusler alloys have been recently identified as promising high‐temperature thermoelectric materials with a figure of merit zT > 1, but their thermal conductivity is still relatively high. Alloying Ta at the Nb site would be highly desirable because the large mass fluctuation between them could effectively scatter phonons and reduce the lattice thermal conductivity. However, practically it is a great challenge due to the high melting point of refractory Ta. Here, the successful synthesis of Ta‐alloyed (Nb_1?xTa_x)_0.8Ti_0.2FeSb (x = 0 – 0.4) solid solutions with significantly reduced thermal conductivity by levitation melting is reported. Because of the similar atomic sizes and chemistry of Nb and Ta, the solid solutions exhibit almost unaltered electrical properties. As a result, an overall zT enhancement from 300 to 1200 K is realized in the single‐phase Ta‐alloyed solid solutions, and the compounds with x = 0.36 and 0.4 reach a maximum zT of 1.6 at 1200 K. This work also highlights that the isoelectronic substitution by atoms with similar size and chemical nature but large mass difference should reduce the lattice thermal conductivity but maintain good electrical properties in thermoelectric materials, which can be a guide for optimizing the figure of merit by alloying.     

DNA intercalative potential of marketed drugs testing positive in in vitro cytogenetics assays

We have previously noted that the Physicians' Desk Reference (PDR) contains over 80 instances in which a drug elicited a positive genotoxic response in one or more in vitro assays, despite having no obvious structural features predictive of covalent drug/DNA interactive potential or known mechanistic basis. Furthermore, in most cases, these drugs were "missed" by computational genotoxicity-predicting models such as DEREK, MCASE and TOPKAT. We have previously reported the application of a V79 cell-based model and a 3D DNA docking model for predicting non-covalent chemical/DNA interactions. Those studies suggested that molecules that are very widely structurally diverse may be capable of intercalating into DNA. To determine whether such non-covalent drug/DNA interactions might be involved in unexpected drug genotoxicity, we evaluated, using both models where possible, 56 marketed pharmaceuticals, 40 of which were reported as being clastogenic in in vitro cytogenetics assays (chromosome aberrations/mouse lymphoma assay). As seen before, the two approaches showed good concordance (62%) and 26 of the 40 (65%) drugs exhibiting in vitro clastogenicity were predicted as intercalators by one or both methods. This finding provides support for the hypothesis that non-covalent DNA interaction may be a common mechanism of clastogenicity for many drugs having no obvious structural alerts for covalent DNA interaction.     

The thiazide-sensitive NaCl cotransporter is targeted for chaperone-dependent endoplasmic reticulum-associated degradation

The thiazide-sensitive NaCl cotransporter (NCC, SLC12A3) mediates salt reabsorption in the distal nephron of the kidney and is the target of thiazide diuretics, which are commonly prescribed to treat hypertension. Mutations in NCC also give rise to Gitelman syndrome, a hereditary salt-wasting disorder thought in most cases to arise from impaired NCC biogenesis through enhanced endoplasmic reticulum-associated degradation (ERAD). Because the machinery that mediates NCC quality control is completely undefined, we employed yeast as a model heterologous expression system to identify factors involved in NCC degradation. We confirmed that NCC was a bona fide ERAD substrate in yeast, as the majority of NCC polypeptide was integrated into ER membranes, and its turnover rate was sensitive to proteasome inhibition. NCC degradation was primarily dependent on the ER membrane-associated E3 ubiquitin ligase Hrd1. Whereas several ER luminal chaperones were dispensable for NCC ERAD, NCC ubiquitination and degradation required the activity of Ssa1, a cytoplasmic Hsp70 chaperone. Compatible findings were observed when NCC was expressed in mammalian kidney cells, as the cotransporter was polyubiquitinated and degraded by the proteasome, and mammalian cytoplasmic Hsp70 (Hsp72) coexpression stimulated the degradation of newly synthesized NCC. Hsp70 also preferentially associated with the ER-localized NCC glycosylated species, indicating that cytoplasmic Hsp70 plays a critical role in selecting immature forms of NCC for ERAD. Together, these results provide the first survey of components involved in the ERAD of a mammalian SLC12 cation chloride cotransporter and provide a framework for future studies on NCC ER quality control.     

Humanized TLR7/8 Expression Drives Proliferative Multisystemic Histiocytosis in C57BL/6 Mice

A humanized TLR7/TLR8 transgenic mouse line was engineered for studies using TLR7/8 ligands as vaccine adjuvants. The mice developed a spontaneous immune-mediated phenotype prior to six months of age characterized by runting, lethargy, blepharitis, and corneal ulceration. Histological examination revealed a marked, multisystemic histiocytic infiltrate that effaced normal architecture. The histological changes were distinct from those previously reported in mouse models of systemic lupus erythematosus. When the mice were crossed with MyD88^−/− mice, which prevented toll-like receptor signaling, the inflammatory phenotype resolved. Illness may be caused by constitutive activation of human TLR7 or TLR8 in the bacterial artificial chromosome positive mice as increased TLR7 and TLR8 expression or activation has previously been implicated in autoimmune disease.     

Tapping to a Slow Tempo in the Presence of Simple and Complex Meters Reveals Experience-Specific Biases for Processing Music

Musical meters vary considerably across cultures, yet relatively little is known about how culture-specific experience influences metrical processing. In Experiment 1, we compared American and Indian listeners'' synchronous tapping to slow sequences. Inter-tone intervals contained silence or to-be-ignored rhythms that were designed to induce a simple meter (familiar to Americans and Indians) or a complex meter (familiar only to Indians). A subset of trials contained an abrupt switch from one rhythm to another to assess the disruptive effects of contradicting the initially implied meter. In the unfilled condition, both groups tapped earlier than the target and showed large tap-tone asynchronies (measured in relative phase). When inter-tone intervals were filled with simple-meter rhythms, American listeners tapped later than targets, but their asynchronies were smaller and declined more rapidly. Likewise, asynchronies rose sharply following a switch away from simple-meter but not from complex-meter rhythm. By contrast, Indian listeners performed similarly across all rhythm types, with asynchronies rapidly declining over the course of complex- and simple-meter trials. For these listeners, a switch from either simple or complex meter increased asynchronies. Experiment 2 tested American listeners but doubled the duration of the synchronization phase prior to (and after) the switch. Here, compared with simple meters, complex-meter rhythms elicited larger asynchronies that declined at a slower rate, however, asynchronies increased after the switch for all conditions. Our results provide evidence that ease of meter processing depends to a great extent on the amount of experience with specific meters.     

Discovery of the first antibacterial small molecule inhibitors of MurB

A series of imidazolinone analogues was synthesized and shown to possess potent MurB inhibitory as well as good antibacterial activity.     

Facilitate insight by non-invasive brain stimulation

Our experiences can blind us. Once we have learned to solve problems by one method, we often have difficulties in generating solutions involving a different kind of insight. Yet there is evidence that people with brain lesions are sometimes more resistant to this so-called mental set effect. This inspired us to investigate whether the mental set effect can be reduced by non-invasive brain stimulation. 60 healthy right-handed participants were asked to take an insight problem solving task while receiving transcranial direct current stimulation (tDCS) to the anterior temporal lobes (ATL). Only 20% of participants solved an insight problem with sham stimulation (control), whereas 3 times as many participants did so (p = 0.011) with cathodal stimulation (decreased excitability) of the left ATL together with anodal stimulation (increased excitability) of the right ATL. We found hemispheric differences in that a stimulation montage involving the opposite polarities did not facilitate performance. Our findings are consistent with the theory that inhibition to the left ATL can lead to a cognitive style that is less influenced by mental templates and that the right ATL may be associated with insight or novel meaning. Further studies including neurophysiological imaging are needed to elucidate the specific mechanisms leading to the enhancement.     

Mutating conserved cysteines in the alphavirus e2 glycoprotein causes virus-specific assembly defects

There are 80 trimeric, glycoprotein spikes that cover the surface of an alphavirus particle. The spikes, which are composed of three E2 and E1 glycoprotein heterodimers, are responsible for receptor binding and mediating fusion between the viral and host-cell membranes during entry. In addition, the cytoplasmic domain of E2 interacts with the nucleocapsid core during the last stages of particle assembly, possibly to aid in particle stability. During assembly, the spikes are nonfusogenic until the E3 glycoprotein is cleaved from E2 in the trans-Golgi network. Thus, a mutation in E2 potentially has effects on virus entry, spike assembly, or spike maturation. E2 is a highly conserved, cysteine-rich transmembrane glycoprotein. We made single cysteine-to-serine mutations within two distinct regions of the E2 ectodomain in both Sindbis virus and Ross River virus. Each of the E2 Cys mutants produced fewer infectious particles than wild-type virus. Further characterization of the mutant viruses revealed differences in particle morphology, fusion activity, and polyprotein cleavage between Sindbis and Ross River virus mutants, despite the mutations being made at corresponding positions in E2. The nonconserved assembly defects suggest that E2 folding and function is species dependent, possibly due to interactions with a virus-specific chaperone.     

Host-range testing of Eucryptorrhynchus brandti (Coleoptera: Curculionidae), a candidate for biological control of tree-of-heaven, Ailanthus altissima

Ailanthus altissima (Mill.) Swingle, tree-of-heaven, is an invasive species native to Asia. It first was introduced into the United States in the 1700 s and now is distributed throughout much of North America. Mechanical and chemical controls are current suppression tactics, however, implementation is costly. A weevil, Eucryptorrhynchus brandti (Harold), was identified in China and imported for quarantine testing in 2004 as a potential biological control agent. Host specificity tests on adult feeding, larval development, and oviposition of this weevil were conducted from 2007 to 2011 on A. altissima and 29 nontarget species. Eucryptorrhynchus brandti adults fed significantly more on A. altissima foliage when compared with all test species. Range of means for feeding on A. altissima was 32.5-106.5 mm(2)/adult/d. In no-choice tests, Simarouba glauca DC, Leitneria floridana Chapm., and Citrus limon (L.) Burm. F., had feeding rates of only 10, 49, and 10%, respectively, compared with the level of feeding on A. altissima. The mean range of adult feeding by E. brandti on all other test species was <7% of feeding on A. altissima (0.0-3.3 ± 5.0 mm(2)/adult/d). In the no-choice larval inoculation tests, larval development only occurred in two of 10 L. floridana seedlings compared with seven of 10 A. altissima seedlings. In the no-choice oviposition tests, oviposition and subsequent larval development did not occur in L. floridiana, whereas all seven A. altissima seedlings supported oviposition and subsequent larval development. The weevil did not appear to be a threat to L. floridana or any other nontarget species tested. Therefore, we conclude that Eucryptorrhynchus brandti is highly host specific to A. altissima.