Development of gas tungsten arc welding using current pulsing technique to preclude chromium carbide precipitation in aerospace-grade alloy 80A

Weldments were produced using gas tungsten arc welding(GTAW) and pulsed current gas tungsten arc welding(PCGTAW) techniques with ERNiCr-3 filler wire. Macro examination revealed that the resultant weldments were free from defects. A refined microstructure was observed in the weldment fabricated through PCGTAW. Scanning electron microscopy(SEM) analysis revealed secondary phases in the grain boundaries. Energy-dispersive X-ray spectroscopy(EDS) analysis revealed that microsegregation of Cr carbide precipitates was completely eradicated through PCGTAW. The microsegregation of Nb precipitates was observed in the GTA and PCGTA weldments. X-ray diffraction(XRD) analysis revealed the existence of M_(23)C?_6 Cr-rich carbide and Ni_8Nb phases in the GTA weldments. By contrast, in the PCGTA weldments, the Ni_8Nb phase was observed. The Cr_2Ti phase was observed in both the GTA and the PCGTA weldments. Tensile tests showed that the strength and ductility of the PCGTA weldments were slightly higher than those of the GTA weldments.     

Intrinsically disordered proteins in crowded milieu: when chaos prevails within the cellular gumbo

Effects of macromolecular crowding on structural and functional properties of ordered proteins, their folding, interactability, and aggregation are well documented. Much less is known about how macromolecular crowding might affect structural and functional behaviour of intrinsically disordered proteins (IDPs) or intrinsically disordered protein regions (IDPRs). To fill this gap, this review represents a systematic analysis of the available literature data on the behaviour of IDPs/IDPRs in crowded environment. Although it was hypothesized that, due to the excluded-volume effects present in crowded environments, IDPs/IDPRs would invariantly fold in the presence of high concentrations of crowding agents or in the crowded cellular environment, accumulated data indicate that, based on their response to the presence of crowders, IDPs/IDPRs can be grouped into three major categories, foldable, non-foldable, and unfoldable. This is because natural cellular environment is not simply characterized by the presence of high concentration of “inert” macromolecules, but represents an active milieu, components of which are engaged in direct physical interactions and soft interactions with target proteins. Some of these interactions with cellular components can cause (local) unfolding of query proteins. In other words, since crowding can cause both folding and unfolding of an IDP or its regions, the outputs of the placing of a query protein to the crowded environment would depend on the balance between these two processes. As a result, and because of the spatio-temporal heterogeneity in structural organization of IDPs, macromolecular crowding can differently affect structures of different IDPs. Recent studies indicate that some IDPs are able to undergo liquid–liquid-phase transitions leading to the formation of various proteinaceous membrane-less organelles (PMLOs). Although interiors of such PMLOs are self-crowded, being characterized by locally increased concentrations of phase-separating IDPs, these IDPs are minimally foldable or even non-foldable at all (at least within the physiologically safe time-frame of normal PMLO existence).     

Protein kinase D inhibitor CRT0066101 suppresses bladder cancer growth in vitro and xenografts via blockade of the cell cycle at G2/M

The protein kinase D (PKD) family of proteins are important regulators of tumor growth, development, and progression. CRT0066101, an inhibitor of PKD, has antitumor activity in multiple types of carcinomas. However, the effect and mechanism of CRT0066101 in bladder cancer are not understood. In the present study, we show that CRT0066101 suppressed the proliferation and migration of four bladder cancer cell lines in vitro. We also demonstrate that CRT0066101 blocked tumor growth in a mouse flank xenograft model of bladder cancer. To further assess the role of PKD in bladder carcinoma, we examined the three PKD isoforms and found that PKD2 was highly expressed in eight bladder cancer cell lines and in urothelial carcinoma tissues from the TCGA database, and that short hairpin RNA (shRNA)-mediated knockdown of PKD2 dramatically reduced bladder cancer growth and invasion in vitro and in vivo, suggesting that the effect of the compound in bladder cancer is mediated through inhibition of PKD2. This notion was corroborated by demonstrating that the levels of phospho-PKD2 were markedly decreased in CRT0066101-treated bladder tumor explants. Furthermore, our cell cycle analysis by flow cytometry revealed that CRT0066101 treatment or PKD2 silencing arrested bladder cancer cells at the G2/M phase, the arrest being accompanied by decreases in the levels of cyclin B1, CDK1 and phospho-CDK1 (Thr161) and increases in the levels of p27^Kip1 and phospho-CDK1 (Thr14/Tyr15). Moreover, CRT0066101 downregulated the expression of Cdc25C, which dephosphorylates/activates CDK1, but enhanced the activity of the checkpoint kinase Chk1, which inhibits CDK1 by phosphorylating/inactivating Cdc25C. Finally, CRT0066101 was found to elevate the levels of Myt1, Wee1, phospho-Cdc25C (Ser216), Gadd45α, and 14-3-3 proteins, all of which reduce the CDK1-cyclin B1 complex activity. These novel findings suggest that CRT0066101 suppresses bladder cancer growth by inhibiting PKD2 through induction of G2/M cell cycle arrest, leading to the blockade of cell cycle progression.     

Degradation of the mitochondrial complex I assembly factor TMEM126B under chronic hypoxia

Cell stress such as hypoxia elicits adaptive responses, also on the level of mitochondria, and in part is mediated by the hypoxia-inducible factor (HIF) 1α. Adaptation of mitochondria towards acute hypoxic conditions is reasonably well understood, while regulatory mechanisms, especially of respiratory chain assembly factors, under chronic hypoxia remains elusive. One of these assembly factors is transmembrane protein 126B (TMEM126B). This protein is part of the mitochondrial complex I assembly machinery. We identified changes in complex I abundance under chronic hypoxia, in association with impaired substrate-specific mitochondrial respiration. Complexome profiling of isolated mitochondria of the human leukemia monocytic cell line THP-1 revealed HIF-1α-dependent deficits in complex I assembly and mitochondrial complex I assembly complex (MCIA) abundance. Of all mitochondrial MCIA members, we proved a selective HIF-1-dependent decrease of TMEM126B under chronic hypoxia. Mechanistically, HIF-1α induces the E3-ubiquitin ligase F-box/WD repeat-containing protein 1A (β-TrCP1), which in turn facilitates the proteolytic degradation of TMEM126B. Attenuating a functional complex I assembly appears critical for cellular adaptation towards chronic hypoxia and is linked to destruction of the mitochondrial assembly factor TMEM126B.     

The carcinofauna found in stomach contents of the flying gurnard (Dactylopterus volitans) on the continental shelf of the Campos Basin,Brazil

A total of 3109 crustaceans belonging to 50 taxa distributed in 42 families were found in 117 analysed stomachs of flying gurnard (Dactylopterus volitans). Samples were obtained in April 2008 by the R/V Gyre using a bottom trawl towed in 12 stations at 14–100 m depth on the continental shelf of the Campos Basin, Brazil. The carcinofauna was analysed and the order Calanoida (Copepoda) found to be the most important item in terms of relative abundance and frequency of occurrence, followed by the order Amphipoda (Peracarida), the infraorder Brachyura (Decapoda), the order Stomatopoda and the subclass Myodocopa (Ostracoda). In the order Calanoida, the species Pontellopsis cf. villosa (Pontellidae) represented 98.04% of total crustacean abundance. The diet of Dactylopterus volitans varied according to fish size, with higher diversity of Crustacea at smaller size classes, decreasing in larger fishes. A similar pattern regarding depth was obtained, with greater diversity of taxa in gurnard stomachs caught at shallower depths. Flying gurnard is considered a generalized carnivore of invertebrates, eating mobile macrobenthic organisms, such as crustaceans, and its diet varies with its life stage, without any specific group as its main food source.     

Prion protein cleavage fragments regulate adult neural stem cell quiescence through redox modulation of mitochondrial fission and SOD2 expression

Neurogenesis continues in the post-developmental brain throughout life. The ability to stimulate the production of new neurones requires both quiescent and actively proliferating pools of neural stem cells (NSCs). Actively proliferating NSCs ensure that neurogenic demand can be met, whilst the quiescent pool makes certain NSC reserves do not become depleted. The processes preserving the NSC quiescent pool are only just beginning to be defined. Herein, we identify a switch between NSC proliferation and quiescence through changing intracellular redox signalling. We show that N-terminal post-translational cleavage products of the prion protein (PrP) induce a quiescent state, halting NSC cellular growth, migration, and neurite outgrowth. Quiescence is initiated by the PrP cleavage products through reducing intracellular levels of reactive oxygen species. First, inhibition of redox signalling results in increased mitochondrial fission, which rapidly signals quiescence. Thereafter, quiescence is maintained through downstream increases in the expression and activity of superoxide dismutase-2 that reduces mitochondrial superoxide. We further observe that PrP is predominantly cleaved in quiescent NSCs indicating a homeostatic role for this cascade. Our findings provide new insight into the regulation of NSC quiescence, which potentially could influence brain health throughout adult life.     

Integrative taxonomy at the nexus of population divergence and speciation in insular speckled rattlesnakes

ABSTRACT

We describe two diminutive species of rattlesnakes (genus Crotalus) from small nearshore islands off the coast of Baja California in the western Gulf of California, Mexico. In order to test the hypothesis that some island populations represent cohesive species entities, we applied linear discriminant analysis and uniform validation procedures to multiple classes of intrinsic trait data. By using previously recognised species to establish a threshold for species recognition, we found that assignment of specimens to either new species was as probable as with other established rattlesnake species within the speckled rattlesnake (Crotalus mitchellii) complex. We also found that assignment of specimens from other island populations was not as probable as for the established species, and these populations are referable to C. pyrrhus. The species endemic to Piojo Island is most closely related to other island and mainland populations of C. pyrrhus whereas the species endemic to Cabeza de Caballo Island is apparently most closely related to C. angelensis, a nearby island endemic of large body size. However, patterns from both mitochondrial and nuclear phylogenies, and phenotypic variation, indicate that evolutionary trajectories of both of these species have been influenced by introgression from C. angelensis. We speculate that collective evidence based on contrasting patterns of nuclear and mitochondrial evolution supports a hybrid origin of the species from Cabeza de Caballo Island followed by exceptionally rapid mitochondrial evolution. Consistent with small body size, both species show a reduction in various scale counts relative to other species of the C. mitchellii species complex, suggesting that dwarfism is not simply a plastic response to insular conditions.

http://www.zoobank.org/urn.lsid:zoobank.org:pub:FBC8A11B-04A3-4231-85CA-3972DF5A42FF     

Collaborative explanation,explanatory roles,and scientific explaining in practice

Scientific explanation is a perennial topic in philosophy of science, but the literature has fragmented into specialized discussions in different scientific disciplines. An increasing attention to scientific practice by philosophers is (in part) responsible for this fragmentation and has put pressure on criteria of adequacy for philosophical accounts of explanation, usually demanding some form of pluralism. This commentary examines the arguments offered by Fagan and Woody with respect to explanation and understanding in scientific practice. I begin by scrutinizing Fagan's concept of collaborative explanation, highlighting its distinctive advantages and expressing concern about several of its assumptions. Then I analyze Woody's attempt to reorient discussions of scientific explanation around functional considerations, elaborating on the wider implications of this methodological recommendation. I conclude with reflections on synergies and tensions that emerge when the two papers are juxtaposed and how these draw attention to critical issues that confront ongoing philosophical analyses of scientific explanation.