Mechanical properties of a Gum-type Ti-Nb-Zr-Fe-O alloy

A new Gum-type alloy (Ti-Nb-Zr-Fe-O) in which Fe is used instead of Ta was subjected to a particular thermomechanical processing scheme to assess whether its mechanical characteristics (fine β-grains with high strength and low modulus) render it suitable as a biomedical implant material. After a homogenization treatment followed by cold-rolling with 50% reduction, the specimens were subjected to one of three different recrystallization treatments at 1073, 1173, and 1273 K. The structural and mechanical properties of all of the treated specimens were analyzed. The mechanical characterization included tensile tests, microhardness determinations, and fractography by scanning electron microscopy. The possible deformation mechanisms were discussed using the Bo-Md diagram. By correlating all of the experimental results, we concluded that the most promising processing variant corresponds to recrystallization at 1073 K, which can provide suitable mechanical characteristics for this type of alloys:high yield and ultimate tensile strengths (1038 and 1083 MPa, respectively), a low modulus of elasticity (62 GPa), and fine crystalline grain size (approximately 50 μm).     

Pluralism and objectivity: Exposing and breaking a circle

The paper argues that Helen Longino’s pluralism implies circularity as it claims a preferably high number of qualified contributions to any scientific discussion that aims for objectivity, but does not regard the question who or what sets and employs the standards that rule the decision who is qualified to contribute and who is not. Therefore, objectivity is premised for a process that is to generate that very objectivity. Philip Kitcher’s ideal of democratization of science seems only to bypass the problem by introducing ideal deliberators tutored by appropriate experts, as for the implementation of this ideal the deliberators and experts, again, would have to be appointed by someone. However, Kitcher’s approach is based on a Rawlsian egalitarism and in this sense calls for political intrusion which could be based on case-by-case decisions. This offers a solution. I will illuminate the problem by some examples from climatology and demonstrate how Kitcher’s approach can help to tackle the problem by a final case study of pluralism in the Intergovernmental Panel on Climate Change.     

Influence of fire and juniper encroachment on birds in high-elevation sagebrush steppe

We examined relationships between high-elevation sagebrush ( Artemisia spp.) steppe habitats altered by prescribed fire and western juniper ( Juniperus occidentalis ) encroachment on breeding distributions of Brewer's Sparrows ( Spizella breweri ), Vesper Sparrows ( Pooecetes gramineus ), Green-tailed Towhees ( Pipilo chlorurus ), and Sage Thrashers ( Oreoscoptes montanus ) on Steens Mountain in southeastern Oregon. In 2000 we conducted fixed-radius point count surveys at 172 sites encompassing burned and unburned sagebrush habitat and a range of juniper densities. For each bird species we developed habitat models using local variables measured in the field and landscape variables derived from remotely sensed data. Akaike's Information Criterion (AIC c ) was used to select the best-approximating model from a suite of a priori candidate models. Brewer's Sparrows, Sage Thrashers, and Green-tailed Towhees were positively related to increasing local sagebrush cover or percent sagebrush in the landscape, whereas Vesper Sparrows were negatively associated with sagebrush cover and positively related to increases in sagebrush fragmentation at local and landscape scales. Including a measure of juniper encroachment substantially improved models for all species in the analysis. Green-tailed Towhees showed a curvilinear response to the amount of juniper in the landscape. All other species showed a strong negative relationship with juniper. Our results indicate that, although changes in sagebrush habitat associated with fire had a negative influence on sagebrush birds, juniper encroachment due to fire suppression also impacted this high-elevation sagebrush bird community.     

Defining the core Arabidopsis thaliana root microbiome

Land plants associate with a root microbiota distinct from the complex microbial community present in surrounding soil. The microbiota colonizing the rhizosphere (immediately surrounding the root) and the endophytic compartment (within the root) contribute to plant growth, productivity, carbon sequestration and phytoremediation. Colonization of the root occurs despite a sophisticated plant immune system, suggesting finely tuned discrimination of mutualists and commensals from pathogens. Genetic principles governing the derivation of host-specific endophyte communities from soil communities are poorly understood. Here we report the pyrosequencing of the bacterial 16S ribosomal RNA gene of more than 600 Arabidopsis thaliana plants to test the hypotheses that the root rhizosphere and endophytic compartment microbiota of plants grown under controlled conditions in natural soils are sufficiently dependent on the host to remain consistent across different soil types and developmental stages, and sufficiently dependent on host genotype to vary between inbred Arabidopsis accessions. We describe different bacterial communities in two geochemically distinct bulk soils and in rhizosphere and endophytic compartments prepared from roots grown in these soils. The communities in each compartment are strongly influenced by soil type. Endophytic compartments from both soils feature overlapping, low-complexity communities that are markedly enriched in Actinobacteria and specific families from other phyla, notably Proteobacteria. Some bacteria vary quantitatively between plants of different developmental stage and genotype. Our rigorous definition of an endophytic compartment microbiome should facilitate controlled dissection of plant-microbe interactions derived from complex soil communities.     

SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors

The molecular determinants of malignant cell behaviours in breast cancer remain only partially understood. Here we show that SHARP1 (also known as BHLHE41 or DEC2) is a crucial regulator of the invasive and metastatic phenotype in triple-negative breast cancer (TNBC), one of the most aggressive types of breast cancer. SHARP1 is regulated by the p63 metastasis suppressor and inhibits TNBC aggressiveness through inhibition of hypoxia-inducible factor 1α (HIF-1α) and HIF-2α (HIFs). SHARP1 opposes HIF-dependent TNBC cell migration in vitro, and invasive or metastatic behaviours in vivo. SHARP1 is required, and sufficient, to limit expression of HIF-target genes. In primary TNBC, endogenous SHARP1 levels are inversely correlated with those of HIF targets. Mechanistically, SHARP1 binds to HIFs and promotes HIF proteasomal degradation by serving as the HIF-presenting factor to the proteasome. This process is independent of pVHL (von Hippel-Lindau tumour suppressor), hypoxia and the ubiquitination machinery. SHARP1 therefore determines the intrinsic instability of HIF proteins to act in parallel to, and cooperate with, oxygen levels. This work sheds light on the mechanisms and pathways by which TNBC acquires invasiveness and metastatic propensity.     

Mutations in DMRT3 affect locomotion in horses and spinal circuit function in mice

Locomotion in mammals relies on a central pattern-generating circuitry of spinal interneurons established during development that coordinates limb movement. These networks produce left-right alternation of limbs as well as coordinated activation of flexor and extensor muscles. Here we show that a premature stop codon in the DMRT3 gene has a major effect on the pattern of locomotion in horses. The mutation is permissive for the ability to perform alternate gaits and has a favourable effect on harness racing performance. Examination of wild-type and Dmrt3-null mice demonstrates that Dmrt3 is expressed in the dI6 subdivision of spinal cord neurons, takes part in neuronal specification within this subdivision, and is critical for the normal development of a coordinated locomotor network controlling limb movements. Our discovery positions Dmrt3 in a pivotal role for configuring the spinal circuits controlling stride in vertebrates. The DMRT3 mutation has had a major effect on the diversification of the domestic horse, as the altered gait characteristics of a number of breeds apparently require this mutation.     

RNA sequencing of pancreatic circulating tumour cells implicates WNT signalling in metastasis

Circulating tumour cells (CTCs) shed into blood from primary cancers include putative precursors that initiate distal metastases. Although these cells are extraordinarily rare, they may identify cellular pathways contributing to the blood-borne dissemination of cancer. Here, we adapted a microfluidic device for efficient capture of CTCs from an endogenous mouse pancreatic cancer model and subjected CTCs to single-molecule RNA sequencing, identifying Wnt2 as a candidate gene enriched in CTCs. Expression of WNT2 in pancreatic cancer cells suppresses anoikis, enhances anchorage-independent sphere formation, and increases metastatic propensity in vivo. This effect is correlated with fibronectin upregulation and suppressed by inhibition of MAP3K7 (also known as TAK1) kinase. In humans, formation of non-adherent tumour spheres by pancreatic cancer cells is associated with upregulation of multiple WNT genes, and pancreatic CTCs revealed enrichment for WNT signalling in 5 out of 11 cases. Thus, molecular analysis of CTCs may identify candidate therapeutic targets to prevent the distal spread of cancer.     

Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17

Frontotemporal dementia (FTD) is the second most common cause of dementia in people under the age of 65 years. A large proportion of FTD patients (35-50%) have a family history of dementia, consistent with a strong genetic component to the disease. In 1998, mutations in the gene encoding the microtubule-associated protein tau (MAPT) were shown to cause familial FTD with parkinsonism linked to chromosome 17q21 (FTDP-17). The neuropathology of patients with defined MAPT mutations is characterized by cytoplasmic neurofibrillary inclusions composed of hyperphosphorylated tau. However, in multiple FTD families with significant evidence for linkage to the same region on chromosome 17q21 (D17S1787-D17S806), mutations in MAPT have not been found and the patients consistently lack tau-immunoreactive inclusion pathology. In contrast, these patients have ubiquitin (ub)-immunoreactive neuronal cytoplasmic inclusions and characteristic lentiform ub-immunoreactive neuronal intranuclear inclusions. Here we demonstrate that in these families, FTD is caused by mutations in progranulin (PGRN) that are likely to create null alleles. PGRN is located 1.7 Mb centromeric of MAPT on chromosome 17q21.31 and encodes a 68.5-kDa secreted growth factor involved in the regulation of multiple processes including development, wound repair and inflammation. PGRN has also been strongly linked to tumorigenesis. Moreover, PGRN expression is increased in activated microglia in many neurodegenerative diseases including Creutzfeldt-Jakob disease, motor neuron disease and Alzheimer's disease. Our results identify mutations in PGRN as a cause of neurodegenerative disease and indicate the importance of PGRN function for neuronal survival.     

Structural basis for gene regulation by a thiamine pyrophosphate-sensing riboswitch

Riboswitches are metabolite-sensing RNAs, typically located in the non-coding portions of messenger RNAs, that control the synthesis of metabolite-related proteins. Here we describe a 2.05 angstroms crystal structure of a riboswitch domain from the Escherichia coli thiM mRNA that responds to the coenzyme thiamine pyrophosphate (TPP). TPP is an active form of vitamin B1, an essential participant in many protein-catalysed reactions. Organisms from all three domains of life, including bacteria, plants and fungi, use TPP-sensing riboswitches to control genes responsible for importing or synthesizing thiamine and its phosphorylated derivatives, making this riboswitch class the most widely distributed member of the metabolite-sensing RNA regulatory system. The structure reveals a complex folded RNA in which one subdomain forms an intercalation pocket for the 4-amino-5-hydroxymethyl-2-methylpyrimidine moiety of TPP, whereas another subdomain forms a wider pocket that uses bivalent metal ions and water molecules to make bridging contacts to the pyrophosphate moiety of the ligand. The two pockets are positioned to function as a molecular measuring device that recognizes TPP in an extended conformation. The central thiazole moiety is not recognized by the RNA, which explains why the antimicrobial compound pyrithiamine pyrophosphate targets this riboswitch and downregulates the expression of thiamine metabolic genes. Both the natural ligand and its drug-like analogue stabilize secondary and tertiary structure elements that are harnessed by the riboswitch to modulate the synthesis of the proteins coded by the mRNA. In addition, this structure provides insight into how folded RNAs can form precision binding pockets that rival those formed by protein genetic factors.