Kallikrein 4 (hK4) and prostate-specific antigen (PSA) are associated with the loss of E-cadherin and an epithelial-mesenchymal transition (EMT)-like effect in prostate cancer cells

Prostate-specific antigen (PSA) and the related kallikrein family of serine proteases are current or emerging biomarkers for prostate cancer detection and progression. Kallikrein 4 (KLK4/hK4) is of particular interest, as KLK4 mRNA has been shown to be elevated in prostate cancer. In this study, we now show that the comparative expression of hK4 protein in prostate cancer tissues, compared with benign glands, is greater than that of PSA and kallikrein 2 (KLK2/hK2), suggesting that hK4 may play an important functional role in prostate cancer progression in addition to its biomarker potential. To examine the roles that hK4, as well as PSA and hK2, play in processes associated with progression, these kallikreins were separately transfected into the PC-3 prostate cancer cell line, and the consequence of their stable transfection was investigated. PC-3 cells expressing hK4 had a decreased growth rate, but no changes in cell proliferation were observed in the cells expressing PSA or hK2. hK4 and PSA, but not hK2, induced a 2.4-fold and 1.7-fold respective increase, in cellular migration, but not invasion, through Matrigel, a synthetic extracellular matrix. We hypothesised that this increase in motility displayed by the hK4 and PSA-expressing PC-3 cells may be related to the observed change in structure in these cells from a typical rounded epithelial-like cell to a spindle-shaped, more mesenchymal-like cell, with compromised adhesion to the culture surface. Thus, the expression of E-cadherin and vimentin, both associated with an epithelial-mesenchymal transition (EMT), was investigated. E-cadherin protein was lost and mRNA levels were significantly decreased in PC-3 cells expressing hK4 and PSA (10-fold and 7-fold respectively), suggesting transcriptional repression of E-cadherin, while the expression of vimentin was increased in these cells. The loss of E-cadherin and associated increase in vimentin are indicative of EMT and provides compelling evidence that hK4, in particular, and PSA have a functional role in the progression of prostate cancer through their promotion of tumour cell migration.

Adaptive online gradient descent

We study the rates of growth of the regret in online convex optimization. First, we show that a simple extension of the algorithm of Hazan et al eliminates the need for a priori knowledge of the lower bound on the second derivatives of the observed functions. We then provide an algorithm, Adaptive Online Gradient Descent, which interpolates between the results of Zinkevich for linear functions and of Hazan et al for strongly convex functions, achieving intermediate rates between [square root T] and [log T]. Furthermore, we show strong optimality of the algorithm. Finally, we provide an extension of our results to general norms.

Fabrication of Nb2O5 nanosheets for high-rate lithium ion storage applications

Nb2O5 nanosheets are successfully synthesized through a facile hydrothermal reaction and followed heating treatment in air. The structural characterization reveals that the thickness of these sheets is around 50 nm and the length of sheets is 500~800 nm. Such a unique two dimensional structure enables the nanosheet electrode with superior performance during the charge-discharge process, such as high specific capacity (~184 mAh.g-1) and rate capability. Even at a current density of 1 A.g-1, the nanosheet electrode still exhibits a specific capacity of ~90 mAh.g-1. These results suggest the Nb2O5 nanosheet is a promising candidate for high-rate lithium ion storage applications.

Regional avian species declines estimated from volunteer-collected long-term data using List Length Analysis

Long-term systematic population monitoring data sets are rare but are essential in identifying changes in species abundance. In contrast, community groups and natural history organizations have collected many species lists. These represent a large, untapped source of information on changes in abundance but are generally considered of little value. The major problem with using species lists to detect population changes is that the amount of effort used to obtain the list is often uncontrolled and usually unknown. It has been suggested that using the number of species on the list, the "list length," can be a measure of effort. This paper significantly extends the utility of Franklin's approach using Bayesian logistic regression. We demonstrate the value of List Length Analysis to model changes in species prevalence (i.e., the proportion of lists on which the species occurs) using bird lists collected by a local bird club over 40 years around Brisbane, southeast Queensland, Australia. We estimate the magnitude and certainty of change for 269 bird species and calculate the probabilities that there have been declines and increases of given magnitudes. List Length Analysis confirmed suspected species declines and increases. This method is an important complement to systematically designed intensive monitoring schemes and provides a means of utilizing data that may otherwise be deemed useless. The results of List Length Analysis can be used for targeting species of conservation concern for listing purposes or for more intensive monitoring. While Bayesian methods are not essential for List Length Analysis, they can offer more flexibility in interrogating the data and are able to provide a range of parameters that are easy to interpret and can facilitate conservation listing and prioritization. © 2010 by the Ecological Society of America.

A method for optimal fit of patient-specific fracture fixation plates

Anatomically pre-contoured fracture fixation plates are a treatment option for bone fractures. A well-fitting plate can be used as a tool for anatomical reduction of the fractured bone. However, recent studies showed that some plates fit poorly for many patients due to considerable shape variations between bones of the same anatomical site. Therefore, the plates have to be manually fitted and deformed by surgeons to fit each patient optimally. The process is time-intensive and labor-intensive, and could lead to adverse clinical implications such as wound infection or plate failure. This paper proposes a new iterative method to simulate the patient-specific deformation of an optimally fitting plate for pre-operative planning purposes. We further demonstrate the validation of the method through a case study. The proposed method involves the integration of four commercially available software tools, Matlab, Rapidform2006, SolidWorks, and ANSYS, each performing specific tasks to obtain a plate shape that fits optimally for an individual tibia and is mechanically safe. A typical challenge when crossing multiple platforms is to ensure correct data transfer. We present an example of the implementation of the proposed method to demonstrate successful data transfer between the four platforms and the feasibility of the method.

Sub-genomic RNA of defective interfering (D.I.) dengue viral particles is replicated in the same manner as full length genomes

The predicted secondary structure of sub-genomic RNA in dengue virus defective interfering (D.I.) particles from patients, or generated in vitro, resembled that of the 3′ and 5′ regions of wild type dengue virus (DENV) genomes. While these structures in the sub-genomic RNA were found to be essential for its replication, their nucleotide sequences were not, so long as any new sequences maintained wild type RNA secondary structure. These observations suggested that these sub-genomic fragments of RNA from dengue viruses were replicated in the same manner as the full length genomes of their wild type, “helper”, viruses and that they probably represent the smallest fragments of DENV RNA that can be replicated during a natural infection. While D.I. particles containing sub-genomic RNA are completely parasitic, the relationship between wild type and D.I. DENV may be symbiotic, with the D.I. particles enhancing the transmission of infectious DENV.

Opsin clines in butterflies suggest novel roles for insect photopigments

Opsins are ancient molecules that enable animal vision by coupling to a vitamin-derived chromophore to form lightsensitive photopigments. The primary drivers of evolutionary diversification in opsins are thought to be visual tasks related to spectral sensitivity and color vision. Typically, only a few opsin amino acid sites affect photopigment spectral sensitivity. We show that opsin genes of the North American butterfly Limenitis arthemis have diversified along a latitudinal cline, consistent with natural selection due to environmental factors. We sequenced single nucleotide(SNP) polymorphisms in the coding regions of the ultraviolet (UVRh), blue (BRh), and long-wavelength (LWRh) opsin genes from ten butterfly populations along the eastern United States and found that a majority of opsin SNPs showed significant clinal variation. Outlier detection and analysis of molecular variance indicated that many SNPs are under balancing selection and show significant population structure. This contrasts with what we found by analysing SNPs in the wingless and EF-1 alpha loci, and from neutral amplified fragment length polymorphisms, which show no evidence of significant locus-specific or genome-wide structure among populations. Using a combination of functional genetic and physiological approaches, including expression in cell culture, transgenic Drosophila, UV-visible spectroscopy, and optophysiology, we show that key BRh opsin SNPs that vary clinally have almost no effect on spectral sensitivity. Our results suggest that opsin diversification in this butterfly is more consistent with natural selection unrelated to spectral tuning. Some of the clinally varying SNPs may instead play a role in regulating opsin gene expression levels or the thermostability of the opsin protein. Lastly, we discuss the possibility that insect opsins might have important, yet-to-be elucidated, adaptive functions in mediating animal responses to abiotic factors, such as temperature or photoperiod.

The O-specific polysaccharide structure and biosynthetic gene cluster of Yersinia pseudotuberculosis serotype O:11

In the Yersinia pseudotuberculosis serotyping scheme, 21 serotypes are present originating from about 30 different O-factors distributed within the species. With regard to the chemical structures of lipopolysaccharides (LPSs) and the genetic basis of their biosynthesis, a number, but not all, of Y. pseudotuberculosis strains representing different serotypes have been investigated. In order to present an overall picture of the relationship between genetics and structures, we have been working on the genetics and structures of various Y. pseudotuberculosis O-specific polysaccharides (OPSs). Here, we present a structural and genetic analysis of the Y. pseudotuberculosis serotype O:11 OPS. Our results showed that this OPS structure has the same backbone as that of Y. pseudotuberculosis O:1b, but with a 6d-l-Altf side-branch instead of Parf. The 3′ end of the gene cluster is the same as that for O:1b and has the genes for synthesis of the backbone and for processing the completed repeat unit. The 5′ end has genes for synthesis of 6d-l-Altf and its transfer to the repeating unit backbone. The pathway for the synthesis of the 6d-l-Altf appears to be different from that for 6d-l-Altp in Y. enterocolitica O:3. The chemical structure of the O:11 repeating unit is [Figure]

The genetics and structure of the O-specific polysaccharide of Yersinia pseudotuberculosis serotype O:10 and its relationship with Escherichia coli O111 and Salmonella enterica O35

The O-specific polysaccharide (OPS) is a variable constituent of the lipopolysaccharide of Gram-negative bacteria. The polymorphic nature of OPSs within a species is usually first defined serologically, and the current serotyping scheme for Yersinia pseudotuberculosis consists of 21 O serotypes of which 15 have been characterized genetically and structurally. Here, we present the structure and DNA sequence of Y. pseudotuberculosis O:10 OPS. The O unit consists of one residue each of d-galactopyranose, N-acetyl-d-galactosamine (2-amino-2-deoxy-d-galactopyranose) and d-glucopyranose in the backbone, with two colitose (3,6-dideoxy-l-xylo-hexopyranose) side-branch residues. This structure is very similar to that shared by Escherichia coli O111 and Salmonella enterica O35. The gene cluster sequences of these serotypes, however, have only low levels of similarity to that of Y. pseudotuberculosis O:10, although there is significant conservation of gene order. Within Y. pseudotuberculosis, the O10 structure is most closely related to the O:6 and O:7 structures.

Genetic characterisation and structural analysis of the O-specific polysaccharide of Yersinia pseudotuberculosis serotype O:1c

Many, but not all, of the current 21 serotypes of Yersinia pseudotuberculosis have been investigated with regard to the chemical structures of their O-specific polysaccharide (OPS) and the genetic basis of their biosynthesis. Completion of the genetics and structures of the remaining serotypes will enhance our understanding of the emerging relationship between genetics and structures within this species. Here, we present a structural and genetic analysis of the Y. pseudotuberculosis serotype O:1c OPS. Our results showed that this OPS has the same backbone as Y. pseudotuberculosis O:2b, but with a 3,6-dideoxy-D-ribo-hexofuranose (paratofuranose, Parf) side-branch instead of a 3,6-dideoxy-D-xylo-hexopyranose (abequopyranose, Abep). The 3'-end of the gene cluster is the same as for O:2b and has the genes for synthesis of the backbone and for processing the completed repeat unit. The 5'-end of the cluster consists of the same genes as O:1b for synthesis of Parf and a related gene for its transfer to the repeating unit backbone.

The O-specific polysaccharide structure and gene cluster of serotype O:12 of the Yersinia pseudotuberculosis complex, and the identification of a novel L-quinovose biosynthesis gene

A major virulence factor for Yersinia pseudotuberculosis is lipopolysaccharide, including O-polysaccharide (OPS). Currently, the OPS based serotyping scheme for Y. pseudotuberculosis includes 21 known O-serotypes, with genetic and structural data available for 17 of them. The completion of the OPS structures and genetics of this species will enable the visualization of relationships between O-serotypes and allow for analysis of the evolutionary processes within the species that give rise to new serotypes. Here we present the OPS structure and gene cluster of serotype O:12, thus adding one more to the set of completed serotypes, and show that this serotype is present in both Y. pseudotuberculosis and the newly identified Y. similis species. The O:12 structure is shown to include two rare sugars: 4-C[(R)-1-hydroxyethyl]-3,6-dideoxy-d-xylo-hexose (d-yersiniose) and 6-deoxy-l-glucopyranose (l-quinovose). We have identified a novel putative guanine diphosphate (GDP)-l-fucose 4-epimerase gene and propose a pathway for the synthesis of GDP-l-quinovose, which extends the known GDP-l-fucose pathway.

Afferent specific regulation of cortical and subcortical synaptic input to the lateral amygdala by norepinephrine

The lateral amygdala (LA) has been extensively implicated in the neurobiology of conditioned fear paradigms. Norepinepherine (NE), especially its beta receptors, has been implicated in consolidation, reconsolidation and extinction of fear memories, and has been proposed as a potential treatment for PTSD (Berlau and McGaugh, NLM, 2006; Debiec and LeDoux, N, 2005)...

Process quality indicators targeting cognitive impairment to support quality of care for older people with cognitive impairment in emergency departments

Objectives The objective of this study was to develop process quality indicators (PQIs) to support the improvement of care services for older people with cognitive impairment in emergency departments (ED). Methods A structured research approach was taken for the development of PQIs for the care of older people with cognitive impairment in EDs, including combining available evidence with expert opinion (phase 1), a field study (phase 2), and formal voting (phase 3). A systematic review of the literature identified ED processes targeting the specific care needs of older people with cognitive impairment. Existing relevant PQIs were also included. By integrating the scientific evidence and clinical expertise, new PQIs were drafted and, along with the existing PQIs, extensively discussed by an advisory panel. These indicators were field tested in eight hospitals using a cohort of older persons aged 70 years and older. After analysis of the field study data (indicator prevalence, variability across sites), in a second meeting, the advisory panel further defined the PQIs. The advisory panel formally voted for selection of those PQIs that were most appropriate for care evaluation. Results In addition to seven previously published PQIs relevant to the care of older persons, 15 new indicators were created. These 22 PQIs were then field tested. PQIs designed specifically for the older ED population with cognitive impairment were only scored for patients with identified cognitive impairment. Following formal voting, a total of 11 PQIs were included in the set. These PQIs targeted cognitive screening, delirium screening, delirium risk assessment, evaluation of acute change in mental status, delirium etiology, proxy notification, collateral history, involvement of a nominated support person, pain assessment, postdischarge follow-up, and ED length of stay. Conclusions This article presents a set of PQIs for the evaluation of the care for older people with cognitive impairment in EDs. The variation in indicator triggering across different ED sites suggests that there are opportunities for quality improvement in care for this vulnerable group. Applied PQIs will identify an emergency services' implementation of care strategies for cognitively impaired older ED patients. Awareness of the PQI triggers at an ED level enables implementation of targeted interventions to improve any suboptimal processes of care. Further validation and utility of the indicators in a wider population is now indicated.

Paralog-specific kinase inhibition of FGFR4: Adding to the arsenal of anti-FGFR agents

In this issue of Cancer Discovery, Hagel and colleagues report the design and the in vitro and in vivo activity of a novel, irreversible, paralog-specific kinase inhibitor of FGFR4, BLU9931. This compound binds covalently to a cysteine residue in the hinge region of FGFR4 but not in FGFR1-3. BLU9931 induces tumor shrinkage in hepatocellular carcinoma models that express a functioning ligand/receptor complex consisting of FGF19/FGFR4/KLB and adds to a growing list of anti-FGFR4 agents.

Telomere length in circulating leukocytes is associated with lung function and disease

Several clinical studies suggest the involvement of premature ageing processes in chronic obstructive pulmonary disease (COPD). Using an epidemiological approach, we studied whether accelerated ageing indicated by telomere length, a marker of biological age, is associated with COPD and asthma, and whether intrinsic age-related processes contribute to the interindividual variability of lung function. Our meta-analysis of 14 studies included 934 COPD cases with 15 846 controls defined according to the Global Lungs Initiative (GLI) criteria (or 1189 COPD cases according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria), 2834 asthma cases with 28 195 controls, and spirometric parameters (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC) of 12 595 individuals. Associations with telomere length were tested by linear regression, adjusting for age, sex and smoking status. We observed negative associations between telomere length and asthma (β= −0.0452, p=0.024) as well as COPD (β= −0.0982, p=0.001), with associations being stronger and more significant when using GLI criteria than those of GOLD. In both diseases, effects were stronger in females than males. The investigation of spirometric indices showed positive associations between telomere length and FEV1 (p=1.07×10−7), FVC (p=2.07×10−5), and FEV1/FVC (p=5.27×10−3). The effect was somewhat weaker in apparently healthy subjects than in COPD or asthma patients. Our results provide indirect evidence for the hypothesis that cellular senescence may contribute to the pathogenesis of COPD and asthma, and that lung function may reflect biological ageing primarily due to intrinsic processes, which are likely to be aggravated in lung diseases.