Miracle-dz/UniFAR-FTUs huggingface dataset:
Hired Guns: Local Government Mergers in New South Wales and the KPMG Modelling Report

Across the developed world, including Australia, public policymaking now rests heavily on commissioned reports generated by for-profit consultants, contrasting starkly with the earlier customary reliance on the civil service to provide informed policy advice to political decision makers. Dependence on commercial consultants is problematic, especially given the moral hazards involved in ‘hired guns’ providing support for policy ‘solutions’ desired by their political paymasters. This paper provides a vivid illustration of some of the dangers flowing from the use of consultants by examining the methodology employed by KPMG in its empirical analysis of the pecuniary consequences of proposed municipal mergers as part of the New South Wales’ (NSW) Government's Fit for the Future local government reform program. We show that the KPMG (2016) modelling methodology is awash with errors which render its conclusions on the financial viability of the NSW merger proposals fatally flawed.
Research design and statistics in biomechanics and motor control

Biomechanics and motor control researchers measure how the body moves and interacts with its environment. The aim of this review paper is to consider some key issues in research methods in biomechanics and motor control. The review is organized into four sections: proposing, conducting, analysing and reporting research. In the first of these, we emphasize the importance of defining a worthy research question and of planning the study before its implementation to prevent later difficulties in the analysis and interpretation of data. In the second section, we cover selection of trial sizes and suggest that using three trials or more may be beneficial to provide more ‘representative’ and valid data. The third section on analysis of data concentrates on effect size statistics, qualitative and numerical trend analysis and cross-correlations. As sample sizes are often small, the use of effect size is recommended to support the results of statistical significance testing. In using cross-correlations, we recommend that scatterplots of one variable against the other, with the identified time lag included, be inspected to confirm that the linear relationship assumption underpinning this statistic is met and, if appropriate, that a linearity transformation be applied. Finally, we consider important information related to the issues above that should be included when reporting research. We recommend reporting checks or corrections for violations of underpinning assumptions, and the effect of these checks or corrections, to assist in advancing knowledge in biomechanics and motor control.
Row planting teff in Ethiopia: Impact on farm-level profitability and labor allocation

Improved technologies are increasingly promoted to farmers in sub-Saharan-African countries to address low agricultural productivity in their staple crops. There is, however, a lack of evidence on how adoption affects farmers’ labor use and profitability at the farm level, as well as the importance gender roles play, all essential drivers for the successful up-scaling of the use of the improved technologies. This paper analyses the labor and profitability impact of the recently introduced row planting technology in teff production in Ethiopia. Based on agronomic evidence in experimental settings, the Government of Ethiopia has focused extension efforts on promoting the widespread uptake of row planting to address low teff yields, replacing the traditional broadcasting method of plant teff. Using an innovative Randomized Controlled Trial set-up, we show that the implementation of row planting at the farm level significantly increases total labor use, but not teff yields, relative to broadcast planting, resulting in a substantial drop in labor productivity when adopting row planting. Moreover, the implementation of row planting has important consequences for inter- and intra-household labor allocation, with relatively more use of non-family labor. The adoption of row planting was further found not to be profitable for farmers in the first year of the promotion campaign, seemingly explaining the limited success in up-scaling the adoption of the technology by farmers in the second year of the program.
Evidence that Tristetraprolin Binds to AU-Rich Elements and Promotes the Deadenylation and Destabilization of Tumor Necrosis Factor Alpha mRNA

ABSTRACT Mice deficient in tristetraprolin (TTP), the prototype of a family of CCCH zinc finger proteins, develop an inflammatory syndrome mediated by excess tumor necrosis factor alpha (TNF-α). Macrophages derived from these mice oversecrete TNF-α, by a mechanism that involves stabilization of TNF-α mRNA, and TTP can bind directly to the AU-rich element (ARE) in TNF-α mRNA (E. Carballo, W. S. Lai, and P. J. Blackshear, Science 281:1001–1005, 1998). We show here that TTP binding to the TNF-α ARE is dependent upon the integrity of both zinc fingers, since mutation of a single cysteine residue in either zinc finger to arginine severely attenuated the binding of TTP to the TNF-α ARE. In intact cells, TTP at low expression levels promoted a decrease in size of the TNF-α mRNA as well as a decrease in its amount; at higher expression levels, the shift to a smaller TNF-α mRNA size persisted, while the accumulation of this smaller species increased. RNase H experiments indicated that the shift to a smaller size was due to TTP-promoted deadenylation of TNF-α mRNA. This CCCH protein is likely to be important in the deadenylation and degradation of TNF-α mRNA and perhaps other ARE-containing mRNAs, both in normal physiology and in certain pathological conditions.
Bruton’s Tyrosine Kinase Is Involved in miR-346-Related Regulation of IL-18 Release by Lipopolysaccharide-Activated Rheumatoid Fibroblast-Like Synoviocytes 1

MicroRNAs (miRNAs) have emerged as key players in the regulation of expression of target mRNAs expression. They have been associated with diverse biological processes, and recent studies have demonstrated that miRNAs play a role in inflammatory responses. We reported previously that LPS-activated fibroblast-like synoviocytes (FLS) isolated from rheumatoid arthritis (RA) patients express IL-18 mRNA but they do not release IL-18. Based on the observation that this inhibition was due to a rapid degradation of IL-18 mRNA, our group has conducted a study to identify miRNAs that could play a role in the “antiinflammatory” response of LPS-activated RA FLS. LPS challenge modulated the expression of 63 miRNAs as assessed by microarray analysis. Fifteen miRNAs were up-regulated, including miR-346, for which overexpression upon LPS treatment was validated by quantitative RT-PCR. We then transfected FLS with an antisense oligonucleotide targeting miR-346 and found that, in these conditions, IL-18 release could be measured upon LPS activation of FLS. Moreover, we also demonstrated that miR-346 indirectly regulated IL-18 release by indirectly inhibiting LPS-induced Bruton’s tyrosine kinase expression in LPS-activated RA FLS. These findings suggest that miRNAs function as regulators that help to fine-tune the inflammatory response in RA.
Functional Asymmetries of Proteasome Translocase Pore*

Background: Proteasomes have six non-identical ATPases that move and unfold protein substrates. Results: Mutating homologous substrate contact residues of each ATPase has diverse effects on degradation and cell growth. Conclusion: Although homologous, each of the six has distinguishable functions. Significance: Structurally similar elements within a complex molecular machine can evolve distinct tasks, diversifying the range of accessible cellular responses. Degradation by proteasomes involves coupled translocation and unfolding of its protein substrates. Six distinct but paralogous proteasome ATPase proteins, Rpt1 to -6, form a heterohexameric ring that acts on substrates. An axially positioned loop (Ar-Φ loop) moves in concert with ATP hydrolysis, engages substrate, and propels it into a proteolytic chamber. The aromatic (Ar) residue of the Ar-Φ loop in all six Rpts of S. cerevisiae is tyrosine; this amino acid is thought to have important functional contacts with substrate. Six yeast strains were constructed and characterized in which Tyr was individually mutated to Ala. The mutant cells were viable and had distinct phenotypes. rpt3, rpt4, and rpt5 Tyr/Ala mutants, which cluster on one side of the ATPase hexamer, were substantially impaired in their capacity to degrade substrates. In contrast, rpt1, rpt2, and rpt6 mutants equaled or exceeded wild type in degradation activity. However, rpt1 and rpt6 mutants had defects that limited cell growth or viability under conditions that stressed the ubiquitin proteasome system. In contrast, the rpt3 mutant grew faster than wild type and to a smaller size, a defect that has previously been associated with misregulation of G1 cyclins. This rpt3 phenotype probably results from altered degradation of cell cycle regulatory proteins. Finally, mutation of five of the Rpt subunits increased proteasome ATPase activity, implying bidirectional coupling between the Ar-Φ loop and the ATP hydrolysis site. The present observations assign specific functions to individual Rpt proteins and provide insights into the diverse roles of the axial loops of individual proteasome ATPases.
Needle-tissue interaction modeling using ultrasound-based motion estimation: Phantom study

Needle insertion simulators find use in a number of medical interventions, such as prostate brachytherapy. A needle insertion simulator has three main components: the needle model, the tissue model, and the model of interaction between the needle and the tissue. In this paper, a new methodology is introduced for the joint modeling of tissue and needle-tissue interactions. The approach consists of the measurement of tissue motion using ultrasound, and of the needle position and base force. Tissue motion is determined using a correlation-based algorithm that processes the ultrasound radiofrequency data. The tissue elastic parameters and the parameters of the tissue-needle interaction model are determined by using numerical optimization to match the response of the needle insertion model to the measured data. Phantom experiments were carried out in which a brachytherapy needle was inserted into a two-layer non-homogeneous phantom mimicking a prostate and its surrounding tissue. Experimental results show good agreement with the model obtained. In particular, the parameters of a three-parameter force model were identified for each layer of the phantom to fit the measured force to the simulated one. Also, the Young's modulus of each layer was identified to match the measured and simulated nodal axial displacements. This is the first report of the use of ultrasound radiofrequency data to characterize tissue motion during needle insertion. As the method is non-invasive and does not involve ionizing radiation, its application in patient studies is feasible.
The Generalized Higher Criticism for Testing SNP-Set Effects in Genetic Association Studies

ABSTRACT It is of substantial interest to study the effects of genes, genetic pathways, and networks on the risk of complex diseases. These genetic constructs each contain multiple SNPs, which are often correlated and function jointly, and might be large in number. However, only a sparse subset of SNPs in a genetic construct is generally associated with the disease of interest. In this article, we propose the generalized higher criticism (GHC) to test for the association between an SNP set and a disease outcome. The higher criticism is a test traditionally used in high-dimensional signal detection settings when marginal test statistics are independent and the number of parameters is very large. However, these assumptions do not always hold in genetic association studies, due to linkage disequilibrium among SNPs and the finite number of SNPs in an SNP set in each genetic construct. The proposed GHC overcomes the limitations of the higher criticism by allowing for arbitrary correlation structures among the SNPs in an SNP-set, while performing accurate analytic p-value calculations for any finite number of SNPs in the SNP-set. We obtain the detection boundary of the GHC test. We compared empirically using simulations the power of the GHC method with existing SNP-set tests over a range of genetic regions with varied correlation structures and signal sparsity. We apply the proposed methods to analyze the CGEM breast cancer genome-wide association study. Supplementary materials for this article are available online.
Dosimetric advantages of IMPT over IMRT for laser-accelerated proton beams

As a clinical application of an exciting scientific breakthrough, a compact and cost-efficient proton therapy unit using high-power laser acceleration is being developed at Fox Chase Cancer Center. The significance of this application depends on whether or not it can yield dosimetric superiority over intensity-modulated radiation therapy (IMRT). The goal of this study is to show how laser-accelerated proton beams with broad energy spreads can be optimally used for proton therapy including intensity-modulated proton therapy (IMPT) and achieve dosimetric superiority over IMRT for prostate cancer. Desired energies and spreads with a varying δE/E were selected with the particle selection device and used to generate spread-out Bragg peaks (SOBPs). Proton plans were generated on an in-house Monte Carlo-based inverse-planning system. Fifteen prostate IMRT plans previously used for patient treatment have been included for comparison. Identical dose prescriptions, beam arrangement and consistent dose constrains were used for IMRT and IMPT plans to show the dosimetric differences that were caused only by the different physical characteristics of proton and photon beams. Different optimization constrains and beam arrangements were also used to find optimal IMPT. The results show that conventional proton therapy (CPT) plans without intensity modulation were not superior to IMRT, but IMPT can generate better proton plans if appropriate beam setup and optimization are used. Compared to IMRT, IMPT can reduce the target dose heterogeneity ((D5–D95)/D95) by up to 56%. The volume receiving 65 Gy and higher (V65) for the bladder and the rectum can be reduced by up to 45% and 88%, respectively, while the volume receiving 40 Gy and higher (V40) for the bladder and the rectum can be reduced by up to 49% and 68%, respectively. IMPT can also reduce the whole body non-target tissue dose by up to 61% or a factor 2.5. This study has shown that the laser accelerator under development has a potential to generate high-quality proton beams for cancer treatment. Significant improvement in target dose uniformity and normal tissue sparing as well as in reduction of whole body dose can be achieved by IMPT with appropriate optimization and beam setup.
Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease

Prion diseases in humans and animals are invariably fatal. Prions are composed of a disease-causing isoform (PrPSc) of the normal host prion protein (PrPC) and replicate by stimulating the conversion of PrPC into nascent PrPSc. We report here that tricyclic derivatives of acridine and phenothiazine exhibit half-maximal inhibition of PrPSc formation at effective concentrations (EC50) between 0.3 μM and 3 μM in cultured cells chronically infected with prions. The EC50 for chlorpromazine was 3 μM, whereas quinacrine was 10 times more potent. A variety of 9-substituted, acridine-based analogues of quinacrine were synthesized, which demonstrated variable antiprion potencies similar to those of chlorpromazine and emphasized the importance of the side chain in mediating the inhibition of PrPSc formation. Thus, our studies show that tricyclic compounds with an aliphatic side chain at the middle ring moiety constitute a new class of antiprion reagents. Because quinacrine and chlorpromazine have been used in humans for many years as antimalarial and antipsychotic drugs, respectively, and are known to pass the blood–brain barrier, we suggest that they are immediate candidates for the treatment of Creutzfeldt–Jakob disease and other prion diseases.
Efficacy, Tolerability and Influence on "Quality of Life" of Nifedipine GITS versus Amlodipine in Elderly Patients with Mild-moderate Hypertension

Objective: The main purpose of this study was to compare efficacy, tolerability and influence on quality of life (QOL) of nifedipine gastrointestinal therapeutic system (NI) 30-60 mg once a day vs amlodipine (AM) 5-10 mg once a day in elderly patients with mild-moderate hypertension. Design: This was a randomized, double-blind, parallel-group, multicenter study. After a 2-week single-blind placebo run-in, patients were randomized to either NI 30 mg or AM 5 mg. Responders continued on the same dosage for 16 additional weeks, while non-responders were titrated to 60 mg NI or 10 mg AM. Methods: Blood pressure was measured by mercury sphygmomanometer and efficacy equivalence of NI and AM tested by covariance analysis. Diastolic blood pressure (DBP) was the primary efficacy parameter, its baseline value being taken as covariate while centers effect and treatment interaction were included as fixed effects in the analysis model. The secondary efficacy variables systolic blood pressure (SBP) and scores for QOL were analyzed according to the same model. Results: At the end of the study, overall mean DBPs, calculated as least-square means (LSMEANS), in the "by protocol" population were 87.5 mmHg for NI and 86.7 for AM (difference 0.8 mmHg with 90% CI-1.2 to 2.8 mmHg). In the "by intention to treat" (ITT) population LSMEANS were 87.6 mmHg for NI and 86.4 mmHg for AM (difference 1.2 mmHg with 90% CI-0.6 to 3.1 mmHg). SBP LSMEANS in the "by protocol" population were 147.7 mmHg for NI and 147.3 mmHg for AM (difference 0.3 mmHg, with 90% CI-3.7 to 4.3); corresponding values in the "by ITT" population were 148.0 mmHg for NI and 147.2 for AM (difference 0.8 mmHg, with 90% CI-2.8 to 4.6). Mean values for QOL parameters were not significantly different. A total of 173 episodes of adverse events were documented in 54 patients (26 NI and 28 AM), dropouts were 15 (20% of group) on NI and 21 (28%) on AM. Conclusions: NI 30-60 mg was shown to be as efficacious and safe as AM 5-10 mg in elderly patients with mild-moderate hypertension. QOL improved compared to baseline with no significant difference between the two drugs, thus confirming a positive class effect for calcium antagonists.
Development of a PCR-based method for the detection of Opisthorchis viverrini in experimentally infected hamsters

Opisthorchis viverrini infection is an endemic disease that causes a serious public health problem in southeast Asia, especially in northeast Thailand. We have developed a PCR method using a pair of primers named OV-6F/OV-6R for detecting O. viverrini eggs in stool samples and compared it with Stoll's egg-count method. The primers were designed based on the pOV-A6 specific DNA probe sequence which gave a 330 base pair product. The PCR method can detect a single egg in artificially inoculated faeces or as little as 2×10-17ng of O. viverrini genomic DNA. The method gave 100% sensitivity in all hamster groups except in animals exposed to the lowest intensity of infection (1 metacercaria/hamster). In the first month of infection, the PCR method was more sensitive than using the egg-count method in all infected groups especially in the light infections. The PCR method was also successfully used in monitoring a therapeutic study. Since the PCR method showed no cross-reaction with Heterophyid flukes, it can be useful for specific identification of O. viverrini eggs in stool samples without the risk of false positives. It also has great potential for application in clinical epidemiological studies.
Autoradiographic localization of endothelin‐1 binding sites in human colonic cancer tissue

Endothelin‐1, a potent vasoconstrictor, has been reported to stimulate mitogenesis in various types of normal and neoplastic cells and to be involved in neurotransmission. Recently, many human cancer cell lines, including those from the human colon, have been shown to produce endothelin. In this study, the occurrence of endothelin‐1 binding sites was investigated in human colonic cancer tissues using in vitro autoradiography. Specific [125I]endothelin‐1 binding sites were identified over tumour vessels and stromal tissues surrounding cancer cell nests. The distribution was heterogeneous, and dense silver grains were localized, especially over clusters of fibroblasts adjacent to the cancer cell nests. Endothelin binding was minimal in the cancer cells, as in the normal crypt epithelium. Quantitative analysis of the autoradiographs demonstrated high affinity (Kd = 0·50 ± 0·06 nM; mean ± SEM) binding sites, with a maximum binding capacity (Bmax) of 40 ± 3·2 amol/mm2 in the cancer tissues. Our results provide evidence that specific endothelin‐1 binding sites are expressed in the stromal tissues including tumour vessels, fibroblasts, and nerve fibres. Endothelin‐1 may play a modulatory role in blood supply, mitogenesis, and neurotransmission in a paracrine fashion through the stromal components in human colonic cancers.
Sex differences in repetitive stereotyped behaviors in autism: Implications for genetic liability

The implications of the well known sex differences in the prevalence of autism spectrum disorder (ASD) are not well understood. The aim of this paper was to investigate whether these differences might be associated with differences in genetic liability. Individuals with ASD (970 families, 2,028 individuals) were recruited as part of the Autism Genome Project (AGP). The families were differentiated into families containing a female (either female–female or male–female) and those with only males. If the sex with the lower prevalence is associated with a greater genetic liability necessary to cross sex‐specific thresholds, the males from female containing families should be more severely affected than males from male only families. Affected subjects from the different types of families with ASD were sampled and compared on the social reciprocity and repetitive behavior scores from the Autism Diagnostic Interview‐Revised (ADI‐R). In general, females had lower repetitive behavior scores than males. More importantly, males from female containing families had higher repetitive behavior scores than males from male–male families. No such differences were apparent on the social reciprocity scores. These results support the hypothesis of a multiple threshold model of genetic liability of ASD with females having a higher liability for affectation status, at least on the repetitive behavior dimension of the disorder. These data also support the dissociation of the different phenotypic dimensions of ASD in terms of its genetic architecture. The implications of these results for linkage and association studies are discussed. © 2011 Wiley Periodicals, Inc.