Using geographically weighted regression to explore the spatially heterogeneous spread of bovine tuberculosis in England and Wales

An understanding of the factors that affect the spread of endemic bovine tuberculosis (bTB) is critical for the development of measures to stop and reverse this spread. Analyses of spatial data need to account for the inherent spatial heterogeneity within the data, or else spatial autocorrelation can lead to an overestimate of the significance of variables. This study used three methods of analysis—least-squares linear regression with a spatial autocorrelation term, geographically weighted regression (GWR) and boosted regression tree (BRT) analysis—to identify the factors that influence the spread of endemic bTB at a local level in England and Wales. The linear regression and GWR methods demonstrated the importance of accounting for spatial differences in risk factors for bTB, and showed some consistency in the identification of certain factors related to flooding, disease history and the presence of multiple genotypes of bTB. This is the first attempt to explore the factors associated with the spread of endemic bTB in England and Wales using GWR. This technique improves on least-squares linear regression approaches by identifying regional differences in the factors associated with bTB spread. However, interpretation of these complex regional differences is difficult and the approach does not lend itself to predictive models which are likely to be of more value to policy makers. Methods such as BRT may be more suited to such a task. Here we have demonstrated that GWR and BRT can produce comparable outputs

Children with cerebral palsy exhibit greater and more regular postural sway than typically developing children

Following recent advances in the analysis of centre-of-pressure (COP) recordings, we examined the structure of COP trajectories in ten children (nine in the analyses) with cerebral palsy (CP) and nine typically developing (TD) children while standing quietly with eyes open (EO) and eyes closed (EC) and with concurrent visual COP feedback (FB). In particular, we quantified COP trajectories in terms of both the amount and regularity of sway. We hypothesised that: (1) compared to TD children, CP children exhibit a greater amount of sway and more regular sway and (2) concurrent visual feedback (creating an external functional context for postural control, inducing a more external focus of attention) decreases both the amount of sway and sway regularity in TD and CP children alike, while closing the eyes has opposite effects. The data were largely in agreement with both hypotheses. Compared to TD children, the amount of sway tended to be larger in CP children, while sway was more regular. Furthermore, the presence of concurrent visual feedback resulted in less regular sway compared to the EO and EC conditions. This effect was less pronounced in the CP group where posturograms were most regular in the EO condition rather than in the EC condition, as in the control group. Nonetheless, we concluded that CP children might benefit from therapies involving postural tasks with an external functional context for postural control

Small-Molecule Synthetic Compound Norcantharidin Reverses Multi-Drug Resistance by Regulating Sonic Hedgehog Signaling in Human Breast Cancer Cells

Multi-drug resistance (MDR), an unfavorable factor compromising treatment efficacy of anticancer drugs, involves upregulated ATP binding cassette (ABC) transporters and activated Sonic hedgehog (Shh) signaling. By preparing human breast cancer MCF-7 cells resistant to doxorubicin (DOX), we examined the effect and mechanism of norcantharidin (NCTD), a small-molecule synthetic compound, on reversing multidrug resistance. The DOX-prepared MCF-7R cells also possessed resistance to vinorelbine, characteristic of MDR. At suboptimal concentration, NCTD significantly inhibited the viability of DOX-sensitive (MCF-7S) and DOX-resistant (MCF-7R) cells and reversed the resistance to DOX and vinorelbine. NCTD increased the intracellular accumulation of DOX in MCF-7R cells and suppressed the upregulated the mdr-1 mRNA, P-gp and BCRP protein expression, but not the MRP-1. The role of P-gp was strengthened by partial reversal of the DOX and vinorelbine resistance by cyclosporine A. NCTD treatment suppressed the upregulation of Shh expression and nuclear translocation of Gli-1, a hallmark of Shh signaling activation in the resistant clone. Furthermore, the Shh ligand upregulated the expression of P-gp and attenuated the growth inhibitory effect of NCTD. The knockdown of mdr-1 mRNA had not altered the expression of Shh and Smoothened in both MCF-7S and MCF-7R cells. This indicates that the role of Shh signaling in MDR might be upstream to mdr-1/P-gp, and similar effect was shown in breast cancer MDA-MB-231 and BT-474 cells. This study demonstrated that NCTD may overcome multidrug resistance through inhibiting Shh signaling and expression of its downstream mdr-1/P-gp expression in human breast cancer cells

Retinoic acid induces HL-60 cell differentiation via the upregulation of miR-663

<p>Abstract</p> <p>Background</p> <p>Differentiation of the acute myeloid leukemia (AML) cell line HL-60 can be induced by all trans-retinoic acid (ATRA); however, the mechanism regulating this process has not been fully characterized.</p> <p>Methods</p> <p>Using bioinformatics and <it>in vitro </it>experiments, we identified the microRNA gene expression profile of HL-60 cells during ATRA induced granulocytic differentiation.</p> <p>Results</p> <p>Six microRNAs were upregulated by ATRA treatment, miR-663, miR-494, miR-145, miR-22, miR-363* and miR-223; and three microRNAs were downregulated, miR-10a, miR-181 and miR-612. Additionally, miR-663 expression was regulated by ATRA. We used a lentivirus (LV) backbone incorporating the spleen focus forming virus (SFFV-F) promoter to drive miR-663 expression, as the CMV (Cytomegalovirus) promoter is ineffective in some lymphocyte cells. Transfection of LV-miR-663 induced significant HL-60 cell differentiation <it>in vitro</it>.</p> <p>Conclusions</p> <p>Our results show miR-663 may play an important role in ATRA induced HL-60 cell differentiation. Lentivirus delivery of miR-663 could potentially be used directly as an anticancer treatment in hematological malignancies</p

Physicochemical property distributions for accurate and rapid pairwise protein homology detection

<p>Abstract</p> <p>Background</p> <p>The challenge of remote homology detection is that many evolutionarily related sequences have very little similarity at the amino acid level. Kernel-based discriminative methods, such as support vector machines (SVMs), that use vector representations of sequences derived from sequence properties have been shown to have superior accuracy when compared to traditional approaches for the task of remote homology detection.</p> <p>Results</p> <p>We introduce a new method for feature vector representation based on the physicochemical properties of the primary protein sequence. A distribution of physicochemical property scores are assembled from 4-mers of the sequence and normalized based on the null distribution of the property over all possible 4-mers. With this approach there is little computational cost associated with the transformation of the protein into feature space, and overall performance in terms of remote homology detection is comparable with current state-of-the-art methods. We demonstrate that the features can be used for the task of pairwise remote homology detection with improved accuracy versus sequence-based methods such as BLAST and other feature-based methods of similar computational cost.</p> <p>Conclusions</p> <p>A protein feature method based on physicochemical properties is a viable approach for extracting features in a computationally inexpensive manner while retaining the sensitivity of SVM protein homology detection. Furthermore, identifying features that can be used for generic pairwise homology detection in lieu of family-based homology detection is important for applications such as large database searches and comparative genomics.</p

Augmented Cardiac Hypertrophy in Response to Pressure Overload in Mice Lacking ELTD1

BACKGROUND: Epidermal growth factor (EGF), latrophilin and seven transmembrane domain-containing protein 1 (ELTD1) is developmentally upregulated in the heart. Little is known about the relationship between ELTD1 and cardiac diseases. Therefore, we aimed to clarify the role of ELTD1 in pressure overload-induced cardiac hypertrophy. METHODS AND RESULTS: C57BL/6J wild-type (WT) mice and ELTD1-knockout (KO) mice were subjected to left ventricular pressure overload by descending aortic banding (AB). KO mice exhibited more unfavorable cardiac remodeling than WT mice 28 days post AB; this remodeling was characterized by aggravated cardiomyocyte hypertrophy, thickening of the ventricular walls, dilated chambers, increased fibrosis, and blunted systolic and diastolic cardiac function. Analysis of signaling pathways revealed enhanced extracellular signal-regulated kinase (ERK) and the c-Jun amino-terminal kinase (JNK) phosphorylation in response to ELTD1 deletion. CONCLUSIONS: ELTD1 deficiency exacerbates cardiac hypertrophy and cardiac function induced by AB-induced pressure overload by promoting both cardiomyocyte hypertrophy and cardiac fibrosis. These effects are suggested to originate from the activation of the ERK and JNK pathways, suggesting that ELTD1 is a potential target for therapies that prevent the development of cardiac disease

Is there an ideal way to initiate antiplatelet therapy with aspirin? A crossover study on healthy volunteers evaluating different dosing schemes with whole blood aggregometry

<p>Abstract</p> <p>Background</p> <p>Guidelines recommend an early initiation of aspirin treatment in patients with acute cerebral ischemia. Comparative studies on the best starting dose for initiating aspirin therapy to achieve a rapid antiplatelet effect do not exist. This study evaluated the platelet inhibitory effect in healthy volunteers by using three different aspirin loading doses to gain a model for initiating antiplatelet treatment in acute strokes patients.</p> <p>Methods</p> <p>Using whole blood aggregometry, this study with a prospective, uncontrolled, open, crossover design examined 12 healthy volunteers treated with three different aspirin loading doses: intravenous 500 mg aspirin, oral 500 mg aspirin, and a course of 200 mg aspirin on two subsequent days followed by a five-day course of 100 mg aspirin. Aspirin low response was defined as change of impedance exceeding 0 Ω after stimulation with arachidonic acid.</p> <p>Results</p> <p>Sufficient antiplatelet effectiveness was gained within 30 seconds when intravenous 500 mg aspirin was used. The mean time until antiplatelet effect was 74 minutes for 500 mg aspirin taken orally and 662 minutes (11.2 hours) for the dose scheme with 200 mg aspirin with a high inter- and intraindividual variability in those two regimes. Platelet aggregation returned to the baseline range during the wash-out phase within 4 days.</p> <p>Conclusion</p> <p>Our study reveals that the antiplatelet effect differs significantly between the three different aspirin starting dosages with a high inter- and intraindividual variability of antiplatelet response in our healthy volunteers. To ensure an early platelet inhibitory effect in acute stroke patients, it could be advantageous to initiate the therapy with an intravenous loading dose of 500 mg aspirin. However, clinical outcome studies must still define the best way to initiate antiplatelet treatment with aspirin.</p