Reduced expression of the presynaptic co-chaperone cysteine string protein alpha (CSP?) does not exacerbate experimentally-induced ME7 prion disease

Infection of mice with the ME7 prion agent results in well-characterised neuropathological changes, which includes vacuolation, neurodegeneration and synaptic degeneration. Presynaptic dysfunction and degeneration is apparent through the progressive reduction in synaptic vesicle proteins and eventual loss of synapses. Cysteine string protein alpha (CSP?), which regulates refolding pathways at the synapse, exhibits an early decline during chronic neurodegeneration implicating it as a mediator of disease mechanisms. CSP? null mice develop a progressive neuronal dysfunction through disruption of the integrity of presynaptic function. In this study, we investigated whether reduced expression of CSP? would exacerbate ME7 prion disease. Wild type (+/+) and heterozygous (+/-) mice, which express about a ?50% reduction in CSP?, were used as a distinct genetic background on which to impose prion disease. +/+ and +/ - mice were inoculated with brain homogenate from either a normal mouse brain (NBH) or from the brain of a mouse which displayed clinical signs of prion disease (ME7). Behavioural tests, western blotting and immunohistochemistry, which resolve key elements of synaptic dysfunction, were used to assess the effect of reduced CSP? on disease. Behavioural tests revealed no change in the progression of disease in ME7-CSP? +/- animals compared to ME7-CSP? +/+ animals. In addition, the accumulation of misfolded PrP(Sc), the diseased associated gliosis or synaptic loss were not different. Thus, the misfolding events that generate synaptic dysfunction and lead to synaptic loss are unlikely to be mediated by a disease associated decrease in the refolding pathways associated with CSP?

Improved timber harvest techniques maintain biodiversity in tropical forests

Tropical forests are selectively logged at 20 times the rate at which they are cleared, and at least a fifth have already been disturbed in this way. In a recent pan-tropical assessment, Burivalova et al. demonstrate the importance of logging intensity as a driver of biodiversity decline in timber estates. Their analyses reveal that species richness of some taxa could decline by 50% at harvest intensities of 38 m3 ha-1. However, they did not consider the extraction techniques that lead to these intensities. Here, we conduct a complementary meta-analysis of assemblage responses to differing logging practices: conventional logging and reduced-impact logging. We show that biodiversity impacts are markedly less severe in forests that utilise reduced-impact logging, compared to those using conventional methods. While supporting the initial findings of Burivalova et al., we go on to demonstrate that best practice forestry techniques curtail the effects of timber extraction regardless of intensity. Therefore, harvest intensities are not always indicative of actual disturbance levels resulting from logging. Accordingly, forest managers and conservationists should advocate practices that offer reduced collateral damage through best practice extraction methods, such as those used in reduced-impact logging. Large-scale implementation of this approach would lead to improved conservation values in the 4 million km2 of tropical forests that are earmarked for timber extraction

Trigger-Point Self-Care for Chronic Neck Pain: Pilot and Feasibility

poster abstractMassage is a non-pharmacological approach for neck pain with building evidence. Trigger points (TrPts) are thought to be associated with chronic neck pain (CNP) and can be treated with massage techniques. Due to massage’s out-of-pocket costs, TrPt self-care (TrPtSC) may serve as a cost-effective treatment that may reach broader populations. No study has examined a) feasibility of conducting TrPtSC training in a research setting, b) ability of such programs to meet stated training objectives, c) adherence to personalized TrPtSC plans, and d) TrPtSC outcomes for CNP. A pilot observational, pre- post-intervention cohort study with 1-, 4-, and 8-week follow-ups was implemented. Participants: self-identified adults with CNP and Neck Disability Index (NDI) ≥4. Measures: pre-/post-TrPtSC training objectives survey, TrPtSC daily self-report log, NDI and 11-point pain rating scale. Intervention: three-hour TrPtSC training with interactive lecture, demonstration, supervised practice, and private assessment with individualized TrPtSC plan development. Handouts and tools were provided for training and home TrPtSC. Participants documented their individualized TrPtSC plan adherence daily. Five participants (women=3; ages 22-58; White=5) enrolled in the study and two separate group training sessions occurred (n=3 & 2, respectively). By the end of the TrPtSC training, all participants agreed or strongly agreed they achieved all intended training objectives. Baseline NDI categorized all participants as mild neck pain with disability (mean NDI=10.4±2.1). Week-1 follow-up: 1 participant had no NDI change, 1 participant worsened, and 3 reported 23-50% improvement. All participants had improved NDI at week-4 and week-8 compared to baseline. Three participants reported 23-30% improvement by study’s end. Our TrPtSC group training approach met objectives and our study design is feasible for larger scale trials. Results suggest TrPtSC may improve CNP outcomes. More robust studies with greater than mild neck pain and disability participants are needed to estimate effect sizes and adequately power larger comparison trials

Response and Resistance to Paradox-Breaking BRAF Inhibitor in Melanomas

FDA-approved BRAF inhibitors produce high response rates and improve overall survival in patients with BRAF V600E/K-mutant melanoma, but are linked to pathologies associated with paradoxical ERK1/2 activation in wild-type BRAF cells. To overcome this limitation, a next-generation paradox-breaking RAF inhibitor (PLX8394) has been designed. Here, we show that by using a quantitative reporter assay, PLX8394 rapidly suppressed ERK1/2 reporter activity and growth of mutant BRAF melanoma xenografts. Ex vivo treatment of xenografts and use of a patient-derived explant system (PDeX) revealed that PLX8394 suppressed ERK1/2 signaling and elicited apoptosis more effectively than the FDA-approved BRAF inhibitor, vemurafenib. Furthermore, PLX8394 was efficacious against vemurafenibresistant BRAF splice variant-expressing tumors and reduced splice variant homodimerization. Importantly, PLX8394 did not induce paradoxical activation of ERK1/2 in wild-type BRAF cell lines or PDeX. Continued in vivo dosing of xenografts with PLX8394 led to the development of acquired resistance via ERK1/2 reactivation through heterogeneous mechanisms; however, resistant cells were found to have differential sensitivity to ERK1/2 inhibitor. These findings highlight the efficacy of a paradox-breaking selective BRAF inhibitor and the use of PDeX system to test the efficacy of therapeutic agents. © 2017 American Association for Cancer Research

Large Scale Structure traced by Molecular Gas at High Redshift

We present observations of redshifted CO(1-0) and CO(2-1) in a field containing an overdensity of Lyman break galaxies (LBGs) at z=5.12. Our Australia Telescope Compact Array observations were centered between two spectroscopically-confirmed z=5.12 galaxies. We place upper limits on the molecular gas masses in these two galaxies of M(H_2) <1.7 x 10^10 M_sun and <2.9 x 10^9 M_sun (2 sigma), comparable to their stellar masses. We detect an optically-faint line emitter situated between the two LBGs which we identify as warm molecular gas at z=5.1245 +/- 0.0001. This source, detected in the CO(2-1) transition but undetected in CO(1-0), has an integrated line flux of 0.106 +/- 0.012 Jy km/s, yielding an inferred gas mass M(H_2)=(1.9 +/- 0.2) x 10^10 M_sun. Molecular line emitters without detectable counterparts at optical and infrared wavelengths may be crucial tracers of structure and mass at high redshift.Comment: 4 pages, accepted for publication in ApJ Letter

Alterations in wall tension and shear stress modulate tyrosine kinase signaling and wall remodeling in experimental vein grafts

AbstractPurpose: Hemodynamic alterations have been implicated as major stimuli for the development of intimal hyperplasia in vein grafts that are implanted in the arterial circulation. Tyrosine kinase is known to mediate cell signaling. However, its role with in vivo mechanotransduction is not yet well defined. We used a novel bioprosthetic collagen tube to provide an external support to vein grafts and examined the subsequent changes in hemodynamics, tyrosine kinase signaling, wall remodeling, and vasomotor function. Methods: Carotid interposition bypass grafting was performed with the reversed jugular vein in New Zealand white rabbits. In the experimental group (n = 15), after the completion of the proximal anastomosis, the vein was passed through a 4-mm collagen tube and the distal anastomosis was performed. The tube support was fashioned to completely cover the vein grafts. The control animals (n = 14) had no tube support. After surgery, the blood pressure and flow rate were measured and the wall tension and shear stress were calculated in the vein grafts on day 3 or day 28 (n = 5 per group). Tyrosine phosphorylation was assessed with the Western blot test in vein grafts at day 3 (n = 4 per group). The intimal and medial dimensions of the vein grafts were assessed with videomorphometry on day 28 (n = 5 per group). The cumulative dose response curves of the vein grafts to contractile and relaxant agonists were determined in isometric tension studies on day 28 (n = 5 per group). Results: The use of tube support reduced wall tension 1.7-fold (P < .01) and increased shear stress 4.8-fold (P < .001) without altering the flow rate or blood pressure. The tyrosine kinase activity was reduced 15-fold (P < .001) in the tube-supported vein grafts. The intimal thickness was reduced by 45% in the tube-supported vein grafts as compared with the control grafts (46 ± 2 mm vs 84 ± 5 mm, respectively; P < .0001), and the media thickness was reduced by 20% (63 ± 8 mm vs 79 ± 4 mm, respectively; P < .05). Isometric tension studies showed preservation of contractile function and modulation of endothelial-dependent dysfunctional relaxation in tube-supported vein grafts. Conclusion: These results show that reduced wall tension and increased shear stress with an external tube support can effectively modulate the signaling, functional, and hyperplastic responses in vein grafts. We conclude that this simple strategy deserves further study and clinical consideration. (J Vasc Surg 1999;29:334-44.