Chemokine mediated signalling within arteries promotes vascular smooth muscle cell recruitment

The preferential accumulation of vascular smooth muscle cells (vSMCs) on arteries versus veins during early development is a well-described phenomenon, but the molecular pathways underlying this polarization are not well understood. In zebrafish, the cxcr4a receptor (mammalian CXCR4) and its ligand cxcl12b (mammalian CXCL12) are both preferentially expressed on arteries at time points consistent with the arrival and differentiation of the first vSMCs during vascular development. We show that autocrine cxcl12b/cxcr4 activity leads to increased production of the vSMC chemoattractant ligand pdgfb by endothelial cells in vitro and increased expression of pdgfb by arteries of zebrafish and mice in vivo. Additionally, we demonstrate that expression of the blood flow-regulated transcription factor klf2a in primitive veins negatively regulates cxcr4/cxcl12 and pdgfb expression, restricting vSMC recruitment to the arterial vasculature. Together, this signalling axis leads to the differential acquisition of vSMCs at sites where klf2a expression is low and both cxcr4a and pdgfb are co-expressed, i.e. arteries during early development.

The acquisition and generalization of fear of touch

ObjectivesContemporary fear-avoidance models of chronic pain posit that fear of pain, and overgeneralization of fear to non-threatening stimuli is a potential pathway to chronic pain. While increasing experimental evidence supports this hypothesis, a comprehensive investigation requires testing in multiple modalities due to the diversity of symptomatology among individuals with chronic pain. In the present study we used an established tactile fear conditioning paradigm as an experimental model of allodynia and spontaneous pain fluctuations, to investigate whether stimulus generalization occurs resulting in fear of touch spreading to new locations.MethodsIn our paradigm, innocuous touch is presented either paired (predictable context) or unpaired (unpredictable context) with a painful electrocutaneous stimulus (pain-US). In the predictable context, vibrotactile stimulation to the index or little finger was paired with the pain-US (CS+), whilst stimulation of the other finger was never paired with pain (CS−). In the unpredictable context, vibrotactile stimulation to the index and little fingers of the opposite hand (CS1 and CS2) was unpaired with pain, but pain-USs occurred unpredictable during the intertrial interval. During the subsequent generalization phase, we tested the spreading of conditioned responses (self-reported fear of touch and pain expectancy) to the (middle and ring) fingers between the CS+ and CS−, and between the CS1 and CS2.ResultsDifferential fear acquisition was evident in the predictable context from increased self-reported pain expectancy and self-reported fear for the CS + compared to the CS−. However, expectancy and fear ratings to the novel generalization stimuli (GS+ and GS−) were comparable to the responses elicited by the CS−. Participants reported equal levels of pain expectancy and fear to the CS1 and CS2 in the unpredictable context. However, the acquired fear did not spread in this context either: participants reported less pain expectancy and fear to the GS1 and GS2 than to the CS1 and CS2. As in our previous study, we did not observe differential acquisition in the startle responses.ConclusionsWhilst our findings for the acquisition of fear of touch replicate the results from our previous study (Biggs et al., 2017), there was no evidence of fear generalization. We discuss the limitations of the present study, with a primary focus on procedural issues that were further investigated with post-hoc analyses, concluding that the present results do not show support for the hypothesis that stimulus generalization underlies spreading of fear of touch to new locations, and discuss how this may be the consequence of a context change that prevented transfer of acquisition.

No1LikesU! – A pilot study on an ecologically valid and highly standardised experimental paradigm to investigate social rejection expectations and their modification

Background Dysfunctional expectations have been suggested as core features in the development and maintenance of mental disorders. Thus, preventing development and promoting modification of dysfunctional expectations through intervention might improve clinical treatment. While there are well-established experimental procedures to investigate the acquisition and modification of dysfunctional performance expectations in major depression, paradigms for investigating other important types of dysfunctional expectations (e.g. social rejection expectations) are currently lacking. We introduce an innovative associative learning paradigm, which can be used to investigate the development, maintenance, and modification of social rejection expectations. Method A pilot sample of 28 healthy participants experienced manipulated social feedback after answering personal questions in supposed webcam conferences. While participants repeatedly received social rejection feedback in a first phase, differential feedback was given in a second phase (social rejection vs. social appreciation). In a third phase, explicit social feedback was omitted. Results Participants developed social rejection expectations in the first phase. For the second phase, we found an interaction effect of experimental condition; i.e. participants adjusted their expectations according to the differential social feedback. In the third phase, learned social expectations remained stable in accordance to the social feedback in the second phase. Conclusion Results indicate that the paradigm can be used to investigate the development, maintenance, and modification of social rejection expectations in healthy participants. This offers broad applications to explore the differential acquisition and modification of social rejection expectations in healthy vs. clinical samples. Further, the paradigm might be used to investigate therapeutic strategies to facilitate expectation change.

Improved Semi-Bit Differential Acquisition Method for Navigation Bit Sign Transition and Code Doppler Compensation in Weak Signal Environment

The presence of code Doppler and navigation bit sign transitions means that the acquisition of global positioning system (GPS) signals is difficult in weak signal environments where the output signal-to-noise ratio (SNR) is significantly reduced. Post-correlation techniques are typically utilised to solve these problems. Despite the advantages of these techniques, the post-correlation techniques suffer from problems caused by the code Doppler and the navigation bit sign transitions. We present an improved semi-bit differential acquisition method which can improve the code Doppler and the bit sign transition issues in the post-correlation techniques. In order to overcome the phenomenon of navigation bit sign transitions, the proposed method utilises the properties of the navigation bit. Since each navigation bit takes as long as 20 ms, there would be 10 ms correlations duration integration time between the received signal and the local coarse/acquisition (C/A) code in which the navigation bit sign transitions will not occur. Consequently, this problem can be cancelled by performing 10 ms correlations in even and odd units separately. Compensation of the code Doppler is also accomplished by shifting the code phase of the correlation results. To validate the performance of our suggested method, simulations are performed based on three data sets. The results show that the quantity of required input SNR to detect at least four satellites in the proposed method is − 48·3 dB, compared with − 20 dB and − 9 dB, respectively, in traditional differential and non-coherent methods.

Vertical selection for nuclear and mitochondrial genomes shapes gut microbiota and modifies risks for complex diseases

Here we postulate that the heritability of complex disease traits previously ascribed solely to the inheritance of the nuclear and mitochondrial genomes is broadened to encompass a third component of the holobiome, the microbiome. To test this, we expanded on the selectively bred low capacity runner/high capacity runner (LCR/HCR) rat exercise model system into four distinct rat holobiont model frameworks including matched and mismatched host nuclear and mitochondrial genomes. Vertical selection of varying nuclear and mitochondrial genomes resulted in differential acquisition of the microbiome within each of these holobiont models. Polygenic disease risk of these novel models were assessed and subsequently correlated with patterns of acquisition and contributions of their microbiomes in controlled laboratory settings. Nuclear-mitochondrial-microbiotal interactions were not for exercise as a reporter of health, but significantly noted for increased adiposity, increased blood pressure, compromised cardiac function, and loss of long-term memory as reporters of disease susceptibility. These findings provide evidence for coselection of the microbiome with nuclear and mitochondrial genomes as an important feature impacting the heritability of complex diseases.

A Systematic Review of Instructional Comparisons in Single-Case Research

Comparison studies conducted to determine which instructional interventions are most efficient for teaching discrete behaviors to individuals with disabilities are potentially valuable, although some threats to internal validity may be more likely in these studies. Studies included in this review typically met common internal validity standards, such as reliability measurement, but often did not include controls specific to comparison designs. Comparisons often included young children with autism and were frequently conducted by researchers in self-contained classroom settings. Systematic instruction was effective in nearly all comparisons, although many included undifferentiated data (i.e., both interventions were equally effective), and within-participant replications were often inconsistent (i.e., outcomes varied across comparisons for a single participant). Results suggest implementers should conduct high-fidelity instruction with corrective and instructive feedback and should choose intervention variations based on participant preference. We recommend researchers include control sets or time-lagged introductions, counterbalance behavior sets, and measure differential acquisition over time.