Using Evolutionary Algorithms for Fitting High-Dimensional Models to Neuronal Data

In the study of neurosciences, and of complex biological systems in general, there is frequently a need to fit mathematical models with large numbers of parameters to highly complex datasets. Here we consider algorithms of two different classes, gradient following (GF) methods and evolutionary algorithms (EA) and examine their performance in fitting a 9-parameter model of a filter-based visual neuron to real data recorded from a sample of 107 neurons in macaque primary visual cortex (V1). Although the GF method converged very rapidly on a solution, it was highly susceptible to the effects of local minima in the error surface and produced relatively poor fits unless the initial estimates of the parameters were already very good. Conversely, although the EA required many more iterations of evaluating the model neuron’s response to a series of stimuli, it ultimately found better solutions in nearly all cases and its performance was independent of the starting parameters of the model. Thus, although the fitting process was lengthy in terms of processing time, the relative lack of human intervention in the evolutionary algorithm, and its ability ultimately to generate model fits that could be trusted as being close to optimal, made it far superior in this particular application than the gradient following methods. This is likely to be the case in many further complex systems, as are often found in neuroscience

Hypnotic analgesia reduces brain responses to pain seen in others.

Brain responses to pain experienced by oneself or seen in other people show consistent overlap in the pain processing network, particularly anterior insula, supporting the view that pain empathy partly relies on neural processes engaged by self-nociception. However, it remains unresolved whether changes in one's own pain sensation may affect empathic responding to others' pain. Here we show that inducing analgesia through hypnosis leads to decreased responses to both self and vicarious experience of pain. Activations in the right anterior insula and amygdala were markedly reduced when participants received painful thermal stimuli following hypnotic analgesia on their own hand, but also when they viewed pictures of others' hand in pain. Functional connectivity analysis indicated that this hypnotic modulation of pain responses was associated with differential recruitment of right prefrontal regions implicated in selective attention and inhibitory control. Our results provide novel support to the view that self-nociception is involved during empathy for pain, and demonstrate the possibility to use hypnotic procedures to modulate higher-level emotional and social processes

Attempting to reduce susceptibility to fraudulent computer pop-ups using malevolence cue identification training

People accept a high number of computer pop-ups containing cues that indicate malevolence when they occur as interrupting tasks during a cognitively demanding memory-based task [1, 2], with younger adults spending only 5.5–6-s before making an accept or decline decision [2]. These findings may be explained by at least three factors: pressure to return to the suspended task to minimize forgetting; adopting non-cognitively demanding inspection strategies; and, having low levels of suspicion [3]. Consequences of such behavior could be potentially catastrophic for individuals and organizations (e.g., in the event of a successful cyber breach), and thus it is crucial to develop effective interventions to reduce susceptibility. The current experiment (N = 50) tested the effectiveness of malevolence cue identification training (MCIT) interventions. During phase 1, participants performed a serial recall task with some trials interrupted by pop-up messages with accept or cancel options that either contained cues (e.g., missing company name, misspelt word) to malevolence (malevolent condition) or no cues (non-malevolent condition). In phase 2, participants were allocated to one of three groups: no MCIT/Control, non-incentivized MCIT/N-IMCIT, or incentivized MCIT/IMCIT. Control group participants only had to identify category-related words (e.g., colors). Participants in intervention conditions were explicitly made aware of the malevolence cues in Phase 1 pop-ups before performing trying to identify malevolence cues within adapted passages of text. The N-IMCIT group were told that their detection accuracy was being ranked against other participants, to induce social comparison. Phase 3 was similar to phase 1, although 50% of malevolent pop-ups contained new cues. MCIT did lead to a significant reduction in the number of malevolent pop-ups accepted under some conditions. Incentivized training did not (statistically) improve performance compared to non-incentivized training. Cue novelty had no effect. Ways of further improving the MCIT training protocol used, as well as theoretical implications, are discussed

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

Developing adaptive control:Age-related differences in task choices and awareness of proactive and reactive control demands

Developmental changes in executive function are often explained in terms of core cognitive processes and associated neural substrates. For example, younger children tend to engage control reactively in the moment as needed, whereas older children increasingly engage control proactively, in anticipation of needing it. Such developments may reflect increasing capacities for active maintenance dependent upon dorsolateral prefrontal cortex. However, younger children will engage proactive control when reactive control is made more difficult, suggesting that developmental changes may also reflect decisions about whether to engage control, and how. We tested awareness of temporal control demands and associated task choices in 5-year-olds and 10-year-olds and adults using a demand selection task. Participants chose between one task that enabled proactive control and another task that enabled reactive control. Adults reported awareness of these different control demands and preferentially played the proactive task option. Ten-year-olds reported awareness of control demands but selected task options at chance. Five-year-olds showed neither awareness nor task preference, but a subsample who exhibited awareness of control demands preferentially played the reactive task option, mirroring their typical control mode. Thus, developmental improvements in executive function may in part reflect better awareness of cognitive demands and adaptive behavior, which may in turn reflect changes in dorsal anterior cingulate in signaling task demands to lateral prefrontal cortex

Estimating Impact Forces of Tail Club Strikes by Ankylosaurid Dinosaurs

BACKGROUND: It has been assumed that the unusual tail club of ankylosaurid dinosaurs was used actively as a weapon, but the biological feasibility of this behaviour has not been examined in detail. Ankylosaurid tail clubs are composed of interlocking vertebrae, which form the handle, and large terminal osteoderms, which form the knob. METHODOLOGY/PRINCIPAL FINDINGS: Computed tomographic (CT) scans of several ankylosaurid tail clubs referred to Dyoplosaurus and Euoplocephalus, combined with measurements of free caudal vertebrae, provide information used to estimate the impact force of tail clubs of various sizes. Ankylosaurid tails are modeled as a series of segments for which mass, muscle cross-sectional area, torque, and angular acceleration are calculated. Free caudal vertebrae segments had limited vertical flexibility, but the tail could have swung through approximately 100 degrees laterally. Muscle scars on the pelvis record the presence of a large M. longissimus caudae, and ossified tendons alongside the handle represent M. spinalis. CT scans showed that knob osteoderms were predominantly cancellous, which would have lowered the rotational inertia of the tail club and made it easier to wield as a weapon. CONCLUSIONS/SIGNIFICANCE: Large knobs could generate sufficient force to break bone during impacts, but average and small knobs could not. Tail swinging behaviour is feasible in ankylosaurids, but it remains unknown whether the tail was used for interspecific defense, intraspecific combat, or both

MDM2 antagonist Nutlin-3a potentiates antitumour activity of cytotoxic drugs in sarcoma cell lines

<p>Abstract</p> <p>Background</p> <p>Frequent failure and severe side effects of current sarcoma therapy warrants new therapeutic approaches. The small-molecule MDM2 antagonist Nutlin-3a activates the p53 pathway and efficiently induces apoptosis in tumours with amplified <it>MDM2 </it>gene and overexpression of MDM2 protein. However, the majority of human sarcomas have normal level of MDM2 and the therapeutic potential of MDM2 antagonists in this group is still unclear. We have investigated if Nutlin-3a could be employed to augment the response to traditional therapy and/or reduce the genotoxic burden of chemotherapy.</p> <p>Methods</p> <p>A panel of sarcoma cell lines with different <it>TP53 </it>and <it>MDM2 </it>status were treated with Nutlin-3a combined with Doxorubicin, Methotrexate or Cisplatin, and their combination index determined.</p> <p>Results</p> <p>Clear synergism was observed when Doxorubicin and Nutlin-3a were combined in cell lines with wild-type <it>TP53 </it>and amplified <it>MDM2</it>, or with Methotrexate in both <it>MDM2 </it>normal and amplified sarcoma cell lines, allowing for up to tenfold reduction of cytotoxic drug dose. Interestingly, Nutlin-3a seemed to potentiate the effect of classical drugs as Doxorubicin and Cisplatin in cell lines with mutated <it>TP53</it>, but inhibited the effect of Methotrexate.</p> <p>Conclusion</p> <p>The use of Nutlin in combination with classical sarcoma chemotherapy shows promising preclinical potential, but since clear biomarkers are still lacking, clinical trials should be followed up with detailed tumour profiling.</p

Prolactin Receptor in Primary Hyperparathyroidism – Expression, Functionality and Clinical Correlations

<div><h3>Background</h3><p>Primary hyperparathyroidism (PHPT) is an endocrine disorder most commonly affecting women, suggesting a role for female hormones and/or their receptors in parathyroid adenomas. We here investigated the prolactin receptor (PRLr) which is associated with tumours of the breast and other organs.</p> <h3>Methodology/Principal Findings</h3><p>PRLr expression was investigated in a panel of 37 patients with sporadic parathyroid tumours and its functionality in cultured parathyroid tumour cells. In comparison with other tissues and breast cancer cells, high levels of prolactin receptor gene (<em>PRLR</em>) transcripts were demonstrated in parathyroid tissues. PRLr products of 60/70 kDa were highly expressed in all parathyroid tumours. In addition varying levels of the 80 kDa PRLr isoform, with known proliferative activity, were demonstrated. In parathyroid tumours, PRLr immunoreactivity was observed in the cytoplasm (in all cases, n = 36), cytoplasmic granulae (n = 16), the plasma membrane (n = 12) or enlarged lysosomes (n = 4). In normal parathyroid rim (n = 28), PRLr was uniformly expressed in the cytoplasm and granulae. In <em>in vitro</em> studies of short-term cultured human parathyroid tumour cells, prolactin stimulation was associated with significant transcriptional changes in JAK/STAT, RIG-I like receptor and type II interferon signalling pathways as documented by gene expression profiling. Moreover, <em>PRLR</em> gene expression in parathyroid tumours was inversely correlated with the patients’ plasma calcium levels.</p> <h3>Conclusions</h3><p>We demonstrate that the prolactin receptor is highly abundant in human parathyroid tissues and that PRLr isoforms expression and PRLr subcellular localisation are altered in parathyroid tumours. Responsiveness of PRLr to physiological levels of prolactin was observed in the form of increased PTH secretion and altered gene transcription with significant increase of RIG-I like receptor, JAK-STAT and Type II interferon signalling pathways. These data suggest a role of the prolactin receptor in parathyroid adenomas.</p> </div

Dissection of a QTL Hotspot on Mouse Distal Chromosome 1 that Modulates Neurobehavioral Phenotypes and Gene Expression

A remarkably diverse set of traits maps to a region on mouse distal chromosome 1 (Chr 1) that corresponds to human Chr 1q21–q23. This region is highly enriched in quantitative trait loci (QTLs) that control neural and behavioral phenotypes, including motor behavior, escape latency, emotionality, seizure susceptibility (Szs1), and responses to ethanol, caffeine, pentobarbital, and haloperidol. This region also controls the expression of a remarkably large number of genes, including genes that are associated with some of the classical traits that map to distal Chr 1 (e.g., seizure susceptibility). Here, we ask whether this QTL-rich region on Chr 1 (Qrr1) consists of a single master locus or a mixture of linked, but functionally unrelated, QTLs. To answer this question and to evaluate candidate genes, we generated and analyzed several gene expression, haplotype, and sequence datasets. We exploited six complementary mouse crosses, and combed through 18 expression datasets to determine class membership of genes modulated by Qrr1. Qrr1 can be broadly divided into a proximal part (Qrr1p) and a distal part (Qrr1d), each associated with the expression of distinct subsets of genes. Qrr1d controls RNA metabolism and protein synthesis, including the expression of ∼20 aminoacyl-tRNA synthetases. Qrr1d contains a tRNA cluster, and this is a functionally pertinent candidate for the tRNA synthetases. Rgs7 and Fmn2 are other strong candidates in Qrr1d. FMN2 protein has pronounced expression in neurons, including in the dendrites, and deletion of Fmn2 had a strong effect on the expression of few genes modulated by Qrr1d. Our analysis revealed a highly complex gene expression regulatory interval in Qrr1, composed of multiple loci modulating the expression of functionally cognate sets of genes

Identification, Replication, and Functional Fine-Mapping of Expression Quantitative Trait Loci in Primary Human Liver Tissue

The discovery of expression quantitative trait loci (“eQTLs”) can help to unravel genetic contributions to complex traits. We identified genetic determinants of human liver gene expression variation using two independent collections of primary tissue profiled with Agilent (n = 206) and Illumina (n = 60) expression arrays and Illumina SNP genotyping (550K), and we also incorporated data from a published study (n = 266). We found that ∼30% of SNP-expression correlations in one study failed to replicate in either of the others, even at thresholds yielding high reproducibility in simulations, and we quantified numerous factors affecting reproducibility. Our data suggest that drug exposure, clinical descriptors, and unknown factors associated with tissue ascertainment and analysis have substantial effects on gene expression and that controlling for hidden confounding variables significantly increases replication rate. Furthermore, we found that reproducible eQTL SNPs were heavily enriched near gene starts and ends, and subsequently resequenced the promoters and 3′UTRs for 14 genes and tested the identified haplotypes using luciferase assays. For three genes, significant haplotype-specific in vitro functional differences correlated directly with expression levels, suggesting that many bona fide eQTLs result from functional variants that can be mechanistically isolated in a high-throughput fashion. Finally, given our study design, we were able to discover and validate hundreds of liver eQTLs. Many of these relate directly to complex traits for which liver-specific analyses are likely to be relevant, and we identified dozens of potential connections with disease-associated loci. These included previously characterized eQTL contributors to diabetes, drug response, and lipid levels, and they suggest novel candidates such as a role for NOD2 expression in leprosy risk and C2orf43 in prostate cancer. In general, the work presented here will be valuable for future efforts to precisely identify and functionally characterize genetic contributions to a variety of complex traits