From whole-brain data to functional circuit models: the zebrafish optomotor response

Detailed descriptions of brain-scale sensorimotor circuits underlying vertebrate behavior remain elusive. Recent advances in zebrafish neuroscience offer new opportunities to dissect such circuits via whole-brain imaging, behavioral analysis, functional perturbations, and network modeling. Here, we harness these tools to generate a brain-scale circuit model of the optomotor response, an orienting behavior evoked by visual motion. We show that such motion is processed by diverse neural response types distributed across multiple brain regions. To transform sensory input into action, these regions sequentially integrate eye- and direction-specific sensory streams, refine representations via interhemispheric inhibition, and demix locomotor instructions to independently drive turning and forward swimming. While experiments revealed many neural response types throughout the brain, modeling identified the dimensions of functional connectivity most critical for the behavior. We thus reveal how distributed neurons collaborate to generate behavior and illustrate a paradigm for distilling functional circuit models from whole-brain data

Multidimensional sexual perfectionism and female sexual function: A longitudinal investigation

Research on multidimensional sexual perfectionism differentiates four forms of sexual perfectionism: self-oriented, partner-oriented, partner-prescribed, and socially prescribed. Self-oriented sexual perfectionism reflects perfectionistic standards people apply to themselves as sexual partners; partner-oriented sexual perfectionism reflects perfectionistic standards people apply to their sexual partner; partner-prescribed sexual perfectionism reflects people’s beliefs that their sexual partner imposes perfectionistic standards on them; and socially prescribed sexual perfectionism reflects people’s beliefs that society imposes such standards on them. Previous studies found partner-prescribed and socially prescribed sexual perfectionism to be maladaptive forms of sexual perfectionism associated with a negative sexual self-concept and problematic sexual behaviors, but only examined cross-sectional relationships. The present article presents the first longitudinal study examining whether multidimensional sexual perfectionism predicts changes in sexual self-concept and sexual function over time. A total of 366 women aged 17-69 years completed measures of multidimensional sexual perfectionism, sexual esteem, sexual anxiety, sexual problem self-blame, and female sexual function (cross-sectional data). Three to six months later, 164 of the women completed the same measures again (longitudinal data). Across analyses, partner-prescribed sexual perfectionism emerged as the most maladaptive form of sexual perfectionism. In the cross-sectional data, partner-prescribed sexual perfectionism showed positive relationships with sexual anxiety, sexual problem self-blame, and intercourse pain and negative relationships with sexual esteem, desire, arousal, lubrication, and orgasmic function. In the longitudinal data, partner-prescribed sexual perfectionism predicted increases in sexual anxiety and decreases in sexual esteem, arousal, and lubrication over time. The findings suggest that partner-prescribed sexual perfectionism contributes to women’s negative sexual self-concept and female sexual dysfunction

Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation

NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells, αβ and γδ T-cell function. This activating receptor recognizes eight distinct ligands (the MHC Class I polypeptide-related sequences (MIC) A andB, and UL16-binding proteins (ULBP)1–6) induced by cellular stress to promote recognition cells perturbed by malignant transformation or microbial infection. Studies into human cytomegalovirus (HCMV) have aided both the identification and characterization of NKG2D ligands (NKG2DLs). HCMV immediate early (IE) gene up regulates NKGDLs, and we now describe the differential activation of ULBP2 and MICA/B by IE1 and IE2 respectively. Despite activation by IE functions, HCMV effectively suppressed cell surface expression of NKGDLs through both the early and late phases of infection. The immune evasion functions UL16, UL142, and microRNA(miR)-UL112 are known to target NKG2DLs. While infection with a UL16 deletion mutant caused the expected increase in MICB and ULBP2 cell surface expression, deletion of UL142 did not have a similar impact on its target, MICA. We therefore performed a systematic screen of the viral genome to search of addition functions that targeted MICA. US18 and US20 were identified as novel NK cell evasion functions capable of acting independently to promote MICA degradation by lysosomal degradation. The most dramatic effect on MICA expression was achieved when US18 and US20 acted in concert. US18 and US20 are the first members of the US12 gene family to have been assigned a function. The US12 family has 10 members encoded sequentially through US12–US21; a genetic arrangement, which is suggestive of an ‘accordion’ expansion of an ancestral gene in response to a selective pressure. This expansion must have be an ancient event as the whole family is conserved across simian cytomegaloviruses from old world monkeys. The evolutionary benefit bestowed by the combinatorial effect of US18 and US20 on MICA may have contributed to sustaining the US12 gene family

3D Hepatic Cultures Simultaneously Maintain Primary Hepatocyte and Liver Sinusoidal Endothelial Cell Phenotypes

Developing in vitro engineered hepatic tissues that exhibit stable phenotype is a major challenge in the field of hepatic tissue engineering. However, the rapid dedifferentiation of hepatic parenchymal (hepatocytes) and non-parenchymal (liver sinusoidal endothelial, LSEC) cell types when removed from their natural environment in vivo remains a major obstacle. The primary goal of this study was to demonstrate that hepatic cells cultured in layered architectures could preserve or potentially enhance liver-specific behavior of both cell types. Primary rat hepatocytes and rat LSECs (rLSECs) were cultured in a layered three-dimensional (3D) configuration. The cell layers were separated by a chitosan-hyaluronic acid polyelectrolyte multilayer (PEM), which served to mimic the Space of Disse. Hepatocytes and rLSECs exhibited several key phenotypic characteristics over a twelve day culture period. Immunostaining for the sinusoidal endothelial 1 antibody (SE-1) demonstrated that rLSECs cultured in the 3D hepatic model maintained this unique feature over twelve days. In contrast, rLSECs cultured in monolayers lost their phenotype within three days. The unique stratified structure of the 3D culture resulted in enhanced heterotypic cell-cell interactions, which led to improvements in hepatocyte functions. Albumin production increased three to six fold in the rLSEC-PEM-Hepatocyte cultures. Only rLSEC-PEM-Hepatocyte cultures exhibited increasing CYP1A1/2 and CYP3A activity. Well-defined bile canaliculi were observed only in the rLSEC-PEM-Hepatocyte cultures. Together, these data suggest that rLSEC-PEM-Hepatocyte cultures are highly suitable models to monitor the transformation of toxins in the liver and their transport out of this organ. In summary, these results indicate that the layered rLSEC-PEM-hepatocyte model, which recapitulates key features of hepatic sinusoids, is a potentially powerful medium for obtaining comprehensive knowledge on liver metabolism, detoxification and signaling pathways in vitro

Anaerobic animals from an ancient, anoxic ecological niche

Tiny marine animals that complete their life cycle in the total absence of light and oxygen are reported by Roberto Danovaro and colleagues in this issue of BMC Biology. These fascinating animals are new members of the phylum Loricifera and possess mitochondria that in electron micrographs look very much like hydrogenosomes, the H2-producing mitochondria found among several unicellular eukaryotic lineages. The discovery of metazoan life in a permanently anoxic and sulphidic environment provides a glimpse of what a good part of Earth's past ecology might have been like in 'Canfield oceans', before the rise of deep marine oxygen levels and the appearance of the first large animals in the fossil record roughly 550-600 million years ago. The findings underscore the evolutionary significance of anaerobic deep sea environments and the anaerobic lifestyle among mitochondrion-bearing cells. They also testify that a fuller understanding of eukaryotic and metazoan evolution will come from the study of modern anoxic and hypoxic habitats

Bias and heteroscedastic memory error in self-reported health behavior: an investigation using covariance structure analysis

BACKGROUND: Frequent use of self-reports for investigating recent and past behavior in medical research requires statistical techniques capable of analyzing complex sources of bias associated with this methodology. In particular, although decreasing accuracy of recalling more distant past events is commonplace, the bias due to differential in memory errors resulting from it has rarely been modeled statistically. METHODS: Covariance structure analysis was used to estimate the recall error of self-reported number of sexual partners for past periods of varying duration and its implication for the bias. RESULTS: Results indicated increasing levels of inaccuracy for reports about more distant past. Considerable positive bias was found for a small fraction of respondents who reported ten or more partners in the last year, last two years and last five years. This is consistent with the effect of heteroscedastic random error where the majority of partners had been acquired in the more distant past and therefore were recalled less accurately than the partners acquired more recently to the time of interviewing. CONCLUSIONS: Memory errors of this type depend on the salience of the events recalled and are likely to be present in many areas of health research based on self-reported behavior

A Novel Statistical Algorithm for Gene Expression Analysis Helps Differentiate Pregnane X Receptor-Dependent and Independent Mechanisms of Toxicity

Genome-wide gene expression profiling has become standard for assessing potential liabilities as well as for elucidating mechanisms of toxicity of drug candidates under development. Analysis of microarray data is often challenging due to the lack of a statistical model that is amenable to biological variation in a small number of samples. Here we present a novel non-parametric algorithm that requires minimal assumptions about the data distribution. Our method for determining differential expression consists of two steps: 1) We apply a nominal threshold on fold change and platform p-value to designate whether a gene is differentially expressed in each treated and control sample relative to the averaged control pool, and 2) We compared the number of samples satisfying criteria in step 1 between the treated and control groups to estimate the statistical significance based on a null distribution established by sample permutations. The method captures group effect without being too sensitive to anomalies as it allows tolerance for potential non-responders in the treatment group and outliers in the control group. Performance and results of this method were compared with the Significant Analysis of Microarrays (SAM) method. These two methods were applied to investigate hepatic transcriptional responses of wild-type (PXR+/+) and pregnane X receptor-knockout (PXR−/−) mice after 96 h exposure to CMP013, an inhibitor of β-secretase (β-site of amyloid precursor protein cleaving enzyme 1 or BACE1). Our results showed that CMP013 led to transcriptional changes in hallmark PXR-regulated genes and induced a cascade of gene expression changes that explained the hepatomegaly observed only in PXR+/+ animals. Comparison of concordant expression changes between PXR+/+ and PXR−/− mice also suggested a PXR-independent association between CMP013 and perturbations to cellular stress, lipid metabolism, and biliary transport

Distribution and correlates of plantar hyperkeratotic lesions in older people

<p>Abstract</p> <p>Background</p> <p>Plantar hyperkeratotic lesions are common in older people and are associated with pain, mobility impairment and functional limitations. However, little has been documented in relation to the frequency or distribution of these lesions. The aim of this study was to document the occurrence of plantar hyperkeratotic lesions and the patterns in which they occur in a random sample of older people.</p> <p>Methods</p> <p>A medical history questionnaire was administered to a random sample of 301 people living independently in the community (117 men, 184 women) aged between 70 and 95 years (mean 77.2, SD 4.9), who also underwent a clinical assessment of foot problems, including the documentation of plantar lesion locations, toe deformities and the presence and severity of hallux valgus.</p> <p>Results</p> <p>Of the 301 participants, 180 (60%) had at least one plantar hyperkeratotic lesion. Those with plantar lesions were more likely to be female (χ²= 18.75, <it>p </it>< 0.01; OR = 2.86), have moderate to severe hallux valgus (χ²= 6.15, <it>p </it>< 0.02; OR = 2.95), a larger dorsiflexion range of motion at the ankle (39.4 ± 9.3 <it>vs </it>36.3 ± 8.4°; <it>t </it>= 2.68, <it>df </it>= 286, <it>p </it>< 0.01), and spent more time on their feet at home (5.1 ± 1.0 <it>vs </it>4.8 ± 1.3 hours, <it>t </it>= -2.46, <it>df </it>= 299, <it>p </it>= 0.01). No associations were found between the presence of plantar lesions and body mass index, obesity, foot posture, dominant foot or forefoot pain. A total of 53 different lesions patterns were observed, with the most common lesion pattern being "roll-off" hyperkeratosis on the medial aspect of the 1^stmetatarsophalangeal joint (MPJ), accounting for 12% of all lesion patterns. "Roll-off" lesions under the 1^stMPJ and interphalangeal joint were significantly associated with moderate to severe hallux valgus (<it>p </it>< 0.05), whereas lesions under the central MPJs were significantly associated with deformity of the corresponding lesser toe (<it>p </it>< 0.05). Factor analysis indicated that 62% of lesion patterns could be grouped under three broad categories, relating to medial, central and lateral locations.</p> <p>Conclusion</p> <p>Plantar hyperkeratotic lesions affect 60% of older people and are associated with female gender, hallux valgus, toe deformity, increased ankle flexibility and time spent on feet, but are not associated with obesity, limb dominance, forefoot pain or foot posture. Although there are a wide range of lesion distribution patterns, most can be classified into medial, central or lateral groups. Further research is required to determine whether these patterns are related to the dynamic function of the foot or other factors such as foot pathology or morphology.</p

Individual biases, cultural evolution, and the statistical nature of language universals: the case of colour naming systems

Language universals have long been attributed to an innate Universal Grammar. An alternative explanation states that linguistic universals emerged independently in every language in response to shared cognitive or perceptual biases. A computational model has recently shown how this could be the case, focusing on the paradigmatic example of the universal properties of colour naming patterns, and producing results in quantitative agreement with the experimental data. Here we investigate the role of an individual perceptual bias in the framework of the model. We study how, and to what extent, the structure of the bias influences the corresponding linguistic universal patterns. We show that the cultural history of a group of speakers introduces population-specific constraints that act against the pressure for uniformity arising from the individual bias, and we clarify the interplay between these two forces