A thermodynamic unification of jamming

Fragile materials ranging from sand to fire-retardant to toothpaste are able to exhibit both solid and fluid-like properties across the jamming transition. Unlike ordinary fusion, systems of grains, foams and colloids jam and cease to flow under conditions that still remain unknown. Here we quantify jamming via a thermodynamic approach by accounting for the structural ageing and the shear-induced compressibility of dry sand. Specifically, the jamming threshold is defined using a non-thermal temperature that measures the 'fluffiness' of a granular mixture. The thermodynamic model, casted in terms of pressure, temperature and free-volume, also successfully predicts the entropic data of five molecular glasses. Notably, the predicted configurational entropy avoids the Kauzmann paradox entirely. Without any free parameters, the proposed equation-of-state also governs the mechanism of shear-banding and the associated features of shear-softening and thickness-invariance.Comment: 16 pgs double spaced. 4 figure

High loading of polygenic risk for ADHD in children with comorbid aggression

Objective: Although attention deficit hyperactivity disorder (ADHD) is highly heritable, genome-wide association studies (GWAS) have not yet identified any common genetic variants that contribute to risk. There is evidence that aggression or conduct disorder in children with ADHD indexes higher genetic loading and clinical severity. The authors examine whether common genetic variants considered en masse as polygenic scores for ADHD are especially enriched in children with comorbid conduct disorder. Method: Polygenic scores derived from an ADHD GWAS meta-analysis were calculated in an independent ADHD sample (452 case subjects, 5,081 comparison subjects). Multivariate logistic regression analyses were employed to compare polygenic scores in the ADHD and comparison groups and test for higher scores in ADHD case subjects with comorbid conduct disorder relative to comparison subjects and relative to those without comorbid conduct disorder. Association with symptom scores was tested using linear regression. Results: Polygenic risk for ADD, derived from the meta-analysis, was higher in the independent ADHD group than in the comparison group. Polygenic score was significantly higher in ADHD case subjects with conduct disorder relative to ADHD case subjects without conduct disorder. ADHD polygenic score showed significant association with comorbid conduct disorder symptoms. This relationship was explained by,the aggression items. Conclusions: Common genetic variation is relevant to ADHD, especially in individuals with comorbid aggression. The findings suggest that the previously published ADHD GWAS meta-analysis contains weak but true associations with common variants, support for which falls below genome-wide significance levels. The findings also highlight the fact that aggression in ADHD indexes genetic as well as clinical severity

Impact of the AHI1 Gene on the Vulnerability to Schizophrenia: A Case-Control Association Study

BackgroundThe Abelson helper integration-1 (AHI1) gene is required for both cerebellar and cortical development in humans. While the accelerated evolution of AHI1 in the human lineage indicates a role in cognitive (dys)function, a linkage scan in large pedigrees identified AHI1 as a positional candidate for schizophrenia. To further investigate the contribution of AHI1 to the susceptibility of schizophrenia, we evaluated the effect of AHI1 variation on the vulnerability to psychosis in two samples from Spain and Germany.Methodology/Principal Findings29 single-nucleotide polymorphisms (SNPs) located in a genomic region including the AHI1 gene were genotyped in two samples from Spain (280 patients with psychotic disorders; 348 controls) and Germany (247 patients with schizophrenic disorders; 360 controls). Allelic, genotypic and haplotype frequencies were compared between cases and controls in both samples separately, as well as in the combined sample. The effect of genotype on several psychopathological measures (BPRS, KGV, PANSS) assessed in a Spanish subsample was also evaluated. We found several significant associations in the Spanish sample. Particularly, rs7750586 and rs911507, both located upstream of the AHI1 coding region, were found to be associated with schizophrenia in the analysis of genotypic (p = 0.0033, and 0.031, respectively) and allelic frequencies (p = 0.001 in both cases). Moreover, several other risk and protective haplotypes were detected (0.006<p<0.036). Joint analysis also supported the association of rs7750586 and rs911507 with the risk for schizophrenia. The analysis of clinical measures also revealed an effect on symptom severity (minimum P value = 0.0037).Conclusions/SignificanceOur data support, in agreement with previous reports, an effect of AHI1 variation on the susceptibility to schizophrenia in central and southern European populations

An experimental study of the intrinsic stability of random forest variable importance measures

BACKGROUND: The stability of Variable Importance Measures (VIMs) based on random forest has recently received increased attention. Despite the extensive attention on traditional stability of data perturbations or parameter variations, few studies include influences coming from the intrinsic randomness in generating VIMs, i.e. bagging, randomization and permutation. To address these influences, in this paper we introduce a new concept of intrinsic stability of VIMs, which is defined as the self-consistence among feature rankings in repeated runs of VIMs without data perturbations and parameter variations. Two widely used VIMs, i.e., Mean Decrease Accuracy (MDA) and Mean Decrease Gini (MDG) are comprehensively investigated. The motivation of this study is two-fold. First, we empirically verify the prevalence of intrinsic stability of VIMs over many real-world datasets to highlight that the instability of VIMs does not originate exclusively from data perturbations or parameter variations, but also stems from the intrinsic randomness of VIMs. Second, through Spearman and Pearson tests we comprehensively investigate how different factors influence the intrinsic stability. RESULTS: The experiments are carried out on 19 benchmark datasets with diverse characteristics, including 10 high-dimensional and small-sample gene expression datasets. Experimental results demonstrate the prevalence of intrinsic stability of VIMs. Spearman and Pearson tests on the correlations between intrinsic stability and different factors show that #feature (number of features) and #sample (size of sample) have a coupling effect on the intrinsic stability. The synthetic indictor, #feature/#sample, shows both negative monotonic correlation and negative linear correlation with the intrinsic stability, while OOB accuracy has monotonic correlations with intrinsic stability. This indicates that high-dimensional, small-sample and high complexity datasets may suffer more from intrinsic instability of VIMs. Furthermore, with respect to parameter settings of random forest, a large number of trees is preferred. No significant correlations can be seen between intrinsic stability and other factors. Finally, the magnitude of intrinsic stability is always smaller than that of traditional stability. CONCLUSION: First, the prevalence of intrinsic stability of VIMs demonstrates that the instability of VIMs not only comes from data perturbations or parameter variations, but also stems from the intrinsic randomness of VIMs. This finding gives a better understanding of VIM stability, and may help reduce the instability of VIMs. Second, by investigating the potential factors of intrinsic stability, users would be more aware of the risks and hence more careful when using VIMs, especially on high-dimensional, small-sample and high complexity datasets

Identification and Replication of Loci Involved in Camptothecin-Induced Cytotoxicity Using CEPH Pedigrees

To date, the Centre d'Etude Polymorphism Humain (CEPH) cell line model has only been used as a pharmacogenomic tool to evaluate which genes are responsible for the disparity in response to a single drug. The purpose of this study was demonstrate the model's ability to establish a specific pattern of quantitative trait loci (QTL) related to a shared mechanism for multiple structurally related drugs, the camptothecins, which are Topoisomerase 1 inhibitors. A simultaneous screen of six camptothecin analogues for in vitro sensitivity in the CEPH cell lines resulted in cytotoxicity profiles and orders of potency which were in agreement with the literature. For all camptothecins studied, heritability estimates for cytotoxic response averaged 23.1±2.6%. Nonparametric linkage analysis was used to identify a relationship between genetic markers and response to the camptothecins. Ten QTLs on chromosomes 1, 3, 5, 6, 11, 12, 16 and 20 were identified as shared by all six camptothecin analogues. In a separate validation experiment, nine of the ten QTLs were replicated at the significant and suggestive levels using three additional camptothecin analogues. To further refine this list of QTLs, another validation study was undertaken and seven of the nine QTLs were independently replicated for all nine camptothecin analogues. This is the first study using the CEPH cell lines that demonstrates that a specific pattern of QTLs could be established for a class of drugs which share a mechanism of action. Moreover, it is the first study to report replication of linkage results for drug-induced cytotoxicity using this model. The QTLs, which have been identified as shared by all camptothecins and replicated across multiple datasets, are of considerable interest; they harbor genes related to the shared mechanism of action for the camptothecins, which are responsible for variation in response

Latent Class Analysis of Antisocial Behavior: Interaction of Serotonin Transporter Genotype and Maltreatment

To improve understanding about genetic and environmental influences on antisocial behavior (ASB), we tested the association of the 44-base pair polymorphism of the serotonin transporter gene (5-HTTLPR) and maltreatment using latent class analysis in 2,488 boys and girls from Wave 1 of the National Longitudinal Study of Adolescent Health. In boys, ASB was defined by three classes (Exclusive Covert, Mixed Covert and Overt, and No Problems) whereas in girls, ASB was defined by two classes (Exclusive Covert, No Problems). In boys, 5-HTTLPR and maltreatment were not significantly related to ASB. However, in girls, maltreatment, but not 5-HTTLPR, was significantly associated with ASB. A significant interaction between 5-HTTLPR and maltreatment was also observed, where maltreated girls homozygous for the short allele were 12 times more likely to be classified in the Exclusive Covert group than in the No Problems group. Structural differences in the latent structure of ASB at Wave 2 and Wave 3 prevented repeat LCA modeling. However, using counts of ASB, 5-HTTLPR, maltreatment, and its interaction were unrelated to overt and covert ASB at Wave 2 and only maltreatment was related to covert ASB at Wave 3. We discuss these findings within the context of sex differences in ASB and relevant models of gene-environment interplay across developmental periods

A systematic review on the effectiveness of physical and rehabilitation interventions for chronic non-specific low back pain

Low back pain (LBP) is a common and disabling disorder in western society. The management of LBP comprises a range of different intervention strategies including surgery, drug therapy, and non-medical interventions. The objective of the present study is to determine the effectiveness of physical and rehabilitation interventions (i.e. exercise therapy, back school, transcutaneous electrical nerve stimulation (TENS), low level laser therapy, education, massage, behavioural treatment, traction, multidisciplinary treatment, lumbar supports, and heat/cold therapy) for chronic LBP. The primary search was conducted in MEDLINE, EMBASE, CINAHL, CENTRAL, and PEDro up to 22 December 2008. Existing Cochrane reviews for the individual interventions were screened for studies fulfilling the inclusion criteria. The search strategy outlined by the Cochrane Back Review Groups (CBRG) was followed. The following were included for selection criteria: (1) randomized controlled trials, (2) adult (≥18 years) population with chronic (≥12 weeks) non-specific LBP, and (3) evaluation of at least one of the main clinically relevant outcome measures (pain, functional status, perceived recovery, or return to work). Two reviewers independently selected studies and extracted data on study characteristics, risk of bias, and outcomes at short, intermediate, and long-term follow-up. The GRADE approach was used to determine the quality of evidence. In total 83 randomized controlled trials met the inclusion criteria: exercise therapy (n = 37), back school (n = 5), TENS (n = 6), low level laser therapy (n = 3), behavioural treatment (n = 21), patient education (n = 1), traction (n = 1), and multidisciplinary treatment (n = 6). Compared to usual care, exercise therapy improved post-treatment pain intensity and disability, and long-term function. Behavioural treatment was found to be effective in reducing pain intensity at short-term follow-up compared to no treatment/waiting list controls. Finally, multidisciplinary treatment was found to reduce pain intensity and disability at short-term follow-up compared to no treatment/waiting list controls. Overall, the level of evidence was low. Evidence from randomized controlled trials demonstrates that there is low quality evidence for the effectiveness of exercise therapy compared to usual care, there is low evidence for the effectiveness of behavioural therapy compared to no treatment and there is moderate evidence for the effectiveness of a multidisciplinary treatment compared to no treatment and other active treatments at reducing pain at short-term in the treatment of chronic low back pain. Based on the heterogeneity of the populations, interventions, and comparison groups, we conclude that there are insufficient data to draw firm conclusion on the clinical effect of back schools, low-level laser therapy, patient education, massage, traction, superficial heat/cold, and lumbar supports for chronic LBP

Toxicity Testing in the 21st Century: Defining New Risk Assessment Approaches Based on Perturbation of Intracellular Toxicity Pathways

The approaches to quantitatively assessing the health risks of chemical exposure have not changed appreciably in the past 50 to 80 years, the focus remaining on high-dose studies that measure adverse outcomes in homogeneous animal populations. This expensive, low-throughput approach relies on conservative extrapolations to relate animal studies to much lower-dose human exposures and is of questionable relevance to predicting risks to humans at their typical low exposures. It makes little use of a mechanistic understanding of the mode of action by which chemicals perturb biological processes in human cells and tissues. An alternative vision, proposed by the U.S. National Research Council (NRC) report Toxicity Testing in the 21st Century: A Vision and a Strategy, called for moving away from traditional high-dose animal studies to an approach based on perturbation of cellular responses using well-designed in vitro assays. Central to this vision are (a) “toxicity pathways” (the innate cellular pathways that may be perturbed by chemicals) and (b) the determination of chemical concentration ranges where those perturbations are likely to be excessive, thereby leading to adverse health effects if present for a prolonged duration in an intact organism. In this paper we briefly review the original NRC report and responses to that report over the past 3 years, and discuss how the change in testing might be achieved in the U.S. and in the European Union (EU). EU initiatives in developing alternatives to animal testing of cosmetic ingredients have run very much in parallel with the NRC report. Moving from current practice to the NRC vision would require using prototype toxicity pathways to develop case studies showing the new vision in action. In this vein, we also discuss how the proposed strategy for toxicity testing might be applied to the toxicity pathways associated with DNA damage and repair

NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns

Purpose: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy. / Methods: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy. / Results: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism. / Conclusion: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic–atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants