147 research outputs found
Dispersive Elastodynamics of 1D Banded Materials and Structures: Design
Within periodic materials and structures, wave scattering and dispersion
occur across constituent material interfaces leading to a banded frequency
response. In an earlier paper, the elastodynamics of one-dimensional periodic
materials and finite structures comprising these materials were examined with
an emphasis on their frequency-dependent characteristics. In this work, a novel
design paradigm is presented whereby periodic unit cells are designed for
desired frequency band properties, and with appropriate scaling, these cells
are used as building blocks for forming fully periodic or partially periodic
structures with related dynamical characteristics. Through this multiscale
dispersive design methodology, which is hierarchical and integrated, structures
can be devised for effective vibration or shock isolation without needing to
employ dissipative damping mechanisms. The speed of energy propagation in a
designed structure can also be dictated through synthesis of the unit cells.
Case studies are presented to demonstrate the effectiveness of the methodology
for several applications. Results are given from sensitivity analyses that
indicate a high level of robustness to geometric variation.Comment: 33 text pages, 27 figure
Rho-associated kinase is a therapeutic target in neuroblastoma
Source at: http://doi.org/10.1073/pnas.1706011114 Neuroblastoma is a peripheral neural system tumor that originates
from the neural crest and is the most common and deadly tumor of
infancy. Here we show that neuroblastoma harbors frequent
mutations of genes controlling the Rac/Rho signaling cascade
important for proper migration and differentiation of neural crest
cells during neuritogenesis. RhoA is activated in tumors from
neuroblastoma patients, and elevated expression of Rho-associated
kinase (ROCK)2 is associated with poor patient survival. Pharmacological
or genetic inhibition of ROCK1 and 2, key molecules in Rho
signaling, resulted in neuroblastoma cell differentiation and
inhibition of neuroblastoma cell growth, migration, and invasion.
Molecularly, ROCK inhibition induced glycogen synthase
kinase 3β-dependent phosphorylation and degradation of MYCN protein.
Small-molecule inhibition of ROCK suppressed MYCN-driven
neuroblastoma growth in TH-MYCN homozygous transgenic mice
and MYCN gene-amplified neuroblastoma xenograft growth in nude
mice. Interference with Rho/Rac signaling might offer therapeutic
perspectives for high-risk neuroblastoma
Prediction of lithium response using genomic data
Predicting lithium response prior to treatment could both expedite therapy and avoid exposure to side effects. Since lithium responsiveness may be heritable, its predictability based on genomic data is of interest. We thus evaluate the degree to which lithium response can be predicted with a machine learning (ML) approach using genomic data. Using the largest existing genomic dataset in the lithium response literature (n = 2210 across 14 international sites; 29% responders), we evaluated the degree to which lithium response could be predicted based on 47,465 genotyped single nucleotide polymorphisms using a supervised ML approach. Under appropriate cross-validation procedures, lithium response could be predicted to above-chance levels in two constituent sites (Halifax, Cohen's kappa 0.15, 95% confidence interval, CI [0.07, 0.24]; and Würzburg, kappa 0.2 [0.1, 0.3]). Variants with shared importance in these models showed over-representation of postsynaptic membrane related genes. Lithium response was not predictable in the pooled dataset (kappa 0.02 [- 0.01, 0.04]), although non-trivial performance was achieved within a restricted dataset including only those patients followed prospectively (kappa 0.09 [0.04, 0.14]). Genomic classification of lithium response remains a promising but difficult task. Classification performance could potentially be improved by further harmonization of data collection procedures
Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium
It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10-8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk
Association of Attention-Deficit/Hyperactivity Disorder and Depression Polygenic Scores with Lithium Response: A Consortium for Lithium Genetics Study
Response to lithium varies widely between individuals with bipolar disorder (BD). Polygenic risk scores (PRSs) can uncover pharmacogenomics effects and may help predict drug response. Patients (N = 2,510) with BD were assessed for long-term lithium response in the Consortium on Lithium Genetics using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and schizophrenia (SCZ) were computed using lassosum and in a model including all three PRSs and other covariates, and the PRS of ADHD (β = −0.14; 95% confidence interval [CI]: −0.24 to −0.03; p value = 0.010) and MDD (β = −0.16; 95% CI: −0.27 to −0.04; p value = 0.005) predicted worse quantitative lithium response. A higher SCZ PRS was associated with higher rates of medication nonadherence (OR = 1.61; 95% CI: 1.34–1.93; p value = 2e−7). This study indicates that genetic risk for ADHD and depression may influence lithium treatment response. Interestingly, a higher SCZ PRS was associated with poor adherence, which can negatively impact treatment response. Incorporating genetic risk of ADHD, depression, and SCZ in combination with clinical risk may lead to better clinical care for patients with BD
Exploring the genetics of lithium response in bipolar disorders
Background: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N = 2064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II. Results: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism. Conclusions: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II
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