A detailed study on the origin of the bandwidth reduction in the Coupling- Efficiency (CE) spectrum for non-uniform grating couplers (nu-GCs) due to a band-pass filter effect is reported. This effect ...is deeply investigated through Finite Difference Time Domain simulations (FDTD) in order to look at the spatial Fourier Transform (sFT) of the nu-GC's emission, which gives the energies and the wavevectors sustained by the overall structure. We show: how to evaluate the bandwidth from the sFT and how the band-pass filter effect arises from the sFT affecting the CE spectrum giving a physical insight on the bandwidth's reduction. Moreover, we also point out how the concept of photonic crystal bandstructure can be applied for such nu-GCs and used as a powerful tool to describe the dispersion of the light inside these non periodic structures. Finally, both the sFT and the bandstructure approaches are shown to give the same outcomes in terms of the bandwidth evaluation and to be in agreement with the CE spectra's behaviours. The entire analysis is proposed also for uniform-GC in order to directly compare the two different types of structures.
Alcohol consumption is known to lead to gene expression changes in the brain. After performing weighted gene co-expression network analyses (WGCNA) on genome-wide mRNA and microRNA (miRNA) expression ...in Nucleus Accumbens (NAc) of subjects with alcohol dependence (AD; N = 18) and of matched controls (N = 18), six mRNA and three miRNA modules significantly correlated with AD were identified (Bonferoni-adj. p≤ 0.05). Cell-type-specific transcriptome analyses revealed two of the mRNA modules to be enriched for neuronal specific marker genes and downregulated in AD, whereas the remaining four mRNA modules were enriched for astrocyte and microglial specific marker genes and upregulated in AD. Gene set enrichment analysis demonstrated that neuronal specific modules were enriched for genes involved in oxidative phosphorylation, mitochondrial dysfunction and MAPK signaling. Glial-specific modules were predominantly enriched for genes involved in processes related to immune functions, i.e. cytokine signaling (all adj. p≤ 0.05). In mRNA and miRNA modules, 461 and 25 candidate hub genes were identified, respectively. In contrast to the expected biological functions of miRNAs, correlation analyses between mRNA and miRNA hub genes revealed a higher number of positive than negative correlations (χ2 test p≤ 0.0001). Integration of hub gene expression with genome-wide genotypic data resulted in 591 mRNA cis-eQTLs and 62 miRNA cis-eQTLs. mRNA cis-eQTLs were significantly enriched for AD diagnosis and AD symptom counts (adj. p = 0.014 and p = 0.024, respectively) in AD GWAS signals in a large, independent genetic sample from the Collaborative Study on Genetics of Alcohol (COGA). In conclusion, our study identified putative gene network hubs coordinating mRNA and miRNA co-expression changes in the NAc of AD subjects, and our genetic (cis-eQTL) analysis provides novel insights into the etiological mechanisms of AD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To provide insights into the biology of opioid dependence (OD) and opioid use (i.e., exposure, OE), we completed a genome-wide analysis comparing 4503 OD cases, 4173 opioid-exposed controls, and ...32,500 opioid-unexposed controls, including participants of European and African descent (EUR and AFR, respectively). Among the variants identified, rs9291211 was associated with OE (exposed vs. unexposed controls; EUR z = -5.39, p = 7.2 × 10
). This variant regulates the transcriptomic profiles of SLC30A9 and BEND4 in multiple brain tissues and was previously associated with depression, alcohol consumption, and neuroticism. A phenome-wide scan of rs9291211 in the UK Biobank (N > 360,000) found association of this variant with propensity to use dietary supplements (p = 1.68 × 10
). With respect to the same OE phenotype in the gene-based analysis, we identified SDCCAG8 (EUR + AFR z = 4.69, p = 10
), which was previously associated with educational attainment, risk-taking behaviors, and schizophrenia. In addition, rs201123820 showed a genome-wide significant difference between OD cases and unexposed controls (AFR z = 5.55, p = 2.9 × 10
) and a significant association with musculoskeletal disorders in the UK Biobank (p = 4.88 × 10
). A polygenic risk score (PRS) based on a GWAS of risk-tolerance (n = 466,571) was positively associated with OD (OD vs. unexposed controls, p = 8.1 × 10
; OD cases vs. exposed controls, p = 0.054) and OE (exposed vs. unexposed controls, p = 3.6 × 10
). A PRS based on a GWAS of neuroticism (n = 390,278) was positively associated with OD (OD vs. unexposed controls, p = 3.2 × 10
; OD vs. exposed controls, p = 0.002) but not with OE (p = 0.67). Our analyses highlight the difference between dependence and exposure and the importance of considering the definition of controls in studies of addiction.
Background
Long noncoding RNA (lncRNA) have been implicated in the etiology of alcohol use. Since lncRNA provide another layer of complexity to the transcriptome, assessing their expression in the ...brain is the first critical step toward understanding lncRNA functions in alcohol use and addiction. Thus, we sought to profile lncRNA expression in the nucleus accumbens (NAc) in a large postmortem alcohol brain sample.
Methods
LncRNA and protein‐coding gene (PCG) expressions in the NAc from 41 subjects with alcohol dependence (AD) and 41 controls were assessed via a regression model. Weighted gene coexpression network analysis was used to identify lncRNA and PCG networks (i.e., modules) significantly correlated with AD. Within the significant modules, key network genes (i.e., hubs) were also identified. The lncRNA and PCG hubs were correlated via Pearson correlations to elucidate the potential biological functions of lncRNA. The lncRNA and PCG hubs were further integrated with GWAS data to identify expression quantitative trait loci (eQTL).
Results
At Bonferroni adj. p‐value ≤ 0.05, we identified 19 lncRNA and 5 PCG significant modules, which were enriched for neuronal and immune‐related processes. In these modules, we further identified 86 and 315 PCG and lncRNA hubs, respectively. At false discovery rate (FDR) of 10%, the correlation analyses between the lncRNA and PCG hubs revealed 3,125 positive and 1,860 negative correlations. Integration of hubs with genotype data identified 243 eQTLs affecting the expression of 39 and 204 PCG and lncRNA hubs, respectively.
Conclusions
Our study identified lncRNA and gene networks significantly associated with AD in the NAc, coordinated lncRNA and mRNA coexpression changes, highlighting potentially regulatory functions for the lncRNA, and our genetic (cis‐eQTL) analysis provides novel insights into the etiological mechanisms of AD.
Alcohol use disorder (AUD) is a debilitating disease with no reliable and efficacious treatment. However, studying the brain transcriptome may
help elucidate the neuropathology of AUD. Using gene network approaches, we provide a glimpse into the complex interactions between coding and
non‐coding RNA from patients with AUD and test the moderating effect of clinically relevant risk genetic elements on these interactions. Furthermore,
genes and genetic elements associated with AUD were contextualized by examining past studies and conducting enrichment
Here, we investigate the mechanism and function of LKB1, a Ser/Thr kinase mutated in Peutz-Jegher syndrome (PJS). We demonstrate that LKB1 physically associates with p53 and regulates specific ...p53-dependent apoptosis pathways. LKB1 protein is present in both the cytoplasm and nucleus of living cells and translocates to mitochondria during apoptosis. In vivo, LKB1 is highly upregulated in pyknotic intestinal epithelial cells. In contrast, polyps arising in Peutz-Jegher patients are devoid of LKB1 staining and have reduced numbers of apoptotic cells. We propose that a deficiency in apoptosis is a key factor in the formation of multiple benign intestinal polyps in PJS patients, and possibly for the subsequent development of malignant tumors in these patients.
Cardiac hypertrophic growth in response to pathological cues is associated with reexpression of fetal genes and decreased cardiac function and is often a precursor to heart failure. In contrast, ...physiologically induced hypertrophy is adaptive, resulting in improved cardiac function. The processes that selectively induce these hypertrophic states are poorly understood. Here, we have profiled 2 repressive epigenetic marks, H3K9me2 and H3K27me3, which are involved in stable cellular differentiation, specifically in cardiomyocytes from physiologically and pathologically hypertrophied rat hearts, and correlated these marks with their associated transcriptomes. This analysis revealed the pervasive loss of euchromatic H3K9me2 as a conserved feature of pathological hypertrophy that was associated with reexpression of fetal genes. In hypertrophy, H3K9me2 was reduced following a miR-217-mediated decrease in expression of the H3K9 dimethyltransferases EHMT1 and EHMT2 (EHMT1/2). miR-217-mediated, genetic, or pharmacological inactivation of EHMT1/2 was sufficient to promote pathological hypertrophy and fetal gene reexpression, while suppression of this pathway protected against pathological hypertrophy both in vitro and in mice. Thus, we have established a conserved mechanism involving a departure of the cardiomyocyte epigenome from its adult cellular identity to a reprogrammed state that is accompanied by reexpression of fetal genes and pathological hypertrophy. These results suggest that targeting miR-217 and EHMT1/2 to prevent H3K9 methylation loss is a viable therapeutic approach for the treatment of heart disease.
The majority of short gamma-ray bursts (SGRBs) are thought to originate from the merger of compact binary systems collapsing directly to form a black hole. However, it has been proposed that both ...SGRBs and long gamma-ray bursts (LGRBs) may, on rare occasions, form an unstable millisecond pulsar (magnetar) prior to final collapse. GRB 090515, detected by the Swift satellite was extremely short, with a T90 of 0.036 ± 0.016 s, and had a very low fluence of 2 × 10−8 erg cm−2 and faint optical afterglow. Despite this, the 0.3–10 keV flux in the first 200 s was the highest observed for an SGRB by the Swift X-ray Telescope (XRT). The X-ray light curve showed an unusual plateau and steep decay, becoming undetectable after ∼500 s. This behaviour is similar to that observed in some long bursts proposed to have magnetars contributing to their emission. In this paper, we present the Swift observations of GRB 090515 and compare it to other gamma-ray bursts (GRBs) in the Swift sample. Additionally, we present optical observations from Gemini, which detected an afterglow of magnitude 26.4 ± 0.1 at T+ 1.7 h after the burst. We discuss potential causes of the unusual 0.3–10 keV emission and suggest it might be energy injection from an unstable millisecond pulsar. Using the duration and flux of the plateau of GRB 090515, we place constraints on the millisecond pulsar spin period and magnetic field.
Abstract Background This is a double blind, placebo-controlled trial that evaluated the efficacy of disulfiram, naltrexone and their combination in patients with co-occurring cocaine and alcohol ...dependence. Methods 208 patients were randomized to disulfiram (250 mg/day), naltrexone (100 mg/day), the combination, or placebo for 11 weeks. Outcomes were in-trial abstinence from cocaine and/or alcohol. Results Few safety concerns were reported, although medication adherence was low in a number of patients for both medications, alone or in combination. In the primary analyses (GEE modeling), abstinence from cocaine as measured by cocaine-negative urines and days of self-reported abstinence from cocaine or alcohol did not differ between placebo and any of the medication groups. However, patients taking disulfiram (alone or in combination) were most likely to achieve combined abstinence from cocaine and alcohol. Secondary analyses revealed that patients taking the disulfiram–naltrexone combination were most likely to achieve 3 consecutive weeks of abstinence from cocaine and alcohol. Conclusion There was an association between disulfiram treatment and abstinence from cocaine and alcohol. More patients taking the disulfiram–naltrexone combination achieved 3 consecutive weeks of abstinence in treatment than placebo-treated patients.
Vesta has a complex cratering history, with ancient terrains as well as recent large impacts that have led to regional resurfacing. Crater counts can help constrain the relative ages of different ...units on Vesta׳s surface, but converting those crater counts to absolute ages requires a chronology function. We present a cratering chronology based on the best current models for the dynamical evolution of asteroid belt, and calibrate it to Vesta using the record of large craters on its surface. While uncertainties remain, our chronology function is broadly consistent with an ancient surface of Vesta as well as other constraints such as the bombardment history of the rest of the inner Solar System and the Ar–Ar age distribution of howardite, eucrite and diogenite (HED) meteorites from Vesta.
•We develop a crater chronology for Vesta based on models of asteroid belt evolution.•Our chronology is consistent with numerous constraints from Vesta.•Application to other large asteroids like Ceres will allow for testing and refinement.
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