Alignment verification for electron beam lithography

Alignment between lithography layers is essential for device fabrication. A minor defect in a single marker can lead to incorrect alignment and this can be the source of wafer reworks. In this paper we show that this can be prevented by using extra alignment markers to check the alignment during patterning, rather than inspecting vernier patterns after the exposure is completed. Accurate vernier patterns can often only be read after pattern transfer has been carried out. We also show that by using a Penrose tile as a marker it is possible to locate the marker to about 1 nm without fully exposing the resist. This means that the marker can be reused with full accuracy, thus improving the layer to layer alignment accuracy. Lithography tool noise limits the process

InGaN/GaN Laser Diodes with High Order Notched Gratings

We report on InGaN/GaN distributed feedback laser diodes with high order gratings emitting at a single wavelength around 428 nm. The 39th order notched gratings have the advantage of a simplified fabrication route with no need for overgrowth. The laser ridge and grating were formed by electron beam lithography followed by ICP etching. The as-cleaved lasers emitted in the pulsed regime with a peak single-mode output power of 15 mW. Optimization of the grating design should lead to higher power single wavelength operation

Pancreatic Transcription Factors Containing Protein Transduction Domains Drive Mouse Embryonic Stem Cells towards Endocrine Pancreas

Protein transduction domains (PTDs), such as the HIV1-TAT peptide, have been previously used to promote the uptake of proteins into a range of cell types, including stem cells. Here we generated pancreatic transcription factors containing PTD sequences and administered these to endoderm enriched mouse embryonic stem (ES) cells under conditions that were designed to mimic the pattern of expression of these factors in the developing pancreas. The ES cells were first cultured as embryoid bodies and treated with Activin A and Bone morphogenetic protein 4 (BMP4) to promote formation of definitive endoderm. Cells were subsequently plated as a monolayer and treated with different combinations of the modified recombinant transcription factors Pdx1 and MafA. The results demonstrate that each transcription factor was efficiently taken up by the cells, where they were localized in the nuclei. RT-qPCR was used to measure the expression levels of pancreatic markers. After the addition of Pdx1 alone for a period of five days, followed by the combination of Pdx1 and TAT-MafA in a second phase, up-regulation of insulin 1, insulin 2, Pdx1, Glut2, Pax4 and Nkx6.1 was observed. As assessed by immunocytochemistry, double positive insulin and Pdx1 cells were detected in the differentiated cultures. Although the pattern of pancreatic markers expression in these cultures was comparable to that of a mouse transformed β-cell line (MIN-6) and human islets, the expression levels of insulin observed in the differentiated ES cell cultures were several orders of magnitude lower. This suggests that, although PTD-TFs may prove useful in studying the role of exogenous TFs in the differentiation of ES cells towards islets and other pancreatic lineages, the amount of insulin generated is well below that required for therapeutically useful cells

GaN-based distributed feedback laser diodes for optical communications

Over the past 20 years, research into Gallium Nitride (GaN) has evolved from LED lighting to Laser Diodes (LDs), with applications ranging from quantum to medical and into communications. Previously, off-the-shelf GaN LDs have been reported with a view on free space and underwater communications. However, there are applications where the ability to select a single emitted wavelength is highly desirable, namely in atomic clocks or in filtered free-space communications systems. To accomplish this, Distributed Feedback (DFB) geometries are utilised. Due to the complexity of overgrowth steps for buried gratings in III-Nitride material systems, GaN DFBs have a grating etched into the sidewall to ensure single mode operation, with wavelengths ranging from 405nm to 435nm achieved. The main motivation in developing these devices is for the cooling of strontium ions (Sr+) in atomic clock applications, but their feasibility for optical communications have also been investigated. Data transmission rates exceeding 1 Gbit/s have been observed in unfiltered systems, and work is currently ongoing to examine their viability for filtered communications. Ultimately, transmission through Wavelength Division Multiplexing (WDM) or Orthogonal Frequency Division Multiplexing (OFDM) is desired, to ensure that data is communicated more coherently and efficiently. We present results on the characterisation of GaN DFBs, and demonstrate their capability for use in filtered optical communications systems

InGaN/GaN Laser Diodes and their Applications

Gallium nitride (GaN) laser diodes are becoming popular sources not only for lighting but for applications ranging from communications to quantum. This paper presents the use of a commercial, off-the-shelf laser diode, with an emission wavelength of 450 nm, for visible light communication, both in free space and for underwater scenarios. Data rates up to 15 Gbit/s have been achieved by making use of orthogonal frequency division multiplexing (OFDM). In addition, distributed feedback (DFB) lasers have been realised emitting at a single wavelength which lend themselves towards applications where high spectral purity is crucial such as atomic clocks or filtered free space transmission systems. These devices have the grating structure etched into the sidewall of the ridge and work is ongoing to measure the linewidth of these lasers with the intended application of cooling Sr+ ions

Applications of Single Frequency Blue Lasers

Gallium nitride (GaN) sources are becoming a regular part of today's world and are now key devices for lighting infrastructures, communications systems and quantum applications, amongst others. In particular, many applications have seen the shift from LEDs to laser diodes to make use of higher powers, higher bandwidths and increased transmission distances. Laser communication systems are well established, however there are applications where the ability to select a single emitted wavelength is highly desirable, such as quantum atomic clocks or in filtered communication systems. Distributed feedback (DFB) lasers have been realised emitting at a single wavelength where the grating structure is etched into the sidewall of the ridge. The main motivation in developing these lasers is for the cooling of ions in atomic clocks; however their feasibility for optical communications is also explored. Narrow linewidth lasers are desirable and this paper will explore how this is achieved. Data rates in excess of 1 Gbit/s have also been achieved in a directly modulated, unfiltered system. These devices lend themselves towards wavelength division multiplexing and filtered optical communications systems and this will be analysed further in the work presented here

Distributed Feedback Lasers for Quantum Cooling Applications

There is an ever-growing need for compact sources which can be used for the cooling process in high accuracy atomic clocks. Current systems make use of large, expensive lasers which are power-hungry and often require frequency doubling in order to hit the required wavelengths. Distributed feedback (DFB) lasers have been fabricated at a number of key wavelengths which would allow chip scale atomic devices with very high accuracy to become a reality. Two key atomic transitions analysed here are 88 Sr + and 87 Rb which require cooling at 422 nm and 780.24 nm, respectively. The vital parameter of the DFB lasers for this application is the linewidth, as very narrow linewidths are required in order for the atomic cooling process to occur. The lasers realised here produce the required power levels, with high side-mode suppression ratios and show good single mode tuning which is important for hitting precise wavelengths. This work will present the latest techniques and results using the DFB lasers at both wavelengths

Insulin Gene Expression Is Regulated by DNA Methylation

BACKGROUND:Insulin is a critical component of metabolic control, and as such, insulin gene expression has been the focus of extensive study. DNA sequences that regulate transcription of the insulin gene and the majority of regulatory factors have already been identified. However, only recently have other components of insulin gene expression been investigated, and in this study we examine the role of DNA methylation in the regulation of mouse and human insulin gene expression. METHODOLOGY/PRINCIPAL FINDINGS:Genomic DNA samples from several tissues were bisulfite-treated and sequenced which revealed that cytosine-guanosine dinucleotide (CpG) sites in both the mouse Ins2 and human INS promoters are uniquely demethylated in insulin-producing pancreatic beta cells. Methylation of these CpG sites suppressed insulin promoter-driven reporter gene activity by almost 90% and specific methylation of the CpG site in the cAMP responsive element (CRE) in the promoter alone suppressed insulin promoter activity by 50%. Methylation did not directly inhibit factor binding to the CRE in vitro, but inhibited ATF2 and CREB binding in vivo and conversely increased the binding of methyl CpG binding protein 2 (MeCP2). Examination of the Ins2 gene in mouse embryonic stem cell cultures revealed that it is fully methylated and becomes demethylated as the cells differentiate into insulin-expressing cells in vitro. CONCLUSIONS/SIGNIFICANCE:Our findings suggest that insulin promoter CpG demethylation may play a crucial role in beta cell maturation and tissue-specific insulin gene expression

Genetic diversity fuels gene discovery for tobacco and alcohol use

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury(1-4). These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries(5). Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.Peer reviewe

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe