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Coronary artery calcification (CAC) is a measure of atherosclerosis and a well-established predictor of coronary artery disease (CAD) events. Here we describe a genome-wide association study (GWAS) of CAC in 22,400 participants from multiple ancestral groups. We confirmed associations with four known loci and identified two additional loci associated with CAC (ARSE and MMP16), with evidence of significant associations in replication analyses for both novel loci. Functional assays of ARSE and MMP16 in human vascular smooth muscle cells (VSMCs) demonstrate that ARSE is a promoter of VSMC calcification and VSMC phenotype switching from a contractile to a calcifying or osteogenic phenotype. Furthermore, we show that the association of variants near ARSE with reduced CAC is likely explained by reduced ARSE expression with the G allele of enhancer variant rs5982944. Our study highlights ARSE as an important contributor to atherosclerotic vascular calcification, and a potential drug target for vascular calcific disease.

We study business cycles with cyclical returns to scale. Contrary to tightly parameterized conventional production functions, we empirically identify strong input complementarity that leads to procyclical returns to scale. We, therefore, propose a flexible translog production function that allows complementarity-induced procyclical returns to scale. We integrate this function into a standard medium-scale dynamic stochastic general equilibrium model. Our estimated model with input complementarity (i) features procyclical returns to scale and acyclical price markups, (ii) better matches the cyclicality of factor shares, and (iii) significantly decreases the contribution of markup shocks to output fluctuations relative to those of the standard model.

To enable emerging applications such as deep machine learning and graph processing, 3D network-on-chip (NoC) enabled heterogeneous manycore platforms that can integrate many processing elements (PEs) are needed. However, designing such complex systems with multiple objectives can be challenging due to the huge associated design space and long evaluation times. To optimize such systems, we propose a new multi-objective design space exploration framework called MOELA that combines the benefits of evolutionary-based search with a learning-based local search to quickly determine PE and communication link placement to optimize multiple objectives (e.g., latency, throughput, and energy) in 3D NoC enabled heterogeneous manycore systems. Compared to state-of-the-art approaches, MOELA increases the speed of finding solutions by up to 128x, leads to a better Pareto Hypervolume (PHV) by up to 12.14x and improves energy-delay-product (EDP) by up to 7.7% in a 5-objective scenario.

Long non-coding RNAs (lncRNAs) are known to perform important regulatory functions in lipid metabolism. Large-scale whole-genome sequencing (WGS) studies and new statistical methods for variant set tests now provide an opportunity to assess more associations between rare variants in lncRNA genes and complex traits across the genome. In this study, we used high-coverage WGS from 66,329 participants of diverse ancestries with measurement of blood lipids and lipoproteins (LDL-C, HDL-C, TC, and TG) in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program to investigate the role of lncRNAs in lipid variability. We aggregated rare variants for 165,375 lncRNA genes based on their genomic locations and conducted rare-variant aggregate association tests using the STAAR (variant-set test for association using annotation information) framework. We performed STAAR conditional analysis adjusting for common variants in known lipid GWAS loci and rare-coding variants in nearby protein-coding genes. Our analyses revealed 83 rare lncRNA variant sets significantly associated with blood lipid levels, all of which were located in known lipid GWAS loci (in a ±500-kb window of a Global Lipids Genetics Consortium index variant). Notably, 61 out of 83 signals (73%) were conditionally independent of common regulatory variation and rare protein-coding variation at the same loci. We replicated 34 out of 61 (56%) conditionally independent associations using the independent UK Biobank WGS data. Our results expand the genetic architecture of blood lipids to rare variants in lncRNAs.

Long non-coding RNAs (lncRNAs) are known to perform important regulatory functions in lipid metabolism. Large-scale whole-genome sequencing (WGS) studies and new statistical methods for variant set tests now provide an opportunity to assess more associations between rare variants in lncRNA genes and complex traits across the genome. In this study, we used high-coverage WGS from 66,329 participants of diverse ancestries with measurement of blood lipids and lipoproteins (LDL-C, HDL-C, TC, and TG) in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program to investigate the role of lncRNAs in lipid variability. We aggregated rare variants for 165,375 lncRNA genes based on their genomic locations and conducted rare-variant aggregate association tests using the STAAR (variant-set test for association using annotation information) framework. We performed STAAR conditional analysis adjusting for common variants in known lipid GWAS loci and rare-coding variants in nearby protein-coding genes. Our analyses revealed 83 rare lncRNA variant sets significantly associated with blood lipid levels, all of which were located in known lipid GWAS loci (in a ±500-kb window of a Global Lipids Genetics Consortium index variant). Notably, 61 out of 83 signals (73%) were conditionally independent of common regulatory variation and rare protein-coding variation at the same loci. We replicated 34 out of 61 (56%) conditionally independent associations using the independent UK Biobank WGS data. Our results expand the genetic architecture of blood lipids to rare variants in lncRNAs.

Long non-coding RNAs (lncRNAs) are known to perform important regulatory functions in lipid metabolism. Large-scale whole-genome sequencing (WGS) studies and new statistical methods for variant set tests now provide an opportunity to assess more associations between rare variants in lncRNA genes and complex traits across the genome. In this study, we used high-coverage WGS from 66,329 participants of diverse ancestries with measurement of blood lipids and lipoproteins (LDL-C, HDL-C, TC, and TG) in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program to investigate the role of lncRNAs in lipid variability. We aggregated rare variants for 165,375 lncRNA genes based on their genomic locations and conducted rare-variant aggregate association tests using the STAAR (variant-set test for association using annotation information) framework. We performed STAAR conditional analysis adjusting for common variants in known lipid GWAS loci and rare-coding variants in nearby protein-coding genes. Our analyses revealed 83 rare lncRNA variant sets significantly associated with blood lipid levels, all of which were located in known lipid GWAS loci (in a ±500-kb window of a Global Lipids Genetics Consortium index variant). Notably, 61 out of 83 signals (73%) were conditionally independent of common regulatory variation and rare protein-coding variation at the same loci. We replicated 34 out of 61 (56%) conditionally independent associations using the independent UK Biobank WGS data. Our results expand the genetic architecture of blood lipids to rare variants in lncRNAs.

Recent trends see a move away from a fixed-resource server-centric datacenter model to a more adaptable "disaggregated" datacenter model. These disaggregated datacenters can then dynamically group resources to the specific requirements of an incoming workload, thereby improving efficiency. To properly utilize these disaggregated datacenters, workload allocation techniques must examine the current state of the datacenter and choose resources that not only optimize the current workload request, but future ones. Since disaggregated datacenters are severely bottlenecked by the available network resources, our work proposes a heuristic-based approach called RISA, which significantly reduces the network usage of workload allocations in disaggregated datacenters. Compared to the state-of-the-art, RISA reduces the power consumption for optical components by 33% and reduces the average CPU-RAM round-trip latency by 50%. Additionally, RISA significantly outperforms the state-of-the-art in terms of execution time., Comment: Clarified some prior work and their citations

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI's Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI's Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.

We study business cycles with cyclical returns to scale. Contrary to tightly parameterized production functions (Cobb-Douglas and Constant Elasticity of Substitution), we empirically identify strong input complementarity that leads to procyclical returns to scale. We therefore propose a flexible translog production function that allows complementarity-induced procyclical returns to scale, and we integrate this function into a standard medium-scale dynamic stochastic general equilibrium (DSGE) model. The estimated model with the procyclical returns to scale (i) features procyclical price markups, (ii) better matches the cyclicality of factor shares, and (iii) decreases by nearly half the contribution of markup shocks to output fluctuations.

Blood lipids are heritable modifiable causal factors for coronary artery disease. Despite well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing (WGS), partly due to limited sample sizes, ancestral diversity, and interpretation of clinical significance. Among 66,329 ancestrally diverse (56% non-European) participants, we associate 428M variants from deep-coverage WGS with lipid levels; ~400M variants were not assessed in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with blood lipids through analysis of common and rare coding variants. We discover several associated rare non-coding variants, largely at Mendelian lipid genes. Notably, we observe rare LDLR intronic variants associated with markedly increased LDL-C, similar to rare LDLR exonic variants. In conclusion, we conducted a systematic whole genome scan for blood lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.

Network-on-chip (NoC) architectures rely on buffers to store flits to cope with contention for router resources during packet switching. Recently, reversible multi-function channel (RMC) buffers have been proposed to simultaneously reduce power and enable adaptive NoC buffering between adjacent routers. While adaptive buffering can improve NoC performance by maximizing buffer utilization, controlling the RMC buffer allocations requires a congestion-aware, scalable, and proactive policy. In this work, we present RACE, a novel reinforcement learning (RL) framework that utilizes better awareness of network congestion and a new reward metric ("falsefulls") to help guide the RL agent towards better RMC buffer control decisions. We show that RACE reduces NoC latency by up to 48.9%, and energy consumption by up to 47.1% against state-of-the-art NoC buffer control policies., Comment: 6 pages, 8 figures, 3 tables

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10-72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10-4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10-5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10-72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10-4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10-5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.

Throughout the COVID-19 pandemic, the most common symptom displayed by patients has been a fever, leading to the use of temperature scanning as a preemptive measure to detect potential carriers of the virus. Human employees with handheld thermometers have been used to fulfill this task, however this puts them at risk as they cannot be physically distanced and the sequential nature of this method leads to great inconveniences and inefficiency. The proposed solution is an autonomously navigating robot capable of conversing and scanning people's temperature to detect fevers and help screen for COVID-19. To satisfy this objective, the robot must be able to (1) navigate autonomously, (2) detect and track people, and (3) get individuals' temperature reading and converse with them if it exceeds 38{\deg}C. An autonomously navigating mobile robot is used with a manipulator controlled using a face tracking algorithm, and an end effector consisting of a thermal camera, smartphone, and chatbot. The goal is to develop a functioning solution that performs the above tasks. In addition, technical challenges encountered and their engineering solutions will be presented, and recommendations will be made for enhancements that could be incorporated when approaching commercialization.

Time of flight based Non-line-of-sight (NLOS) imaging approaches require precise calibration of illumination and detector positions on the visible scene to produce reasonable results. If this calibration error is sufficiently high, reconstruction can fail entirely without any indication to the user. In this work, we highlight the necessity of building autocalibration into NLOS reconstruction in order to handle mis-calibration. We propose a forward model of NLOS measurements that is differentiable with respect to both, the hidden scene albedo, and virtual illumination and detector positions. With only a mean squared error loss and no regularization, our model enables joint reconstruction and recovery of calibration parameters by minimizing the measurement residual using gradient descent. We demonstrate our method is able to produce robust reconstructions using simulated and real data where the calibration error applied causes other state of the art algorithms to fail.

By lowering the number of vertical connections in fully connected 3D networks-on-chip (NoCs), partially connected 3D NoCs (PC-3DNoCs) help alleviate reliability and fabrication issues. This paper proposes a novel, adaptive congestion- and energy-aware elevator-selection scheme called AdEle to improve the traffic distribution in PC-3DNoCs. AdEle employs an offline multi-objective simulated-annealing-based algorithm to find good elevator subsets and an online elevator selection policy to enhance elevator selection during routing. Compared to the state-of- the-art techniques under different real-application traffics and configuration scenarios, AdEle improves the network latency by 10.9% on average (up to 14.6%) with less than 6.9% energy consumption overhead., Comment: This paper will be published in Proc. IEEE/ACM Design Automation Conference (DAC) 2021

Few investigations have evaluated the 3-dimensional (3D) accuracy of digital implant scans. The aim of this study was to evaluate the performance of 10 intraoral scanners (IOSs) (CEREC Omnicam, CEREC Primescan, CS 3600, DWIO, i500, iTero Element, PlanScan, Trios 2, Trios 3, and True Definition) in obtaining the accurate positions of 6 cylinders simulating implant scan bodies. Digital scans of each IOS were compared with the reference dataset obtained by means of a coordinate measuring machine. Deviation from the actual positions of the 6 cylinders along the XYZ axes and the overall 3D deviation of the digital scan were calculated. The type of IOSs and position of simulated cylindrical scan bodies affected the magnitude and direction of deviations on trueness. The lowest amount of deviation was found at the cylinder next to the reference origin, while the highest deviation was evident at the contralateral side for all IOSs (p < 0.001). Among the tested IOSs, the CEREC Primescan and Trios 3 had the highest trueness followed by i500, Trios 2, and iTero Element, albeit not statistically significant (p > 0.05), and the DWIO and PlasScan had the lowest trueness in partially edentulous mandible digital implant scans (p < 0.001).

Whole-genome sequencing (WGS) can improve assessment of low-frequency and rare variants, particularly in non-European populations that have been underrepresented in existing genomic studies. The genetic determinants of C-reactive protein (CRP), a biomarker of chronic inflammation, have been extensively studied, with existing genome-wide association studies (GWASs) conducted in >200,000 individuals of European ancestry. In order to discover novel loci associated with CRP levels, we examined a multi-ancestry population (n = 23,279) with WGS (∼38× coverage) from the Trans-Omics for Precision Medicine (TOPMed) program. We found evidence for eight distinct associations at the CRP locus, including two variants that have not been identified previously (rs11265259 and rs181704186), both of which are non-coding and more common in individuals of African ancestry (∼10% and ∼1% minor allele frequency, respectively, and rare or monomorphic in 1000 Genomes populations of East Asian, South Asian, and European ancestry). We show that the minor (G) allele of rs181704186 is associated with lower CRP levels and decreased transcriptional activity and protein binding in vitro, providing a plausible molecular mechanism for this African ancestry-specific signal. The individuals homozygous for rs181704186-G have a mean CRP level of 0.23 mg/L, in contrast to individuals heterozygous for rs181704186 with mean CRP of 2.97 mg/L and major allele homozygotes with mean CRP of 4.11 mg/L. This study demonstrates the utility of WGS in multi-ethnic populations to drive discovery of complex trait associations of large effect and to identify functional alleles in noncoding regulatory regions.

Heterogeneous manycore architectures are the key to efficiently execute compute- and data-intensive applications. Through silicon via (TSV)-based 3D manycore system is a promising solution in this direction as it enables integration of disparate computing cores on a single system. However, the achievable performance of conventional through-silicon-via (TSV)-based 3D systems is ultimately bottlenecked by the horizontal wires (wires in each planar die). Moreover, current TSV 3D architectures suffer from thermal limitations. Hence, TSV-based architectures do not realize the full potential of 3D integration. Monolithic 3D (M3D) integration, a breakthrough technology to achieve - More Moore and More Than Moore - and opens up the possibility of designing cores and associated network routers using multiple layers by utilizing monolithic inter-tier vias (MIVs) and hence, reducing the effective wire length. Compared to TSV-based 3D ICs, M3D offers the true benefits of vertical dimension for system integration: the size of a MIV used in M3D is over 100x smaller than a TSV. In this work, we demonstrate how M3D-enabled vertical core and uncore elements offer significant performance and thermal improvements in manycore heterogeneous architectures compared to its TSV-based counterpart. To overcome the difficult optimization challenges due to the large design space and complex interactions among the heterogeneous components (CPU, GPU, Last Level Cache, etc.) in an M3D-based manycore chip, we leverage novel design-space exploration algorithms to trade-off different objectives. The proposed M3D-enabled heterogeneous architecture, called HeM3D, outperforms its state-of-the-art TSV-equivalent counterpart by up to 18.3% in execution time while being up to 19 degrees Celcius cooler., Comment: This work has been accepted in ACM Transactions on Design Automation of Electronic Systems

Due to amount of data involved in emerging deep learning and big data applications, operations related to data movement have quickly become the bottleneck. Data-centric computing (DCC), as enabled by processing-in-memory (PIM) and near-memory processing (NMP) paradigms, aims to accelerate these types of applications by moving the computation closer to the data. Over the past few years, researchers have proposed various memory architectures that enable DCC systems, such as logic layers in 3D stacked memories or charge sharing based bitwise operations in DRAM. However, application-specific memory access patterns, power and thermal concerns, memory technology limitations, and inconsistent performance gains complicate the offloading of computation in DCC systems. Therefore, designing intelligent resource management techniques for computation offloading is vital for leveraging the potential offered by this new paradigm. In this article, we survey the major trends in managing PIM and NMP-based DCC systems and provide a review of the landscape of resource management techniques employed by system designers for such systems. Additionally, we discuss the future challenges and opportunities in DCC management., Comment: Accepted to appear in Journal of Low Power Electronics and Applications

The complement system is an innate immune pathway typically thought of as part of the first line of defence against "non-self" species. In the context of cancer, complement has been described to have an active role in facilitating cancer-associated processes such as increased proliferation, angiogenesis and migration. Several cellular members of the tumour microenvironment express and/or produce complement proteins locally, including tumour cells. Dysregulation of the complement system has been reported in numerous tumours and increased expression of complement activation fragments in cancer patient specimens correlates with poor patient prognosis. Importantly, genetic or pharmacological targeting of complement has been shown to reduce tumour growth in several cancer preclinical models, suggesting that complement could be an attractive therapeutic target. Hypoxia (low oxygen) is frequently found in solid tumours and has a profound biological impact on cellular and non-cellular components of the tumour microenvironment. In this review, we focus on hypoxia since this is a prevailing feature of the tumour microenvironment that, like increased complement, is typically associated with poor prognosis. Furthermore, interesting links between hypoxia and complement have been recently proposed but never collectively reviewed. Here, we explore how hypoxia alters regulation of complement proteins in different cellular components of the tumour microenvironment, as well as the downstream biological consequences of this regulation.

The aim of this study was to evaluate the trueness of 5 intraoral scanners (IOSs) for digital impression of simulated implant scan bodies in a partially edentulous model. A 3D printed partially edentulous mandible model made of Co-Cr with a total of 6 bilaterally positioned cylinders in the canine, second premolar, and second molar area served as the study model. Digital scans of the model were made with a reference scanner (steroSCAN neo) and 5 IOSs (CEREC Omnicam, CS3600, i500, iTero Element, and TRIOS 3) (n = 10). For each IOS's dataset, the XYZ coordinates of the cylinders were obtained from the reference point and the deviations from the reference scanner were calculated using a 3D reverse engineering program (Rapidform). The trueness values were analyzed by Kruskal-Wallis test and Mann-Whitney post hoc test. Direction and amount of deviation differed among cylinder position and among IOSs. Regardless of the IOS type, the cylinders positioned on the left second molar, nearest to the scanning start point, showed the smallest deviation. The deviation generally increased further away from scanning start point towards the right second molar. TRIOS 3 and i500 outperformed the other IOSs for partially edentulous digital impression. The accuracy of the CEREC Omnicam, CS3600, and iTero Element were similar on the left side, but they showed more deviations on the right side of the arch when compared to the other IOSs. The accuracy of IOS is still an area that needs to be improved.

Monolithic 3D (M3D) technology enables high density integration, performance, and energy-efficiency by sequentially stacking tiers on top of each other. M3D-based network-on-chip (NoC) architectures can exploit these benefits by adopting tier partitioning for intra-router stages. However, conventional fabrication methods are infeasible for M3D-enabled designs due to temperature related issues. This has necessitated lower temperature and temperature-resilient techniques for M3D fabrication, leading to inferior performance of transistors in the top tier and interconnects in the bottom tier. The resulting inter-tier process variation leads to performance degradation of M3D-enabled NoCs. In this work, we demonstrate that without considering inter-tier process variation, an M3D-enabled NoC architecture overestimates the energy-delay-product (EDP) on average by 50.8% for a set of SPLASH-2 and PARSEC benchmarks. As a countermeasure, we adopt a process variation aware design approach. The proposed design and optimization method distribute the intra-router stages and inter-router links among the tiers to mitigate the adverse effects of process variation. Experimental results show that the NoC architecture under consideration improves the EDP by 27.4% on average across all benchmarks compared to the process-oblivious design., Comment: Submitted to IEEE TVLSI (Under Review)

The rising use of deep learning and other big-data algorithms has led to an increasing demand for hardware platforms that are computationally powerful, yet energy-efficient. Due to the amount of data parallelism in these algorithms, high-performance 3D manycore platforms that incorporate both CPUs and GPUs present a promising direction. However, as systems use heterogeneity (e.g., a combination of CPUs, GPUs, and accelerators) to improve performance and efficiency, it becomes more pertinent to address the distinct and likely conflicting communication requirements (e.g., CPU memory access latency or GPU network throughput) that arise from such heterogeneity. Unfortunately, it is difficult to quickly explore the hardware design space and choose appropriate tradeoffs between these heterogeneous requirements. To address these challenges, we propose the design of a 3D Network-on-Chip (NoC) for heterogeneous manycore platforms that considers the appropriate design objectives for a 3D heterogeneous system and explores various tradeoffs using an efficient ML-based multi-objective optimization technique. The proposed design space exploration considers the various requirements of its heterogeneous components and generates a set of 3D NoC architectures that efficiently trades off these design objectives. Our findings show that by jointly considering these requirements (latency, throughput, temperature, and energy), we can achieve 9.6% better Energy-Delay Product on average at nearly iso-temperature conditions when compared to a thermally-optimized design for 3D heterogeneous NoCs. More importantly, our results suggest that our 3D NoCs optimized for a few applications can be generalized for unknown applications as well. Our results show that these generalized 3D NoCs only incur a 1.8% (36-tile system) and 1.1% (64-tile system) average performance loss compared to application-specific NoCs., Comment: Published in IEEE Transactions on Computers

Sequence libraries that cover all k-mers enable universal, unbiased measurements of binding to both oligonucleotides and peptides. While the number of k-mers grows exponentially in k, space on all experimental platforms is limited. Here, we shrink k-mer library sizes by using joker characters, which represent all characters in the alphabet simultaneously. We present the JokerCAKE (joker covering all k-mers) algorithm for generating a short sequence such that each k-mer appears at least p times with at most one joker character per k-mer. By running our algorithm on a range of parameters and alphabets, we show that JokerCAKE produces near-optimal sequences. Moreover, through comparison with data from hundreds of DNA-protein binding experiments and with new experimental results for both standard and JokerCAKE libraries, we establish that accurate binding scores can be inferred for high-affinity k-mers using JokerCAKE libraries. JokerCAKE libraries allow researchers to search a significantly larger sequence space using the same number of experimental measurements and at the same cost. We present a new compact sequence design that covers all k-mers utilizing joker characters and develop an efficient algorithm to generate such designs. We show through simulations and experimental validation that these sequence designs are useful for identifying high-affinity binding sites at significantly reduced cost and space. Keywords: sequence libraries; microarray design; de Bruijn graph, National Institutes of Health (U.S.) (Grant R01GM081871)

BackgroundRNAs within extracellular vesicles (EVs) have potential as diagnostic biomarkers for patients with cancer and are identified in a variety of biofluids. Glioblastomas (GBMs) release EVs containing RNA into cerebrospinal fluid (CSF). Here we describe a multi-institutional study of RNA extracted from CSF-derived EVs of GBM patients to detect the presence of tumor-associated amplifications and mutations in epidermal growth factor receptor (EGFR).MethodsCSF and matching tumor tissue were obtained from patients undergoing resection of GBMs. We determined wild-type (wt)EGFR DNA copy number amplification, as well as wtEGFR and EGFR variant (v)III RNA expression in tumor samples. We also characterized wtEGFR and EGFRvIII RNA expression in CSF-derived EVs.ResultsEGFRvIII-positive tumors had significantly greater wtEGFR DNA amplification (P = 0.02) and RNA expression (P = 0.03), and EGFRvIII-positive CSF-derived EVs had significantly more wtEGFR RNA expression (P = 0.004). EGFRvIII was detected in CSF-derived EVs for 14 of the 23 EGFRvIII tissue-positive GBM patients. Conversely, only one of the 48 EGFRvIII tissue-negative patients had the EGFRvIII mutation detected in their CSF-derived EVs. These results yield a sensitivity of 61% and a specificity of 98% for the utility of CSF-derived EVs to detect an EGFRvIII-positive GBM.ConclusionOur results demonstrate CSF-derived EVs contain RNA signatures reflective of the underlying molecular genetic status of GBMs in terms of wtEGFR expression and EGFRvIII status. The high specificity of the CSF-derived EV diagnostic test gives us an accurate determination of positive EGFRvIII tumor status and is essentially a less invasive "liquid biopsy" that might direct mutation-specific therapies for GBMs.

Convolutional Neural Networks (CNNs) have shown a great deal of success in diverse application domains including computer vision, speech recognition, and natural language processing. However, as the size of datasets and the depth of neural network architectures continue to grow, it is imperative to design high-performance and energy-efficient computing hardware for training CNNs. In this paper, we consider the problem of designing specialized CPU-GPU based heterogeneous manycore systems for energy-efficient training of CNNs. It has already been shown that the typical on-chip communication infrastructures employed in conventional CPU-GPU based heterogeneous manycore platforms are unable to handle both CPU and GPU communication requirements efficiently. To address this issue, we first analyze the on-chip traffic patterns that arise from the computational processes associated with training two deep CNN architectures, namely, LeNet and CDBNet, to perform image classification. By leveraging this knowledge, we design a hybrid Network-on-Chip (NoC) architecture, which consists of both wireline and wireless links, to improve the performance of CPU-GPU based heterogeneous manycore platforms running the above-mentioned CNN training workloads. The proposed NoC achieves 1.8x reduction in network latency and improves the network throughput by a factor of 2.2 for training CNNs, when compared to a highly-optimized wireline mesh NoC. For the considered CNN workloads, these network-level improvements translate into 25% savings in full-system energy-delay-product (EDP). This demonstrates that the proposed hybrid NoC for heterogeneous manycore architectures is capable of significantly accelerating training of CNNs while remaining energy-efficient., Comment: Accepted in a future publication of IEEE Transactions on Computers

Tight collaboration between experts of machine learning and manycore system design is necessary to create a data-driven manycore design framework that integrates both learning and expert knowledge. Such a framework will be necessary to address the rising complexity of designing large-scale manycore systems and machine learning techniques., Comment: To appear in a future publication of IEEE Computer

Analysis of extracellular vesicles (EVs) derived from plasma or cerebrospinal fluid (CSF) has emerged as a promising biomarker platform for therapeutic monitoring in glioblastoma patients. However, the contents of the various subpopulations of EVs in these clinical specimens remain poorly defined. Here we characterize the relative abundance of miRNA species in EVs derived from the serum and cerebrospinal fluid of glioblastoma patients. EVs were isolated from glioblastoma cell lines as well as the plasma and CSF of glioblastoma patients. The microvesicle subpopulation was isolated by pelleting at 10,000×g for 30 min after cellular debris was cleared by a 2000×g (20 min) spin. The exosome subpopulation was isolated by pelleting the microvesicle supernatant at 120,000×g (120 min). qRT-PCR was performed to examine the distribution of miR-21, miR-103, miR-24, and miR-125. Global miRNA profiling was performed in select glioblastoma CSF samples. In plasma and cell line derived EVs, the relative abundance of miRNAs in exosome and microvesicles were highly variable. In some specimens, the majority of the miRNA species were found in exosomes while in other, they were found in microvesicles. In contrast, CSF exosomes were enriched for miRNAs relative to CSF microvesicles. In CSF, there is an average of one molecule of miRNA per 150-25,000 EVs. Most EVs derived from clinical biofluids are devoid of miRNA content. The relative distribution of miRNA species in plasma exosomes or microvesicles is unpredictable. In contrast, CSF exosomes are the major EV compartment that harbor miRNAs.

Herein, we present an adult case of medulloblastoma who received chemotherapy, radiation therapy and stem cell transplantation, and underwent multiple surgical resections for what were thought to be recurrences; however pathology confirmed a diagnosis of relapsing tumefactive lesions. This phenomenon seems to be a consequence of stem cell transplantation rather than a simple radiation treatment effect.

Monozygotic or 'identical' twins have been widely studied to dissect the relative contributions of genetics and environment in human diseases. In multiple sclerosis (MS), an autoimmune demyelinating disease and common cause of neurodegeneration and disability in young adults, disease discordance in monozygotic twins has been interpreted to indicate environmental importance in its pathogenesis. However, genetic and epigenetic differences between monozygotic twins have been described, challenging the accepted experimental model in disambiguating the effects of nature and nurture. Here we report the genome sequences of one MS-discordant monozygotic twin pair, and messenger RNA transcriptome and epigenome sequences of CD4(+) lymphocytes from three MS-discordant, monozygotic twin pairs. No reproducible differences were detected between co-twins among approximately 3.6 million single nucleotide polymorphisms (SNPs) or approximately 0.2 million insertion-deletion polymorphisms. Nor were any reproducible differences observed between siblings of the three twin pairs in HLA haplotypes, confirmed MS-susceptibility SNPs, copy number variations, mRNA and genomic SNP and insertion-deletion genotypes, or the expression of approximately 19,000 genes in CD4(+) T cells. Only 2 to 176 differences in the methylation of approximately 2 million CpG dinucleotides were detected between siblings of the three twin pairs, in contrast to approximately 800 methylation differences between T cells of unrelated individuals and several thousand differences between tissues or between normal and cancerous tissues. In the first systematic effort to estimate sequence variation among monozygotic co-twins, we did not find evidence for genetic, epigenetic or transcriptome differences that explained disease discordance. These are the first, to our knowledge, female, twin and autoimmune disease individual genome sequences reported.

Monozygotic or 'identical' twins have been widely studied to dissect the relative contributions of genetics and environment in human diseases. In multiple sclerosis (MS), an autoimmune demyelinating disease and common cause of neurodegeneration and disability in young adults, disease discordance in monozygotic twins has been interpreted to indicate environmental importance in its pathogenesis. However, genetic and epigenetic differences between monozygotic twins have been described, challenging the accepted experimental model in disambiguating the effects of nature and nurture. Here we report the genome sequences of one MS-discordant monozygotic twin pair, and messenger RNA transcriptome and epigenome sequences of CD4(+) lymphocytes from three MS-discordant, monozygotic twin pairs. No reproducible differences were detected between co-twins among approximately 3.6 million single nucleotide polymorphisms (SNPs) or approximately 0.2 million insertion-deletion polymorphisms. Nor were any reproducible differences observed between siblings of the three twin pairs in HLA haplotypes, confirmed MS-susceptibility SNPs, copy number variations, mRNA and genomic SNP and insertion-deletion genotypes, or the expression of approximately 19,000 genes in CD4(+) T cells. Only 2 to 176 differences in the methylation of approximately 2 million CpG dinucleotides were detected between siblings of the three twin pairs, in contrast to approximately 800 methylation differences between T cells of unrelated individuals and several thousand differences between tissues or between normal and cancerous tissues. In the first systematic effort to estimate sequence variation among monozygotic co-twins, we did not find evidence for genetic, epigenetic or transcriptome differences that explained disease discordance. These are the first, to our knowledge, female, twin and autoimmune disease individual genome sequences reported.

BackgroundSongbirds hold great promise for biomedical, environmental and evolutionary research. A complete draft sequence of the zebra finch genome is imminent, yet a need remains for application of genomic resources within a research community traditionally focused on ethology and neurobiological methods. In response, we developed a core set of genomic tools and a novel collaborative strategy to probe gene expression in diverse songbird species and natural contexts.ResultsWe end-sequenced cDNAs from zebra finch brain and incorporated additional sequences from community sources into a database of 86,784 high quality reads. These assembled into 31,658 non-redundant contigs and singletons, which we annotated via BLAST search of chicken and human databases. The results are publicly available in the ESTIMA:Songbird database. We produced a spotted cDNA microarray with 20,160 addresses representing 17,214 non-redundant products of an estimated 11,500-15,000 genes, validating it by analysis of immediate-early gene (zenk) gene activation following song exposure and by demonstrating effective cross hybridization to genomic DNAs of other songbird species in the Passerida Parvorder. Our assembly was also used in the design of the "Lund-zfa" Affymetrix array representing approximately 22,000 non-redundant sequences. When the two arrays were hybridized to cDNAs from the same set of male and female zebra finch brain samples, both arrays detected a common set of regulated transcripts with a Pearson correlation coefficient of 0.895. To stimulate use of these resources by the songbird research community and to maintain consistent technical standards, we devised a "Community Collaboration" mechanism whereby individual birdsong researchers develop experiments and provide tissues, but a single individual in the community is responsible for all RNA extractions, labelling and microarray hybridizations.ConclusionImmediately, these results set the foundation for a coordinated set of 25 pla

BackgroundSongbirds hold great promise for biomedical, environmental and evolutionary research. A complete draft sequence of the zebra finch genome is imminent, yet a need remains for application of genomic resources within a research community traditionally focused on ethology and neurobiological methods. In response, we developed a core set of genomic tools and a novel collaborative strategy to probe gene expression in diverse songbird species and natural contexts.ResultsWe end-sequenced cDNAs from zebra finch brain and incorporated additional sequences from community sources into a database of 86,784 high quality reads. These assembled into 31,658 non-redundant contigs and singletons, which we annotated via BLAST search of chicken and human databases. The results are publicly available in the ESTIMA:Songbird database. We produced a spotted cDNA microarray with 20,160 addresses representing 17,214 non-redundant products of an estimated 11,500-15,000 genes, validating it by analysis of immediate-early gene (zenk) gene activation following song exposure and by demonstrating effective cross hybridization to genomic DNAs of other songbird species in the Passerida Parvorder. Our assembly was also used in the design of the "Lund-zfa" Affymetrix array representing approximately 22,000 non-redundant sequences. When the two arrays were hybridized to cDNAs from the same set of male and female zebra finch brain samples, both arrays detected a common set of regulated transcripts with a Pearson correlation coefficient of 0.895. To stimulate use of these resources by the songbird research community and to maintain consistent technical standards, we devised a "Community Collaboration" mechanism whereby individual birdsong researchers develop experiments and provide tissues, but a single individual in the community is responsible for all RNA extractions, labelling and microarray hybridizations.ConclusionImmediately, these results set the foundation for a coordinated set of 25 pla

We study business cycles with cyclical returns to scale. Contrary to tightly parameterized production functions (Cobb-Douglas and Constant Elasticity of Substitution), we empirically identify strong input complementarity that leads to procyclical returns to scale. We therefore propose a flexible translog production function that allows complementarity-induced procyclical returns to scale, and we integrate this function into a standard medium-scale dynamic stochastic general equilibrium (DSGE) model. The estimated model with the procyclical returns to scale (i) features procyclical price markups, (ii) better matches the cyclicality of factor shares, and (iii) decreases by nearly half the contribution of markup shocks to output fluctuations.

We study business cycles with cyclical returns to scale. Contrary to tightly parameterized production functions (Cobb-Douglas and Constant Elasticity of Substitution), we empirically identify strong input complementarity that leads to procyclical returns to scale. We therefore propose a flexible translog production function that allows complementarity-induced procyclical returns to scale, and we integrate this function into a standard medium-scale dynamic stochastic general equilibrium (DSGE) model. The estimated model with the procyclical returns to scale (i) features procyclical price markups, (ii) better matches the cyclicality of factor shares, and (iii) decreases by nearly half the contribution of markup shocks to output fluctuations.