A High-Performance Triple Patterning Layout Decomposer with Balanced Density

Triple patterning lithography (TPL) has received more and more attentions from industry as one of the leading candidate for 14nm/11nm nodes. In this paper, we propose a high performance layout decomposer for TPL. Density balancing is seamlessly integrated into all key steps in our TPL layout decomposition, including density-balanced semi-definite programming (SDP), density-based mapping, and density-balanced graph simplification. Our new TPL decomposer can obtain high performance even compared to previous state-of-the-art layout decomposers which are not balanced-density aware, e.g., by Yu et al. (ICCAD'11), Fang et al. (DAC'12), and Kuang et al. (DAC'13). Furthermore, the balanced-density version of our decomposer can provide more balanced density which leads to less edge placement error (EPE), while the conflict and stitch numbers are still very comparable to our non-balanced-density baseline

Filling Knowledge Gaps in a Broad-Coverage Machine Translation System

Knowledge-based machine translation (KBMT) techniques yield high quality in domains with detailed semantic models, limited vocabulary, and controlled input grammar. Scaling up along these dimensions means acquiring large knowledge resources. It also means behaving reasonably when definitive knowledge is not yet available. This paper describes how we can fill various KBMT knowledge gaps, often using robust statistical techniques. We describe quantitative and qualitative results from JAPANGLOSS, a broad-coverage Japanese-English MT system.Comment: 7 pages, Compressed and uuencoded postscript. To appear: IJCAI-9

Congenital Midline Nodules on the Chin and Sternum

History: A 5-day old black male full-term neonate born via vacuum-assisted delivery for non-reassuring fetal heart rate presented with congenital presentation of two asymptomatic midline lesions which appeared asymptomatic. There was no history of seizures, ophthalmologic findings, abnormalities in head circumference, height, weight or limb size. Newborn screening examination was unremarkable. Examination: On the midline submental chin there was a soft, brown dome-shaped plaque measuring 0.8-centimeters with a circumferential ring of light brown pigmentation; on the midline upper chest there was a light brown 2-millimeter dome-shaped papule. Course and Therapy: Ultrasound of the submental chin lesion revealed a 0.5 x 0.8 x 0.4-centimeter heterogeneously hypoechoic structure with a peripheral soft tissue rind. Punch biopsies of the submental chin and the midline upper chest revealed haphazardly arranged striated muscle fibers in the dermis, some of which inserted directly into the epidermis. The muscle fibers were highlighted by Masson’s trichrome and myogenin. Alcian blue revealed increased dermal mucin. Discussion: Striated muscle hamartomas (SMH) are rare, benign congenital skin tumors characterized by haphazard arrangement of mature striated skeletal muscle, collagen, nerve bundles, and adipose tissue in the dermal and subcutaneous tissue. Although a rare entity, it is important to recognize this benign hamartoma as a congenital midline defect. Conservative management with clinical monitoring is recommended if cosmetically acceptable, as spontaneous regression over a period of years has been reported. Surgical excision may be pursued; however, the hamartoma may recur.https://scholarlycommons.henryford.com/merf2020caserpt/1133/thumbnail.jp

Genome editing of HBG1 and HBG2 to induce fetal hemoglobin

Induction of fetal hemoglobin (HbF) via clustered regularly interspaced short palindromic repeats/Cas9-mediated disruption of DNA regulatory elements that repress gamma-globin gene (HBG1 and HBG2) expression is a promising therapeutic strategy for sickle cell disease (SCD) and beta-thalassemia, although the optimal technical approaches and limiting toxicities are not yet fully defined. We disrupted an HBG1/HBG2 gene promoter motif that is bound by the transcriptional repressor BCL11A. Electroporation of Cas9 single guide RNA ribonucleoprotein complex into normal and SCD donor CD34+ hematopoietic stem and progenitor cells resulted in high frequencies of on-target mutations and the induction of HbF to potentially therapeutic levels in erythroid progeny generated in vitro and in vivo after transplantation of hematopoietic stem and progenitor cells into nonobese diabetic/severe combined immunodeficiency/Il2rgamma-/-/KitW41/W41 immunodeficient mice. On-target editing did not impair CD34+ cell regeneration or differentiation into erythroid, T, B, or myeloid cell lineages at 16 to 17 weeks after xenotransplantation. No off-target mutations were detected by targeted sequencing of candidate sites identified by circularization for in vitro reporting of cleavage effects by sequencing (CIRCLE-seq), an in vitro genome-scale method for detecting Cas9 activity. Engineered Cas9 containing 3 nuclear localization sequences edited human hematopoietic stem and progenitor cells more efficiently and consistently than conventional Cas9 with 2 nuclear localization sequences. Our studies provide novel and essential preclinical evidence supporting the safety, feasibility, and efficacy of a mechanism-based approach to induce HbF for treating hemoglobinopathies

ZNF410 represses fetal globin by devoted control of CHD4/NuRD [preprint]

Major effectors of adult-stage fetal globin silencing include the transcription factors (TFs) BCL11A and ZBTB7A/LRF and the NuRD chromatin complex, although each has potential on-target liabilities for rational β-hemoglobinopathy therapeutic inhibition. Here through CRISPR screening we discover ZNF410 to be a novel fetal hemoglobin (HbF) repressing TF. ZNF410 does not bind directly to the γ-globin genes but rather its chromatin occupancy is solely concentrated at CHD4, encoding the NuRD nucleosome remodeler, itself required for HbF repression. CHD4 has two ZNF410-bound regulatory elements with 27 combined ZNF410 binding motifs constituting unparalleled genomic clusters. These elements completely account for ZNF410’s effects on γ-globin repression. Knockout of ZNF410 reduces CHD4 by 60%, enough to substantially de-repress HbF while avoiding the cellular toxicity of complete CHD4 loss. Mice with constitutive deficiency of the homolog Zfp410 are born at expected Mendelian ratios with unremarkable hematology. ZNF410 is dispensable for human hematopoietic engraftment potential and erythroid maturation unlike known HbF repressors. These studies identify a new rational target for HbF induction for the β-hemoglobin disorders with a wide therapeutic index. More broadly, ZNF410 represents a special class of gene regulator, a conserved transcription factor with singular devotion to regulation of a chromatin subcomplex

Effects of Mental Fatigue on Endurance Performance in the Heat

PURPOSE: Mental fatigue is a psychobiological state caused by prolonged periods of demanding cognitive activity and has been observed to decrease time-trial (TT) endurance performance by ~3,5% in normal ambient temperatures. Recently it has been suggested that heat may augment the negative effect of mental fatigue on cognitive performance, raising the question whether it may also amplify the effect of mental fatigue on TT-performance. METHODS: In 30 °C and 30% relative humidity, ten endurance-trained male athletes (Age: 22 ± 3 y; Wmax: 332 ± 41 W) completed two experimental conditions: intervention (I; 45-min Stroop task) and control (C; 45-min documentary). Pre and post intervention/control, cognitive performance was followed up with a 5-min Flanker task. Thereafter subjects cycled for 45 min at a fixed pace equal to 60%-Wmax, immediately followed by a self-paced TT in which they had to produce a fixed amount of work (equal to cycling 15 min at 80%-Wmax) as fast as possible. RESULTS: Self-reported mental fatigue was significantly higher after I compared to C (P<0.05). Moreover electroencephalographic measures also indicated the occurrence of mental fatigue during the Stroop (P<0.05). TT-time did not differ between conditions (I: 906 ± 30 s, C: 916 ± 29 s). Throughout exercise, physiological (heart rate, blood lactate, core and skin temperature) and perceptual measures (perception of effort and thermal sensation) were not affected by mental fatigue. CONCLUSION: No negative effects of mild mental fatigue were observed on performance and the physiological and perceptual responses to endurance exercise in the heat. Most plausibly mild mental fatigue does not reduce endurance performance when the brain is already stressed by a hot environment

Enhanced Cas12a editing in mammalian cells and zebrafish

Type V CRISPR-Cas12a systems provide an alternate nuclease platform to Cas9, with potential advantages for specific genome editing applications. Here we describe improvements to the Cas12a system that facilitate efficient targeted mutagenesis in mammalian cells and zebrafish embryos. We show that engineered variants of Cas12a with two different nuclear localization sequences (NLS) on the C terminus provide increased editing efficiency in mammalian cells. Additionally, we find that pre-crRNAs comprising a full-length direct repeat (full-DR-crRNA) sequence with specific stem-loop G-C base substitutions exhibit increased editing efficiencies compared with the standard mature crRNA framework. Finally, we demonstrate in zebrafish embryos that the improved LbCas12a and FnoCas12a nucleases in combination with these modified crRNAs display high mutagenesis efficiencies and low toxicity when delivered as ribonucleoprotein complexes at high concentration. Together, these results define a set of enhanced Cas12a components with broad utility in vertebrate systems