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BackgroundMicrophthalmia, anophthalmia, and coloboma (MAC) spectrum disease encompasses a group of eye malformations which play a role in childhood visual impairment. Although the predominant cause of eye malformations is known to be heritable in nature, with 80% of cases displaying loss-of-function mutations in the ocular developmental genes OTX2 or SOX2, the genetic abnormalities underlying the remaining cases of MAC are incompletely understood. This study intended to identify the novel genes and pathways required for early eye development. Additionally, pathways involved in eye formation during embryogenesis are also incompletely understood. This study aims to identify the novel genes and pathways required for early eye development through systematic forward screening of the mammalian genome.ResultsQuery of the International Mouse Phenotyping Consortium (IMPC) database (data release 17.0, August 01, 2022) identified 74 unique knockout lines (genes) with genetically associated eye defects in mouse embryos. The vast majority of eye abnormalities were small or absent eyes, findings most relevant to MAC spectrum disease in humans. A literature search showed that 27 of the 74 lines had previously published knockout mouse models, of which only 15 had ocular defects identified in the original publications. These 12 previously published gene knockouts with no reported ocular abnormalities and the 47 unpublished knockouts with ocular abnormalities identified by the IMPC represent 59 genes not previously associated with early eye development in mice. Of these 59, we identified 19 genes with a reported human eye phenotype. Overall, mining of the IMPC data yielded 40 previously unimplicated genes linked to mammalian eye development. Bioinformatic analysis showed that several of the IMPC genes colocalized to several protein anabolic and pluripotency pathways in early eye development. Of note, our analysis suggests that the serine-glycine pathway producing glycine, a mitochondrial one-carbon donator to folate one-carbon metabolism (FOCM), is essential for eye formation.ConclusionsUsing genome-wide phenotype screening of single-gene knockout mouse lines, STRING analysis, and bioinformatic methods, this study identified genes heretofore unassociated with MAC phenotypes providing models to research novel molecular and cellular mechanisms involved in eye development. These findings have the potential to hasten the diagnosis and treatment of this congenital blinding disease.

Additional file 1: eTable 1. PRISMA 2020 checklist of the current network meta-analysis. eTable 2. Keyword used in each database and search results. eTable 3. Excluded studies and reason. eTable 4. Characteristics of the included studies. eTable 5. A League table of the changes of quality of life. B: League table of the rate of any adverse event. C: League table of the rate of local discomfort. D:League table of the drop-out rate. eTable 6. A SUCRA of the changes of cognition function-overall. B: SUCRA of the changes of cognition function: measured with MMSE. C: SUCRA of the changes of cognition function: measured with ADAS-Cog. D: SUCRA of the changes of quality of life. E: SUCRA of the rate of any adverse event. F: SUCRA of the rate of local discomfort. G: SUCRA of the drop-out rate. eTable 7. Inconsistency of different intervention. eTable 8. Estimated between-studies standard deviation of different outcome. eTable 9. GRADE evaluation quality of evidence for primary outcome. eFigure1. Test for transitivity assumption of primary outcome: changes of cognition function-overall. eFigure2. A network structure of NMA of changes of quality of life. B network structure of NMA of safety profile in aspect of rate of any adverse event. C network structure of NMA of safety profile in aspect of rate of any local discomfort. D network structure of NMA of acceptability in aspect of drop-out rate. eFigure3. A forest plot of NMA of change of quality of life. B forest plot of NMA of safety profile in aspect of rate of any adverse event. C forest plot of NMA of safety profile in aspect of rate of any local discomfort. D forest plot of NMA of acceptability in aspect of drop-out rate. eFigure4. A overview of risk of bias. B detailed risk of bias in each study. eFigure5. A Funnel plot of changes of cognition function: overall. B Egger’s regression of changes of cognition function: overall. C Funnel plot of changes of cognition function: MMSE measurement. D Egger’s regression of changes of cognition function: MMSE measurement. E Funnel plot of changes of cognition function: ADAS-Cog measurement. F Egger’s regression of changes of cognition function: ADAS-Cog measurement. G Funnel plot of changes of quality of life. H Egger’s regression of changes of quality of life. I Funnel plot of safety profile in aspect of rate of any adverse event. J Egger’s regression of safety profile in aspect of rate of any adverse event. K Funnel plot of safety profile in aspect of rate of any local discomfort. L Egger’s regression of safety profile in aspect of rate of any local discomfort. M Funnel plot of acceptability in aspect of drop-out rate. N Egger’s regression of acceptability in aspect of drop-out rate.

Objective To systematically examine the effectiveness and tolerability of psilocybin for treating end-of-life anxiety symptoms.Methods The Medline, Embase, CENTRAL, and PsycINFO databases were searched up to November 25, 2020. We enrolled clinical trials investigating psilocybin for treating end-of-life anxiety symptoms. Meta-analysis was conducted using random-effects model.Results Overall, five studies were included, revealing that psilocybin was superior to the placebo in treating state anxiety at 1 day (Hedges’ g, -0.70; 95% confidence interval, -1.01 to -0.39) and 2 weeks (-1.03; -1.47 to -0.60) after treatment. Psilocybin was more effective than placebo in treating trait anxiety at 1 day (-0.71; -1.15 to -0.26), 2 weeks (-1.08; -1.80 to -0.36), and 6 months (-0.84; -1.37 to -0.30) after treatment. Psilocybin was associated with transient elevation in systolic (19.00; 13.58–24.41 mm Hg) and diastolic (8.66; 5.18–12.15 mm Hg) blood pressure compared with placebo. The differences between psilocybin and placebo groups with regard to allcause discontinuation, serious adverse events, and heart rates were nonsignificant.Conclusion Psilocybin-assisted therapy could ameliorate end-of-life anxiety symptoms without serious adverse events. Because of the small sample sizes of the included studies and high heterogeneity on long-term outcomes, future randomized controlled trials with large sample sizes are needed.

Additional file 2.

Additional file 2: Fig. S1. WoL and cell essentiality scores. Fig. S2. WoL and cell essentiality categorisation. Fig. S3. WoL and additional gene features. Fig. S4. WoL and paralogues features. Fig. S5. WoL and additional disease features. Fig. S6. Prediction of early lethal genes. Fig. S7. Enrichment analysis of genes sharing attributes with a BIEM gene among the EL category.

Supplemental material, sj-docx-1-aut-10.1177_13623613221138690 for Association of labor epidural analgesia exposure with long-term risk of autism spectrum disorder in offspring: A meta-analysis of observational studies by Kuo-Chuan Hung, Jen-Yin Chen, Chung-Hsi Hsing, Chih-Wei Hsu, Ping-Hsin Liu, Ying-Jen Chang, Jui-Yi Chen, Sheng-Fu Chiu and Cheuk-Kwan Sun in Autism

Additional file 1: Table S1. Gene features: Human cellular essential genes. Table S2. Gene features: Gene expression in human brain. Table S3. Gene features: Intolerance to variation metrics and paralogues. Table S4. Disease features. Table S5. HPO phenotypes Odds Ratios. Table S6. Comparison of our approach based on EL genes with other strategies based on standard scores thresholds: F-score. Table S7. Odds Ratios and 95% CI from multiple logistic regression analysis.

Additional file 1.

Supplemental material, sj-docx-1-taj-10.1177_20406223221098114 for The comparative effectiveness of antidepressants for youths with major depressive disorder: a nationwide population-based study in Taiwan by Sheng-Yu Lee, Liang-Jen Wang, Yao-Hsu Yang and Chih-Wei Hsu in Therapeutic Advances in Chronic Disease

This paper describes a video coding technology proposal submitted by MediaTek in April 2018 in response to a joint call for proposals (CfP) issued by ITU-T VCEG and ISO/IEC MPEG. The proposal uses the conventional block-based hybrid coding approach with a breakthrough design of block structure, substantial improvements of coding tools, and new inventions of loop filtering techniques. First, the block structure is designed using a highly flexible partitioning scheme, where each coding tree unit in a picture is split into multiple coding units (CUs) by a recursive quaternary tree followed by a recursive binary-ternary tree. The prediction unit (PU) and transform unit (TU) concepts are unified with the CU concept, i.e., PU and TU are basically the same as CU. Moreover, inter prediction, intra prediction, transform, quantization, in-loop filtering, and entropy coding are all improved. Finally, new loop filtering techniques are invented, where the proposed convolutional neural network loop filtering is of particular interest. The proposed video codec achieves 43.81% average bit rate savings based on objective measures compared to the High Efficiency Video Coding (HEVC) anchors and is among the best-performing CfP responses both objectively and subjectively. It has been partially adopted into the working draft of the Versatile Video Coding (VVC) standard.

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery., Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery.

Supplemental material, sj-pdf-1-taj-10.1177_2040622321995690 for Lack of association between erythropoietin treatment and risk of depression in patients with end-stage kidney disease on maintenance dialysis: a nationwide database study in Taiwan by Pao-Yen Lin, Lung-Chih Li, Liang-Jen Wang, Yao-Hsu Yang and Chih-Wei Hsu in Therapeutic Advances in Chronic Disease

Supplemental material, sj-pdf-1-taj-10.1177_2040622321995690 for Lack of association between erythropoietin treatment and risk of depression in patients with end-stage kidney disease on maintenance dialysis: a nationwide database study in Taiwan by Pao-Yen Lin, Lung-Chih Li, Liang-Jen Wang, Yao-Hsu Yang and Chih-Wei Hsu in Therapeutic Advances in Chronic Disease

This paper overviews the motion vector coding and block merging techniques in the Versatile Video Coding (VVC) standard developed by the Joint Video Experts Team (JVET). In general, inter-prediction techniques in VVC can be classified into two major groups: ""whole block-based inter prediction"" and ""subblock-based inter prediction"". In this paper, we focus on techniques for whole block-based inter prediction. As in its predecessor, High Efficiency Video Coding (HEVC), whole block-based inter prediction in VVC is represented by adaptive motion vector prediction (AMVP) mode or merge mode. Newly introduced features purely for AMVP mode include symmetric motion vector difference and adaptive motion vector resolution. The features purely for merge mode include pairwise average merge, merge with motion vector difference, combined inter-intra prediction and geometric partitioning mode. Coding tools such as history-based motion vector prediction and bidirectional prediction with coding unit weights can be applied on both AMVP mode and merge mode. This paper discusses the design principles and the implementation of the new inter-prediction methods. Using objective metrics, simulation results show that the methods overviewed in the paper can jointly achieve 6.2% and 4.7% BD-rate savings on average with the random access and low-delay configurations, respectively. Significant subjective picture quality improvements of some tools are also reported when comparing the resulting pictures at same bitrates.

We develop RecSim NG, a probabilistic platform that supports natural, concise specification and learning of models for multi-agent recommender systems simulation. RecSim NG is a scalable, modular, differentiable simulator implemented in Edward2 and TensorFlow.

Exploration policies in Bayesian bandits maximize the average reward over problem instances drawn from some distribution $\mathcal{P}$. In this work, we learn such policies for an unknown distribution $\mathcal{P}$ using samples from $\mathcal{P}$. Our approach is a form of meta-learning and exploits properties of $\mathcal{P}$ without making strong assumptions about its form. To do this, we parameterize our policies in a differentiable way and optimize them by policy gradients, an approach that is general and easy to implement. We derive effective gradient estimators and introduce novel variance reduction techniques. We also analyze and experiment with various bandit policy classes, including neural networks and a novel softmax policy. The latter has regret guarantees and is a natural starting point for our optimization. Our experiments show the versatility of our approach. We also observe that neural network policies can learn implicit biases expressed only through the sampled instances.

Most bandit algorithm designs are purely theoretical. Therefore, they have strong regret guarantees, but also are often too conservative in practice. In this work, we pioneer the idea of algorithm design by minimizing the empirical Bayes regret, the average regret over problem instances sampled from a known distribution. We focus on a tractable instance of this problem, the confidence interval and posterior width tuning, and propose an efficient algorithm for solving it. The tuning algorithm is analyzed and evaluated in multi-armed, linear, and generalized linear bandits. We report several-fold reductions in Bayes regret for state-of-the-art bandit algorithms, simply by optimizing over a small sample from a distribution.

[This corrects the article DOI: 10.1038/s42003-018-0226-0.].

This corrects the article DOI: 10.1038/nature19356.

This paper provides a technical overview of a newly added in-loop filtering technique, sample adaptive offset (SAO), in High Efficiency Video Coding (HEVC). The key idea of SAO is to reduce sample distortion by first classifying reconstructed samples into different categories, obtaining an offset for each category, and then adding the offset to each sample of the category. The offset of each category is properly calculated at the encoder and explicitly signaled to the decoder for reducing sample distortion effectively, while the classification of each sample is performed at both the encoder and the decoder for saving side information significantly. To achieve low latency of only one coding tree unit (CTU), a CTU-based syntax design is specified to adapt SAO parameters for each CTU. A CTU-based optimization algorithm can be used to derive SAO parameters of each CTU, and the SAO parameters of the CTU are inter leaved into the slice data. It is reported that SAO achieves on average 3.5% BD-rate reduction and up to 23.5% BD-rate reduction with less than 1% encoding time increase and about 2.5% decoding time increase under common test conditions of HEVC reference software version 8.0.

Approximately one-third of all mammalian genes are essential for life. Phenotypes resulting from knockouts of these genes in mice have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5,000 knockout mouse lines, here we identify 410 lethal genes during the production of the first 1,751 unique gene knockouts. Using a standardized phenotyping platform that incorporates high-resolution 3D imaging, we identify phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts.

Oxidative stress is involved in many neurodegenerative processes leading to age-related cognitive decline. Coffee, a widely consumed beverage, is rich in many bioactive components, including polyphenols with antioxidant potential. In this study, regular and decaffeinated samples of both roasted and green coffee all showed high hydrophilic antioxidant activity in vitro, whereas lipophilic antioxidant activities were on average 30-fold higher in roasted than in green coffee samples. In primary neuronal cell culture, pretreatment with green and roasted coffees (regular and decaffeinated) protected against subsequent H(2)O(2)-induced oxidative stress and improved neuronal cell survival (green coffees increased neuron survival by 78%, compared to 203% by roasted coffees). All coffee extracts inhibited ERK1/2 activation, indicating a potential attenuating effect in stress-induced neuronal cell death. Interestingly, only roasted coffee extracts inhibited JNK activation, evidencing a distinctive neuroprotective benefit. Analysis of coffee phenolic compounds revealed that roasted coffees contained high levels of chlorogenic acid lactones (CGLs); a significant correlation between CGLs and neuroprotective efficacy was observed (R(2) = 0.98). In conclusion, this study showed that roasted coffees are high in lipophilic antioxidants and CGLs, can protect neuronal cells against oxidative stress, and may do so by modulation of the ERK1/2 and JNK signaling pathways.

Background and purpose: Traumatic brain injury (TBI) triggers a complex series of inflammatory responses that contribute to secondary tissue damage. The aim of this study was to investigate the effect of baicalein, a flavonoid possessing potent anti-inflammatory properties, on functional and histological outcomes and inflammatory cytokine expression, following TBI in rats. Experimental approach: Rats subjected to controlled cortical impact injury were injected with baicalein (30 mg kg−1) or vehicle immediately after injury or daily for 4 days. Neurological status was evaluated using the rotarod, adhesive removal, modified neurological severity scores and beam walk tests. Contusion volume and neuronal degeneration were measured using cresyl violet and FluoroJade B (FJB) histochemistry. Levels of tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) mRNA and protein were assessed by real-time quantitative reverse transcriptase-PCR, enzyme-linked immunosorbent assay and immunohistochemistry. Key results: Single-dose and multiple-dose treatment with baicalein significantly improved functional recovery and reduced contusion volumes up to day 28 post-injury, although multiple-dose baicalein was the more effective treatment. Single-dose baicalein also significantly reduced the number of degenerating neurons (31%) on post-injury day 1 as indicated by FJB staining. These changes were associated with significantly decreased levels, at the contusion site, of TNF-α, IL-1β and IL-6 mRNA at 6 h, and cytokine protein on day 1 post-injury. Conclusions and implications: Post-injury treatment with baicalein improved functional and histological outcomes and reduced induction of proinflammatory cytokines in rat TBI. The neuroprotective effect of baicalein may be related to a decreased inflammatory response following the injury. British Journal of Pharmacology (2008) 155, 1279–1296; doi:10.1038/bjp.2008.345; published online 8 September 2008

We report the structure and emission properties of ternary (In,Ga)N nanowires (NWs) embedded with self-assembled quantum dots (SAQDs). InGaN NWs are fabricated by the reaction of In, Ga and NH 3 via a vapor-liquid-solid (VLS) mechanism, using Au as the catalyst. By simply varying the growth temperature, In-rich or Ga-rich ternary NWs have been produced. X-ray diffraction, Raman studies and transmission electron microscopy reveal a phase-separated microstructure wherein the isovalent heteroatoms are self-aggregated, forming SAQDs embedded in NWs. The SAQDs are observed to dominate the emission behavior of both In-rich and Ga-rich NWs. Temperature-dependent photoluminescence (PL) measurements indicate relaxation of excited electrons from the matrix of the Ga-rich NWs to their embedded SAQDs. A multi-level band schema is proposed for the case of In-rich NWs, which showed an anomalous enhancement in the PL peak intensity with increasing temperature accompanies with red shift in its peak position.

In this paper, we study strategies in incremental planning for ordering and grouping subproblems partitioned by the subgoals of a planning problem when each sub-problem is solved by a basic planner. To generate a rich set of partial orders for ordering subproblems, we propose a new ordering algorithm based on a relaxed plan built from the initial state to the goal state. The new algorithm considers both the initial and the goal states and can effectively order subgoals in such a way that greatly reduces the number of invalidations during incremental planning. We have also considered trade-offs between the granularity of the subgoal sets and the complexity of solving the overall planning problem. We show an optimal region of grain size that minimizes the total complexity of incremental planning. We propose an efficient strategy to dynamically adjust the grain size in partitioning in order to operate in this optimal region. We further evaluate a redundant-execution scheme that uses two different subgoal orders in order to improve the quality of the plans generated without greatly sacrificing run-time efficiency. Experimental results on using three basic planners (metric-FF, YAHSP, and LPG-TD-speed) show that our strategies are general for improving the time and quality of each of these planners across various benchmarks

In this paper, we present the partitioning of mutual-exclusion (mutex) constraints in temporal planning problems and its implementation in the SGPlan4 planner. Based on the strong locality of mutex constraints observed in many benchmarks of the Fourth International Planning Competition (IPC4), we propose to partition the constraints of a planning problem into groups based on their subgoals. Constraint partitioning leads to significantly easier subproblems that are similar to the original problem and that can be efficiently solved by the same planner with some modifications to its objective function. We present a partition-and-resolve strategy that looks for locally optimal subplans in constraint-partitioned temporal planning subproblems and that resolves those inconsistent global constraints across the subproblems. We also discuss some implementation details of SGPlan4, which include the resolution of violated global constraints, techniques for handling producible resources, landmark analysis, path finding and optimization, search-space reduction, and modifications of Metric-FF when used as a basic planner in SGPlan4. Last, we show results on the sensitivity of each of these techniques in quality-time trade-offs and experimentally demonstrate that SGPlan4 is effective for solving the IPC3 and IPC4 benchmarks.

We report diameter-selective growth of GaN nanowires (NWs) by using mono-dispersed Au nanoparticles (NPs) on a ligand-modified Si substrate. The thiol-terminal silane was found to be effective in producing well-dispersed Au NPs in low density on Si substrates so that the agglomeration of Au NPs during growth could be avoided. The resultant GaN NWs exhibited a narrow diameter distribution and their mean diameter was always larger than, while keeping a deterministic relation with, the size of the Au NPs from which they were grown. A self-regulating steady growth model is proposed to account for the size-control process.

An MPEG-4 video coding SOC design is presented in this paper. We adopt platform-based architecture with an embedded RISC core and efficient memory organization. A motion estimator supporting predictive diamond search and spiral full search is implemented for compromise between compression performance and design cost. The proposed data reuse scheme reduces required memory access bandwidth. For texture coding path, an interleaving DCT/IDCT scheduling with substructure sharing technique is proposed. Several key modules are integrated into an efficient platform in hardware/software co-design fashion. The cost-efficient video encoder SOC consumes 256.8 mW at 40 MHz and achieves real-time encoding of 30 CIF (352×288) frames per second.

High-quality single crystal indium nitride nanorods were grown on Si substrates by catalytic chemical vapor deposition. Both Raman and high resolution transmission electron microscopic analyses suggested that even a minute amount of oxygen, from the residual oxygen in the growth environment and/or native oxide on the Si, would effectively help the growth of InN nanorods. The In2O3 formed on Au nanoparticles helped dissolve nitrogen as a catalyst with the subsequent growth of InN nanorods. Variations in the apparent color and photoluminescence (PL) spectra of the InN nanorods were observed. For the optically brown InN nanorods that exhibited diameters in the range of 30–50 nm, the PL study showed a peak at 1.9 eV, the possible origins of which are discussed. In contrast, for the optically black InN nanorods that exhibited diameters in the range of 50–100 nm, the PL peak at approximately 0.766 eV measured at 20 K was attributed to band edge emission.

The formation of homojunctions and heterojunctions on two-dimensional (2D) substrates plays a key role in the device performance of thin films. Accelerating the progress of device fabrication in nanowires (NWs) also necessitates a similar understanding in the one-dimensional (1D) system. Nanohomojunction (GaN on GaN) and nanoheterojunction (InN on GaN) nanorods (NRs) were formed in a two-step growth process by a vapor–liquid–solid (VLS) mechanism. Ga2O3 nanoribbons were formed using Ni as catalyst in a chemical vapor deposition (CVD) technique and then completely converted to GaN NWs with NH3 as reactant gas. An Au catalyst is used in the second step of the VLS process to grow GaN and InN NRs on GaN NWs using CVD techniques. A morphological study showed the formation of nanobrushes with different structural symmetries and sub-symmetries in both homogeneous and heterogeneous systems. Structural characterizations showed nearly defect-free growth of nanohomojunction (GaN) and nanoheterojunction (InN) NRs on 1D GaN NW substrates.

The decomposition method is currently one of the major methods for solving support vector machines. An important issue of this method is the selection of working sets. In this paper through the design of decomposition methods for bound-constrained SVM formulations we demonstrate that the working set selection is not a trivial task. Then from the experimental analysis we propose a simple selection of the working set which leads to faster convergences for difficult cases. Numerical experiments on different types of problems are conducted to demonstrate the viability of the proposed method.

We report the morphology, composition, and interaction mechanisms of silicon surface gratings fabricated with the fourth harmonic (266 nm) of a Q-switched Nd:YAG laser. We paid particular attention to the laser fluence dependence of silicon grating formation. It was found that at low fluence levels, grating formation was mainly caused by silicon oxidation. However, at high fluence levels gratings were formed with thermal ablation. In the former case, it was found that water vapor, instead of oxygen molecules, in the air was the key species providing oxygen for silicon oxidation. In the latter case, grating morphology was controlled by laser fluence level. These conclusions were supported by the measurement results of atomic force microscopy, energy-dispersive x-ray spectroscopy, Fourier-transform infrared spectroscopy, and chemical etching. The results of real-time monitoring of grating growth are also reported.

BACKGROUND: Obesity is a multifactorial disease that arises from complex interactions between genetic predisposition and environmental factors. Leptin is central to the regulation of energy metabolism and control of body weight in mammals. METHODOLOGY/PRINCIPAL FINDINGS: To better recapitulate the complexity of human obesity syndrome, we applied N-ethyl-N-nitrosourea (ENU) mutagenesis in combination with a set of metabolic assays in screening mice for obesity. Mapping revealed linkage to the chromosome 6 within a region containing mouse Leptin gene. Sequencing on the candidate genes identified a novel T-to-A mutation in the third exon of Leptin gene, which translates to a V145E amino acid exchange in the leptin propeptide. Homozygous Leptin(145E/145E) mutant mice exhibited morbid obesity, accompanied by adipose hypertrophy, energy imbalance, and liver steatosis. This was further associated with severe insulin resistance, hyperinsulinemia, dyslipidemia, and hyperleptinemia, characteristics of human obesity syndrome. Hypothalamic leptin actions in inhibition of orexigenic peptides NPY and AgRP and induction of SOCS1 and SOCS3 were attenuated in Leptin(145E/145E) mice. Administration of exogenous wild-type leptin attenuated hyperphagia and body weight increase in Leptin(145E/145E) mice. However, mutant V145E leptin coimmunoprecipitated with leptin receptor, suggesting that the V145E mutation does not affect the binding of leptin to its receptor. Molecular modeling predicted that the mutated residue would form hydrogen bond with the adjacent residues, potentially affecting the structure and formation of an active complex with leptin receptor within that region. CONCLUSIONS/SIGNIFICANCE: Thus, our evolutionary, structural, and in vivo metabolic information suggests the residue 145 as of special function significance. The mouse model harboring leptin V145E mutation will provide new information on the current understanding of leptin biology and novel mouse model for the study of human obesity syndrome.

We demonstrate a rationale for using GaN nanowires (GaNNWs) in label-free DNA-sensing using dual routes of electrochemical impedance spectroscopy (EIS) and photoluminescence (PL) measurements, employing a popular target DNA with anthrax lethal factor (LF) sequence. The in situ EIS reveals that both high surface area and surface band-bending in the nanowires, providing more binding sites and surface-enhanced charge transfer, respectively, are responsible for the enhanced sensitivity to surface-immobilized DNA molecules. The net electron-transfer resistance can be readily deconvoluted into two components because of the coexistence of two interfaces, GaN/DNA and DNA/electrolyte interfaces, in series. Interestingly, the former, decreasing with LF concentration (C(LF)), serves as a signature for the extent of hybridization, while the latter as a fingerprint for DNA modification. For PL-sensing, the band-edge emission of GaNNWs serves as a parameter for DNA modification, which quenches exponentially with C(LF) as the incident light is increasingly blocked from reaching the core nanowire by rapidly developing a UV-absorbing DNA sheath at high C(LF). Furthermore, successful application for detection of "hotspot" mutations, related to the human p53 tumor-suppressor gene, revealed excellent selectivity and specificity, down to picomolar concentration, even in the current unoptimized sensor design/condition, and in the presence of mutations and noncomplementary strands, suggesting the potential pragmatic application in complex clinical samples.

The support vector machine (SVM) is a new and promising technique for pattern recognition. It requires the solution of a large dense quadratic programming problem. Traditional optimization methods cannot be directly applied due to memory restrictions. Up to now, very few methods can handle the memory problem and an important one is the "decomposition method." However, there is no convergence proof so far. In this paper, we connect this method to projected gradient methods and provide theoretical proofs for a version of decomposition methods. An extension to bound-constrained formulation of SVM is also provided.We then show that this convergence proof is valid for general decomposition methods if their working set selection meets a simple requirement.

Support vector machines (SVMs) were originally designed for binary classification. How to effectively extend it for multiclass classification is still an ongoing research issue. Several methods have been proposed where typically we construct a multiclass classifier by combining several binary classifiers. Some authors also proposed methods that consider all classes at once. As it is computationally more expensive to solve multiclass problems, comparisons of these methods using large-scale problems have not been seriously conducted. Especially for methods solving multiclass SVM in one step, a much larger optimization problem is required so up to now experiments are limited to small data sets. In this paper we give decomposition implementations for two such "all-together" methods. We then compare their performance with three methods based on binary classifications: "one-against-all," "one-against-one," and directed acyclic graph SVM (DAGSVM). Our experiments indicate that the "one-against-one" and DAG methods are more suitable for practical use than the other methods. Results also show that for large problems methods by considering all data at once in general need fewer support vectors.

The application of frequent patterns in classification appeared in sporadic studies and achieved initial success in the classification of relational data, text documents and graphs. In this paper, we conduct a systematic exploration of frequent pattern-based classification, and provide solid reasons supporting this methodology. It was well known that feature combinations (patterns) could capture more underlying semantics than single features. However, inclusion of infrequent patterns may not significantly improve the accuracy due to their limited predictive power. By building a connection between pattern frequency and discriminative measures such as information gain and Fisher score, we develop a strategy to set minimum support in frequent pattern mining for generating useful patterns. Based on this strategy, coupled with a proposed feature selection algorithm, discriminative frequent patterns can be generated for building high quality classifiers. We demonstrate that the frequent pattern-based classification framework can achieve good scalability and high accuracy in classifying large datasets. Empirical studies indicate that significant improvement in classification accuracy is achieved (up to 12% in UCI datasets) using the so-selected discriminative frequent patterns.

This paper presents a cost-effective platform architecture design for MPEG-4 video coding. A fast motion estimator architecture supporting predictive diamond search and spiral full search with halfway termination is implemented to make good compromise between compression performance and design cost. An efficient block-level scheduling for texture coding engine is employed to reduce the hardware cost. Both these key modules are integrated into an efficient platform in hardware/software co-design fashion. With high degree of optimization in both algorithm and architecture levels, a cost-efficient video encoder is implemented. It consumes 256.8 mW at 40 MHz and achieves real-time encoding of 30 CIF (352/spl times/288) frames per second.

A cost-effective hardware architecture of integer, half, and quarter-pel motion estimation for MPEG-4 Advanced Simple Profile is proposed in this paper. Three-step hierarchy scheme is employed to cope with different pixel accuracy. For integer-pel estimation, the proposed computation-controllable algorithm makes it easy to be integrated into the coding system according to the power, quality, and timing conditions. For half and quarter-pel motion estimation, hardware-oriented algorithm and related architecture are proposed for cost reduction and provide 1.63 to 4.81 dB improvement in PSNR quality. The implementation takes 15K gates at 54MHz for sequences of CIF format at 30 fps.

MPEG-4 Fine Granularity Scalability (FGS) provides bandwidth adaptation and error resilience features for streaming applications. In this paper, by estimating the required computational power for FGS in a video encoding system, an efficient FGS implementation method is exploited. With the proposed hardware-oriented optimization approaches, a hardwired FGS block-level processing core is proposed to provide a cost-effective solution to FGS implementation. The proposed hardware core can support profile level 5, frame size 720/spl times/576, 30Hz, for real-time streaming applications at 54 MHz.

For MPEG-4 texture coding, an efficient Interleaving DCT and IDCT Schedule (IDIS) is proposed. With this scheme, the DCT-Q-IQ-IDCT coding loop can be implemented with no buffers and least latency, which in turn makes the number of buffers for MC a minimum of two. Also by the characteristics of IDIS, a substructure sharing technique is applied for DC/AC prediction with Q and IQ to reduce hardware cost further. All the functions are integrated to comprise the block engine for texture coding operations in the MPEG-4 video standard. For a encoding sequence of 720/spl times/480 at 30 fps, real-time requirement can be achieved at 54 MHz. The proposed scheduling can be further applied to other video coding standards for a cost-effective SOC implementation.

Sprite coding, which is a new coding tool in MPEG-4, can achieve high coding efficiency with high subjective quality at low bit rate. Many sprite generation algorithms have been proposed; however, the computational intensity is very high and the quality is not good enough because of the limitation of simple motion models. A novel sprite generation algorithm is proposed with several new techniques. A frame skipping technique can generate the sprite using only several important frames to accelerate the process and achieve similar subjective quality. In addition, boundary matching and multiple sprites techniques can overcome the limitation of simple motion models to achieve high subjective quality with little computation overhead. Experiments show the proposed algorithm is 46 times faster than the algorithms in MPEG-4 VM and have high subjective quality. These techniques can be also applied with other sprite generation algorithms.

The pulse break-up phenomenon during nonlinear coupling in directional couplers made of Kerr media, such as optical fiber, can lead to pulse narrowing and has been used for passive mode-locking of Er-doped fiber lasers [1,2]. In this paper, we demonstrate the similar mechanism in directional couplers made of two parallel semiconductor optical amplifiers. In such a directional coupler with an appropriate length, the leading edge of an input pulse can couple into the cross amplifier; however, the high power of the central part saturates the bar amplifier and breaks the phase-matching condition for linear coupling. Because of the long recovering time of gain saturation, the trailing edge of the input pulse is effectively depressed, although it stays in the bar amplifier. Therefore, the pulse is effectively narrowed. By placing such a directional coupler in a ring cavity, we have numerically shown that periodical short pulses evolved from a long pulse inside the cavity under appropriate conditions, similar to the passively mode-locking results using a saturable absorber. To extract laser energy, we used the cross amplifier as the output coupler and found that the peak power (pulse width) of the mode-locked output could be higher (shorter) than the intracavity peak power (pulse width). A detailed investigation showed that the relative strength of the output pulse and the intracavity pulse depended on the length of the directional coupler. Also, we found that mode-locking results could be adjusted by the relative gain of the two amplifiers. There exists quite a large parameter space for the mode-locking phenomenon to occur. This implies that the implementation of such a passively mode-locked semiconductor laser should be feasible.

This study demonstrates the utility of functionalized GaN nanowires (GaNNWs) for electrochemical detection of nucleic acids, in aqueous solution, using cyclic voltammetry. In order to link probe DNA to the NW surface, we employed an organosulfur compound, 3-mercaptopropyl trimethoxysilane (MPTS), to functionalize the GaNNW surface. Interestingly, the MPTS-modified GaNNWs exhibited a potential window of 4.5 V, the widest reported to date, with very low background current, which provides an advantage for sensing DNA immobilization/hybridization, down to sub-pM concentration, via monitoring adenine and guanine oxidation. The oxidation of guanine was characterized by its peak potential and peak current, where the former serves as a fingerprint for DNA hybridization and the latter as a parameter for the extent of hybridization. Moreover, the GaNNW-based sensor exhibited excellent consistency in hybridization-dehybridization-rehybridization cycles.

The authors demonstrate the coalescence overgrowth of GaN nano-columns on a (111) Si substrate with metalorganic chemical vapor deposition to show high-quality optical properties in the overgrown film. Plan-view scanning electron microscopy (SEM) shows coalesced surface morphology, although hexagonal structures are still visible in the images. The cross-section cathodoluminescence (CL) image shows more efficient emission in the overgrowth layer than from the nano-column layer. The plan-view CL image demonstrates that the emitted light is mainly from the hexagonal structures. The photoluminescence measurement result indicates that the emission efficiency of the overgrown layer is even higher than that of an undoped GaN thin film of high quality. The presence of hexagonal structures correlates to surface roughness values in the range of several nanometres.

Typically, placing a quasi-phase matched nonlinear optics crystal in a resonance cavity, such as the cases of optical parametric oscillator (OPO) and second-harmonic oscillator (SHO), can lead to efficient wavelength conversion. With the end faces well polished and HR-coated, compact devices can be achieved. Because we have successfully developed a simple laser ablation method for grating formation on LiNbO3, here we propose an alternative of making compact OPO’s or SHO’s by using distributed Bragg reflectors (DBR’s). Such a device has the advantage of smaller output spectral widths due to the use of gratings. In this paper, we present the results of our numerical simulations for DBR SHO’s and OPO’s based on periodically poled LiNbO3 (PPLN). The basic device design is to first fabricate a channel waveguide on a PPLN crystal and then make two gratings at the ends of the waveguide. The longer (shorter) grating serves as the end mirror (output coupler). The fundamental (pump) for a SHO (OPO) is incident from the side of the end mirror. The grating period is designed for the Bragg reflection and hence oscillation of the second harmonic (signal) of a SHO (OPO). We have found that the numerical results of the output of such a device depended on the cavity dimensions, pump power level and phase mismatch parameter of the grating. Therefore, it is expected that for fixed cavity dimensions and pump power, the device should provide the output with the optimum phase mismatch parameter. Figure 1 (filled circles) shows the second harmonic output vs. the normalized phase mismatch parameter (δ/κ) of a DBR SHO when the fundamental input is 10 KW/cm2. There are two peak values when the normalized mismatch parameters are 0.225 and 0.668. For comparison, the dashed line shows the result when the gratings are removed (single pass second-harmonic generation). Note that with the DBR’s, the output can be enhanced by at least 13 dB.