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Pulsar timing arrays (PTAs), aimed at detecting gravitational waves (GWs) in the $1\sim 100$ nHz range, have recently made significant strides. Compelling evidence has emerged for a common spectrum signal spatially correlated among pulsars, following a Hellings-Downs (HD) pattern, which is crucial for detecting a gravitational-wave background (GWB). However, the HD curve is expected for discrete and non-interfering sources, which is unlikely to hold in realistic scenarios with potential interference among numerous GW sources, such as the supermassive black-hole binaries. Incorporating interference was previously expected to introduce an irreducible uncertainty (known as "cosmic variance") in discerning the HD correlation; however, our work reveals how this interference generates measurable frequency-dependent spatial correlations distinct from the HD curve. The spatial correlations for interfering sources (referred to as "ISC") still exhibit contributions in the quadrupole and higher orders, resembling the HD correlation and encoding the nature of GW radiations. We apply these novel correlations to search for a GWB in the NANOGrav 15-year data set. In an optimistic estimation, our findings show a Bayes factor of $33.7\pm 3.2$ comparing ISC to the HD correlation, and an improvement in optimal statistic signal-to-noise ratio from $4.9\pm 1.1$ for the HD correlation to $6.6\pm 1.7$ for the ISC, highlighting the significant enhancement in evidence for detecting a GWB through incorporating interference., Comment: 18 pages, 6 figures; minor revision and typo corrected

Text-to-image (T2I) models, such as Stable Diffusion, have exhibited remarkable performance in generating high-quality images from text descriptions in recent years. However, text-to-image models may be tricked into generating not-safe-for-work (NSFW) content, particularly in sexual scenarios. Existing countermeasures mostly focus on filtering inappropriate inputs and outputs, or suppressing improper text embeddings, which can block explicit NSFW-related content (e.g., naked or sexy) but may still be vulnerable to adversarial prompts inputs that appear innocent but are ill-intended. In this paper, we present SafeGen, a framework to mitigate unsafe content generation by text-to-image models in a text-agnostic manner. The key idea is to eliminate unsafe visual representations from the model regardless of the text input. In this way, the text-to-image model is resistant to adversarial prompts since unsafe visual representations are obstructed from within. Extensive experiments conducted on four datasets demonstrate SafeGen's effectiveness in mitigating unsafe content generation while preserving the high-fidelity of benign images. SafeGen outperforms eight state-of-the-art baseline methods and achieves 99.1% sexual content removal performance. Furthermore, our constructed benchmark of adversarial prompts provides a basis for future development and evaluation of anti-NSFW-generation methods.

The recent detection of a stochastic signal in the NANOGrav 15-year data set has aroused great interest in uncovering its origin. However, the evidence for the Hellings-Downs correlations, a key signature of the gravitational-wave background (GWB) predicted by general relativity, remains inconclusive. In this letter, we search for an isotropic non-tensorial GWB, allowed by general metric theories of gravity, in the NANOGrav 15-year data set. Our analysis reveals a Bayes factor of approximately 2.5, comparing the quadrupolar (tensor transverse, TT) correlations to the scalar transverse (ST) correlations, suggesting that the ST correlations provide a comparable explanation for the observed stochastic signal in the NANOGrav data. We obtain the median and the $90\%$ equal-tail amplitudes as $\mathcal{A}_\mathrm{ST} = 7.8^{+5.1}_{-3.5} \times 10^{-15}$ at the frequency of 1/year. Furthermore, we find that the vector longitudinal (VL) and scalar longitudinal (SL) correlations are weakly and strongly disfavoured by data, respectively, yielding upper limits on the amplitudes: $\mathcal{A}_\mathrm{VL}^{95\%} \lesssim 1.7 \times 10^{-15}$ and $\mathcal{A}_\mathrm{SL}^{95\%} \lesssim 7.4 \times 10^{-17}$. Lastly, we fit the NANOGrav data with the general transverse (GT) correlations parameterized by a free parameter $\alpha$. Our analysis yields $\alpha=1.74^{+1.18}_{-1.41}$, thus excluding both the TT ($\alpha=3$) and ST ($\alpha=0$) models at the $90\%$ confidence level., Comment: 9 pages, 4 figures, 3 tables; match the published version

NANOGrav, EPTA, PPTA, and CPTA have announced the evidence for a stochastic signal from their latest data sets. Supermassive black hole binaries (SMBHBs) are supposed to be the most promising gravitational-wave (GW) sources of pulsar timing arrays. Assuming an astro-informed formation model, we use the NANOGrav 15-year data set to constrain the gravitational wave background (GWB) from SMBHBs. Our results prefer a large turn-over eccentricity of the SMBHB orbit when GWs begin to dominate the SMBHBs evolution. Furthermore, the GWB spectrum is extrapolated to the space-borne GW detector frequency band by including inspiral-merge-cutoff phases of SMBHBs and should be detected by LISA, Taiji and TianQin in the near future., Comment: 8 pages, 3 figures, 3 tables

The recently detected stochastic signal by several pulsar timing array collaborations, offers an opportunity to scrutinize the fundamental properties of gravity, including the potential mass of the graviton. In this study, we analyze the NANOGrav 15-year data set to search for a stochastic gravitational wave background with modified Hellings-Downs correlations predicted by massive gravity. While the Bayesian analysis comparing the massive gravity to massless gravity within the effective searchable mass range of $m_g\in [3\times 10^{-25}, 8 \times 10^{-24}]\,\rm{eV}/c^2$ does not yield an explicit upper bound as all the Bayes factors are smaller than $3$, the combined consideration of the minimum frequency inherent in a massive gravity and the observed spectrum leads to an upper limit of $m_g<8.2\times 10^{-24}\,\rm{eV}/c^2$., Comment: 6 pages, 1 figure, 1 table

General relativity predicts that gravitational waves propagate at the speed of light. Although ground-based gravitational-wave detectors have successfully constrained the velocity of gravitational waves in the high-frequency range, extending this constraint to the lower frequency range remains a challenge. In this work, we utilize the deviations in the overlap reduction function for a gravitational-wave background within pulsar timing arrays to investigate the velocity of gravitational waves in the nanohertz frequency band. By analyzing the NANOGrav 15-year data set, we obtain a well-constrained lower bound for the velocity of gravitational waves that $v \gtrsim 0.87\,c$, where $c$ is the speed of light., Comment: 6 pages, 1 figure, 1 table

In the frequency band of Laser Interferometer Space Antenna (LISA), extensive research has been conducted on the impact of foreground confusion noise generated by galactic binaries within the Milky Way galaxy. Additionally, the recent evidence for a stochastic signal, announced by the NANOGrav, EPTA, PPTA, CPTA and InPTA, indicates that the stochastic gravitational-wave background generated by supermassive black hole binaries (SMBHBs) can contribute a strong background noise within in LISA band. Given the presence of such strong noise, it is expected to have a considerable impacts on LISA's scientific missions. In this work, we investigate the impacts of the SGWB generated by SMBHBs on the detection of massive black hole binaries (MBHBs), verified galactic binaries (VGBs) and extreme mass ratio inspirals (EMRIs) in the context of LISA, and find it crucial to resolve and eliminate the exceed noise from the SGWB to ensure the success of LISA's missions., Comment: 6 pages, 3 figures

Automatic speech recognition (ASR) systems have been shown to be vulnerable to adversarial examples (AEs). Recent success all assumes that users will not notice or disrupt the attack process despite the existence of music/noise-like sounds and spontaneous responses from voice assistants. Nonetheless, in practical user-present scenarios, user awareness may nullify existing attack attempts that launch unexpected sounds or ASR usage. In this paper, we seek to bridge the gap in existing research and extend the attack to user-present scenarios. We propose VRIFLE, an inaudible adversarial perturbation (IAP) attack via ultrasound delivery that can manipulate ASRs as a user speaks. The inherent differences between audible sounds and ultrasounds make IAP delivery face unprecedented challenges such as distortion, noise, and instability. In this regard, we design a novel ultrasonic transformation model to enhance the crafted perturbation to be physically effective and even survive long-distance delivery. We further enable VRIFLE's robustness by adopting a series of augmentation on user and real-world variations during the generation process. In this way, VRIFLE features an effective real-time manipulation of the ASR output from different distances and under any speech of users, with an alter-and-mute strategy that suppresses the impact of user disruption. Our extensive experiments in both digital and physical worlds verify VRIFLE's effectiveness under various configurations, robustness against six kinds of defenses, and universality in a targeted manner. We also show that VRIFLE can be delivered with a portable attack device and even everyday-life loudspeakers., Comment: Accepted by NDSS Symposium 2024. Please cite this paper as "Xinfeng Li, Chen Yan, Xuancun Lu, Zihan Zeng, Xiaoyu Ji, Wenyuan Xu. Inaudible Adversarial Perturbation: Manipulating the Recognition of User Speech in Real Time. In Network and Distributed System Security (NDSS) Symposium 2024."

Automatic Speaker Recognition Systems (SRSs) have been widely used in voice applications for personal identification and access control. A typical SRS consists of three stages, i.e., training, enrollment, and recognition. Previous work has revealed that SRSs can be bypassed by backdoor attacks at the training stage or by adversarial example attacks at the recognition stage. In this paper, we propose Tuner, a new type of backdoor attack against the enrollment stage of SRS via adversarial ultrasound modulation, which is inaudible, synchronization-free, content-independent, and black-box. Our key idea is to first inject the backdoor into the SRS with modulated ultrasound when a legitimate user initiates the enrollment, and afterward, the polluted SRS will grant access to both the legitimate user and the adversary with high confidence. Our attack faces a major challenge of unpredictable user articulation at the enrollment stage. To overcome this challenge, we generate the ultrasonic backdoor by augmenting the optimization process with random speech content, vocalizing time, and volume of the user. Furthermore, to achieve real-world robustness, we improve the ultrasonic signal over traditional methods using sparse frequency points, pre-compensation, and single-sideband (SSB) modulation. We extensively evaluate Tuner on two common datasets and seven representative SRS models, as well as its robustness against seven kinds of defenses. Results show that our attack can successfully bypass speaker recognition systems while remaining effective to various speakers, speech content, etc. To mitigate this newly discovered threat, we also provide discussions on potential countermeasures, limitations, and future works of this new threat., Comment: Published in Internet of Things Journal (IoT-J)

Background: Atherosclerosis is the predominant cause of cardiovascular diseases. Existing studies suggest that the development of atherosclerosis is closely related to inflammation and immunity, but whether there are differences and similarities between atherosclerosis occurring at different sites is still unknown. We elucidated the pathological characteristics of peripheral vascular diseases by using bioinformatic analyses on immune cells and inflammation-related gene expression in atherosclerotic arteries and plaques. Methods: Eight data sets regarding atherosclerosis were downloaded from the Gene Expression Omnibus database. Human immune genes were obtained from the IMMPORT website. The samples were scored and divided into highand low-immune groups. Then the samples were analysed using weighted gene co-expression network analysis, while the modules were analysed using functional enrichment. The protein–protein interaction network was constructed using the STRING and Cytoscape databases. The hub immune genes were screened, and the correlation between hub immune genes and immune cells was analysed. Results: Immune cells and their functions were significantly different during atherosclerosis development. The infiltration proportion of immune cells was approximately similar in samples from different sources of patients with carotid atherosclerosis. However, the sensitivity of lower extremity atherosclerosis samples to immune cells is lower than that of carotid atherosclerosis samples.The samples from the plaque and artery were mainly infiltrated by macrophages, T cells and mast cells. After immune cells were assessed, resting NK cells, activated mast cells and M0 macrophages were found to be key immune cells in atherosclerosis and plaque formation. In addition, CCL4, TLR2, IL1B and PTPRC were considered to be immune marker genes in atherosclerosis development. Conclusion: Bioinformatic data analysis confirms the essential role of immune cells in cardiovascular diseas, Oxidative medicine and cellular longevity, 2022, art. no. 5491038; 2022

Widespread therapeutic use of ketamine is limited by adverse effects and poor oral bioavailability, therefore improved formulations are required. In this project, mucoadhesive and orally disintegrating buccal films containing plain ketamine or ketamine-loaded microparticles were developed and characterised. Pharmacokinetic properties of optimized films were compared against ketamine oral solution and sublingual lozenges in rabbits. Results showed that buccal films may be preferable in pain management, due to enhanced bioavailability and sustained ketamine absorption.

An important goal in artificial intelligence is to create agents that can both interact naturally with humans and learn from their feedback. Here we demonstrate how to use reinforcement learning from human feedback (RLHF) to improve upon simulated, embodied agents trained to a base level of competency with imitation learning. First, we collected data of humans interacting with agents in a simulated 3D world. We then asked annotators to record moments where they believed that agents either progressed toward or regressed from their human-instructed goal. Using this annotation data we leveraged a novel method - which we call "Inter-temporal Bradley-Terry" (IBT) modelling - to build a reward model that captures human judgments. Agents trained to optimise rewards delivered from IBT reward models improved with respect to all of our metrics, including subsequent human judgment during live interactions with agents. Altogether our results demonstrate how one can successfully leverage human judgments to improve agent behaviour, allowing us to use reinforcement learning in complex, embodied domains without programmatic reward functions. Videos of agent behaviour may be found at https://youtu.be/v_Z9F2_eKk4.

Creating agents that can interact naturally with humans is a common goal in artificial intelligence (AI) research. However, evaluating these interactions is challenging: collecting online human-agent interactions is slow and expensive, yet faster proxy metrics often do not correlate well with interactive evaluation. In this paper, we assess the merits of these existing evaluation metrics and present a novel approach to evaluation called the Standardised Test Suite (STS). The STS uses behavioural scenarios mined from real human interaction data. Agents see replayed scenario context, receive an instruction, and are then given control to complete the interaction offline. These agent continuations are recorded and sent to human annotators to mark as success or failure, and agents are ranked according to the proportion of continuations in which they succeed. The resulting STS is fast, controlled, interpretable, and representative of naturalistic interactions. Altogether, the STS consolidates much of what is desirable across many of our standard evaluation metrics, allowing us to accelerate research progress towards producing agents that can interact naturally with humans. A video may be found at https://youtu.be/YR1TngGORGQ.

Using mathematical modeling and human subjects experiments, this research explores the extent to which emerging webcams might leak recognizable textual and graphical information gleaming from eyeglass reflections captured by webcams. The primary goal of our work is to measure, compute, and predict the factors, limits, and thresholds of recognizability as webcam technology evolves in the future. Our work explores and characterizes the viable threat models based on optical attacks using multi-frame super resolution techniques on sequences of video frames. Our models and experimental results in a controlled lab setting show it is possible to reconstruct and recognize with over 75% accuracy on-screen texts that have heights as small as 10 mm with a 720p webcam. We further apply this threat model to web textual contents with varying attacker capabilities to find thresholds at which text becomes recognizable. Our user study with 20 participants suggests present-day 720p webcams are sufficient for adversaries to reconstruct textual content on big-font websites. Our models further show that the evolution towards 4K cameras will tip the threshold of text leakage to reconstruction of most header texts on popular websites. Besides textual targets, a case study on recognizing a closed-world dataset of Alexa top 100 websites with 720p webcams shows a maximum recognition accuracy of 94% with 10 participants even without using machine-learning models. Our research proposes near-term mitigations including a software prototype that users can use to blur the eyeglass areas of their video streams. For possible long-term defenses, we advocate an individual reflection testing procedure to assess threats under various settings, and justify the importance of following the principle of least privilege for privacy-sensitive scenarios.

Traffic light recognition is essential for fully autonomous driving in urban areas. In this paper, we investigate the feasibility of fooling traffic light recognition mechanisms by shedding laser interference on the camera. By exploiting the rolling shutter of CMOS sensors, we manage to inject a color stripe overlapped on the traffic light in the image, which can cause a red light to be recognized as a green light or vice versa. To increase the success rate, we design an optimization method to search for effective laser parameters based on empirical models of laser interference. Our evaluation in emulated and real-world setups on 2 state-of-the-art recognition systems and 5 cameras reports a maximum success rate of 30% and 86.25% for Red-to-Green and Green-to-Red attacks. We observe that the attack is effective in continuous frames from more than 40 meters away against a moving vehicle, which may cause end-to-end impacts on self-driving such as running a red light or emergency stop. To mitigate the threat, we propose redesigning the rolling shutter mechanism., Comment: To be published in USENIX Security 2022

Human language learners are exposed to a trickle of informative, context-sensitive language, but a flood of raw sensory data. Through both social language use and internal processes of rehearsal and practice, language learners are able to build high-level, semantic representations that explain their perceptions. Here, we take inspiration from such processes of "inner speech" in humans (Vygotsky, 1934) to better understand the role of intra-agent speech in embodied behavior. First, we formally pose intra-agent speech as a semi-supervised problem and develop two algorithms that enable visually grounded captioning with little labeled language data. We then experimentally compute scaling curves over different amounts of labeled data and compare the data efficiency against a supervised learning baseline. Finally, we incorporate intra-agent speech into an embodied, mobile manipulator agent operating in a 3D virtual world, and show that with as few as 150 additional image captions, intra-agent speech endows the agent with the ability to manipulate and answer questions about a new object without any related task-directed experience (zero-shot). Taken together, our experiments suggest that modelling intra-agent speech is effective in enabling embodied agents to learn new tasks efficiently and without direct interaction experience.

Self-aggregation and the hemolytic effect limit the application of gamma-cyclodextrin (gamma-CD) in bioactive molecular delivery systems. In this study, gamma-CD was modified by grafting onto bovine serum albumin protein (BSA), with epichlorohydrin (ECH) acting as the cross-linking agent. The effects of BSA concentration, reaction temperature, pH and time on the grafting rate were studied, and the gamma-CD-BSA complex with a grafting rate of 99.5 +/- 0.1% +/- 0.06)% was achieved. The complex was confirmed using H-1 NMR and FT-IR spectra. Compared with gamma-CD, the hemolytic effect and self-aggregation of gamma-CD-BSA were significantly reduced, and the encapsulation efficiency of curcumin was increased by 10.8%. The results of scanning electron microscopy showed that both gamma-CD and gamma-CDBSA nanoparticles were formed and the structure of the gamma-CD-BSA complex was more uniform. The pH stability and salt stability of gamma-CD-BSA were higher than gamma-CD. The release rate of gamma-CD-BSA was 15.2 +/- 0.2% after 2 h at pH 1.2, and 57 +/- 1% after 4 h at pH 7.2. The gamma-CD-BSA nanoparticles could protect curcumin in acidic environments and release it in neutral environments. The results suggested a promising wall material for delivery of hydrophobic substances.

A common vision from science fiction is that robots will one day inhabit our physical spaces, sense the world as we do, assist our physical labours, and communicate with us through natural language. Here we study how to design artificial agents that can interact naturally with humans using the simplification of a virtual environment. We show that imitation learning of human-human interactions in a simulated world, in conjunction with self-supervised learning, is sufficient to produce a multimodal interactive agent, which we call MIA, that successfully interacts with non-adversarial humans 75% of the time. We further identify architectural and algorithmic techniques that improve performance, such as hierarchical action selection. Altogether, our results demonstrate that imitation of multi-modal, real-time human behaviour may provide a straightforward and surprisingly effective means of imbuing agents with a rich behavioural prior from which agents might then be fine-tuned for specific purposes, thus laying a foundation for training capable agents for interactive robots or digital assistants. A video of MIA's behaviour may be found at https://youtu.be/ZFgRhviF7mY

Inferring the abstract relational and causal structure of the world is a major challenge for reinforcement-learning (RL) agents. For humans, language--particularly in the form of explanations--plays a considerable role in overcoming this challenge. Here, we show that language can play a similar role for deep RL agents in complex environments. While agents typically struggle to acquire relational and causal knowledge, augmenting their experience by training them to predict language descriptions and explanations can overcome these limitations. We show that language can help agents learn challenging relational tasks, and examine which aspects of language contribute to its benefits. We then show that explanations can help agents to infer not only relational but also causal structure. Language can shape the way that agents to generalize out-of-distribution from ambiguous, causally-confounded training, and explanations even allow agents to learn to perform experimental interventions to identify causal relationships. Our results suggest that language description and explanation may be powerful tools for improving agent learning and generalization., Comment: ICML 2022; 23 pages

This study investigates how short-term debt and debt capacity help firms to make efficient financing decisions and reduce underinvestment problem. The sample includes Chinese nonfinancial firms listed on the Shanghai and Shenzhen Stock Exchanges over the period 2007 to 2017. The findings indicate that short-term debt is positively related to leverage. The results also indicate that growth positively influences leverage. The results further show that short-term debt enhances the positive impact of growth on leverage. These findings reveal that short-term debt makes firms financially flexible, and allows them to obtain more cost-effective debt by repricing and renegotiation of debt contracts in the presence of valuable growth opportunities. Furthermore, the results illustrate that debt capacity is positively associated with leverage, suggesting that debt capacity helps firms to have an easy access to the credit market and reduce liquidity risk. Overall, the findings remain consistent across different types of firms (state-owned [S.O.E.] and non-state-owned enterprises [N.S.O.E.]) and by considering alternative proxy of growth.

A deeper understanding of the comparative advantage of emerging markets in agricultural export can be gained by analysing the spatial connections of emerging markets through the framework provided by the diamond model. The geographic economics factors are transformed to interconnections of emerging markets by a genetic algorithm based on Mahalanobis distances. The spatial effect of geographic economics factors on export competitiveness of agriculture is further identified by spatial modelling. The irrigated land area, competitive labour cost, foreign direct investment (F.D.I.), and export market opportunity are important to further develop the export competitiveness of the agriculture industry from emerging markets based on spatial modelling. Also there is a spatial disturbances effect in agricultural export of emerging markets based on transformed interconnections structured by geographic economic factors. A fuzzy cluster analysis is further performed, and the stationary solution of clusters in dynamic transition across market segments is analysed by a Markov Chain. It is further found that the distribution of emerging markets with a higher level of export competitiveness can be more concentrated in clusters with lower levels of proportion. The findings of this research can offer support to global managers in further understanding the spatial effect of geographic economics factors on export competitiveness of agriculture from emerging markets

We evaluate the performance of Whittle index policy for restless Markovian bandits, when the number of bandits grows. It is proven in [30] that this performance is asymptotically optimal if the bandits are indexable and the associated deterministic system has a global attractor fixed point. In this paper we show that, under the same conditions, the convergence rate is exponential in the number of bandits, unless the fixed point is singular (to be defined later). Our proof is based on the nature of the deterministic equation governing the stochastic system: We show that it is a piecewise affine continuous dynamical system inside the simplex of the empirical measure of the bandits. Using simulations and numerical solvers, we also investigate the cases where the conditions for the exponential rate theorem are violated, notably when attracting limit cycles appear, or when the fixed point is singular. We illustrate our theorem on a Markovian fading channel model, which has been well studied in the literature. Finally, we extend our synchronous model results to the asynchronous model.

A common vision from science fiction is that robots will one day inhabit our physical spaces, sense the world as we do, assist our physical labours, and communicate with us through natural language. Here we study how to design artificial agents that can interact naturally with humans using the simplification of a virtual environment. This setting nevertheless integrates a number of the central challenges of artificial intelligence (AI) research: complex visual perception and goal-directed physical control, grounded language comprehension and production, and multi-agent social interaction. To build agents that can robustly interact with humans, we would ideally train them while they interact with humans. However, this is presently impractical. Therefore, we approximate the role of the human with another learned agent, and use ideas from inverse reinforcement learning to reduce the disparities between human-human and agent-agent interactive behaviour. Rigorously evaluating our agents poses a great challenge, so we develop a variety of behavioural tests, including evaluation by humans who watch videos of agents or interact directly with them. These evaluations convincingly demonstrate that interactive training and auxiliary losses improve agent behaviour beyond what is achieved by supervised learning of actions alone. Further, we demonstrate that agent capabilities generalise beyond literal experiences in the dataset. Finally, we train evaluation models whose ratings of agents agree well with human judgement, thus permitting the evaluation of new agent models without additional effort. Taken together, our results in this virtual environment provide evidence that large-scale human behavioural imitation is a promising tool to create intelligent, interactive agents, and the challenge of reliably evaluating such agents is possible to surmount.

Under globalization, small and medium enterprises (SMEs) that predominate Taiwan’s economy have been primarily original equipment manufacturers (OEMs) continuing to adjust operating strategies in order to extend supply chains and enhance competitiveness. This paper adopts the big data composed of 104,377 Taiwanese manufacturers from the 2011 Industry, Commerce, and Service Census to assess impact of the business life cycle, brand revenue, R&D spending, and internationalization on value creation. Major findings are as follows. First, the link of the firm’s operating years with value creation is characterized by a quadratic U-shaped curve where the minimum point corresponds to 15 years of operation, suggesting a cost of lower value added for new ventures at the early stage of development. Second, a reversed U-shaped curve of value creation is found as regards brand revenue and R&D spending, with the greater impact of the latter. Third, the impact of overseas investment and export expansion is also captured by a reversed U-shaped curve, with greater impact for the former. Fourth, an asymmetric grin curve rather than a smile curve is found in Taiwan’s manufacturers, whose value creation can be strengthened by strategies that focus on the learning curve, internationalization, internet, operating scale, and capital intensity.

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Pharmacology and Physiology, 2016., Heart failure is one of the leading causes of death both in the United States and worldwide; therefore, discovering new drugs for the treatment of heart failure is a critical area of research. Cyclic nucleotide phosphodiesterases (PDEs) may represent compelling therapeutic targets in the treatment of heart failure. However, the function of phosphodiesterase 1C (PDE1C) remains largely unknown. Herein, we studied the expression, regulation, function, and underlying mechanisms of PDE1C in the pathogenesis of cardiac remodeling and dysfunction in vitro and in vivo. PDE1C expression is upregulated in mouse and human failing hearts, and by conducting comparative studies in cardiomyocytes isolated from wild type and global genetic PDE1C knockout (PDE1C-KO) mice, we determined that PDE1C depletion protects against cell death and hypertrophy induced by Ang II or isoproterenol treatment, indicating a potent cardioprotective role for PDE1C. This protective effect was reliant on cAMP/PKA activation, and involved PDE1C coupling to adenosine A2 receptors, indicating that PDE1C may regulate cAMP produced by these receptors. Furthermore, when subjected to pressure overload-induced heart failure, PDE1C-KO mice developed significantly reduced cardiac hypertrophy, fibrosis, apoptosis, and dysfunction relative to PDE1C-WT mice. Furthermore, treatment of PDE1C-KO TAC mice with an adenosine receptor antagonist reversed many of the protective effects of PDE1C-KO. Finally, as PDE1C inhibition or depletion appears to potentiate a particular cAMP pool in cardiomyocytes, we hypothesized that PDE1C inhibition could potentiate cAMP efflux, activating the extracellular cAMP-adenosine pathway, which could potentially act on either cardiomyocytes or fibroblasts in a protective fashion. Remarkably, we found that this pathway does appear to be active in cardiomyocytes, and that inhibition of any element of this pathway significantly reduced the protective effects of PDE1C depletion or inhibition on

The mechanisms of renal fibrogenesis after ureteral obstruction remain unclear. We tried to primarily expand mesenchymal stem cells from renal tissues and then investigated their role in fibrogenesis after ureteral obstruction. Unilateral ureteral obstruction was induced by ligating the left ureteral duct of adult C57BL/6 mice. We collected the kidneys for experiments at 2, 7,and 14 days after operation. Histological analysis showed obviously fibrotic changes in the left kidney at 7 days and further increased at 14 days after ureteral obstruction. To expand mesenchymal stem cells, we minced the renal tissues into small explants (about 1 mm 3 )and cultured onto 10 cm dishes. Interestingly, the outgrowth of cells was observed significantly earlier from the explants of the obstructed left kidney than that of the unobstructed right kidney. These expanded cells showed the potency of adipogenic, osteogenic, and chondrogenic differentiations and positively expressed with CD44 and partly expressed with CD90, CD105, and CD106, but negatively expressed with CD34, CD45, and FSP1, suggesting the phenotype of mesenchymal stem-like cells (MSLCs). The mouse fibrosis RT 2 profiler PCR array showed that many genes were changed over 2-fold in the MSLCs expanded from both kidneys at 2, 7, and 14 days after operation. Interestingly,profibrotic genes were prevalently enhanced in the left kidney with ureteral obstruction. Histological analysis also showed obviously infiltration of inflammatory cells in the left kidney at 14 days after operation. Our data indicate the potential role of resident MSLCs in renal fibrogenesis after ureteral obstruction, but further experiments are required to understand the relevant mechanisms., Stem Cells International, 2019, art.no.2543171; 2019

Lu-Lu Huang,1,2 Mei Tang,1,2 Qian-Qian Du,1,2 Chun-Xia Liu,1,2 Chen Yan,2 Jin-Ling Yang,3 Yan Li1,2  1Department of Pharmacology, Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People’s Republic of China; 2Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People’s Republic of China; 3Department of Biosynthesis, State Key Laboratory of Bioactive Substance and Function of Natural Medicines and Key Laboratory of Biosynthesis of Natural Products of National Health and Family Planning Commission, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, People’s Republic of ChinaCorrespondence: Yan LiInstitute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, People’s Republic of ChinaTel +86 10 6316 9181Email lyhzytt@163.comBackground: A biosynthetic ginsenoside, 3-O-β-D-glucopyranosyl-12-O-β-D-glucopyranosyl-dammar-24-ene-3β, 12β, 20S-triol (C3C12PPD), showed antitumor activity against many tumor cells in vitro, especially had better anti-lung cancer activity than Rg3 in vitro and in vivo. However, the effects and molecular mechanisms of C3C12PPD on non-small cell lung cancer (NSCLC) remain unclear. According to previous studies, we hypothesized ginsenoside C3C12PPD could inhibit the tumor growth of NSCLC by targeting proliferation, migration and angiogenesis.Methods: A thiazolyl blue tetrazolium bromide assay (MTT) was performed to evaluate cell viability. Additionally, Transwell and tube formation assays were conducted to analyze cell migration and angiogenesis. The Lewis and A549 tum

The objective of this study is to explore all the elements of bribery in public administration in third countries by focusing our research on Ghana public administration and the techniques used by the internal auditors to struggle them. Nevertheless the questionnaires worn in this research permitted to obtain data from workers of selected public administration in order to clarify the importance of the Law established Internal Audit Agency Act (IAA Act), 2003 (Act 658) to struggle bribery. So after fourteen (14) years, there was an empirical evidence to prove that IAA has a real effect on bribery. However, Internal Audit Agency Act (IAA Act) 2003 (Act 658) has played an important role to maintain financial discipline and clearness. The research has also employed Structural Equation Model (SEM) including conceptual model of bribery, endogenous and exogenous variables to analyze the relation between bribery and an adequate internal audit profession (AIAP) in Ghana through Directors and Managers of selected public administrations. The study examined cautiously the effect the effect of the establishment of Internal Audit Agency Act, 2003 (Act 658) in struggling bribery in public administration in Ghana and gave advices for further research. Keywords: Struggle, Bribery, Public Administration, Internal Auditing, Ghana, Structural Equation Modeling

Nonlinear optical processes, which govern the interaction of strong optical signals (e.g., laser beams or pulses) with the media in which these signals propagate, are of great importance for creation of coherent light sources at the frequency bands where the conventional lasers either perform poorly or are unavailable at all [1]. Moreover, the nonlinear processes are of interest because of their potential application in signal processing, mode-locking, pulse compression, etc. [2-4]. The efficiency of a nonlinear parametric process critically depends on relative phase locking of the interacting waves, which is formally expressed by the so-called phase matching condition requiring that phase velocities of all involved waves coincide. In typical optical media this condition cannot be naturally satisfied due to the refractive index dispersion.

Radiotherapy for cancer patients damages normal tissues, thereby inducing an inflammatory response and promoting cancer metastasis. We investigated whether nicaraven, a compound with radioprotective and anti-inflammatory properties, could attenuate radiation-induced cancer metastasis to the lungs of mice. Nicaraven and amifostine, another commercial radioprotective agent, had limited effects on both the radiosensitivity of Lewis lung carcinoma cells in vitro and radiation-induced tumor growth inhibition in vivo. Using experimental and spontaneous metastasis models, we confirmed that thorax irradiation with 5 Gy X-rays dramatically increased the number of tumors in the lungs. Interestingly, the number of tumors in the lungs was significantly reduced by administering nicaraven but not by administering amifostine daily after radiation exposure. Furthermore, nicaraven administration effectively inhibited CCL8 expression and macrophage recruitment in the lungs 1 day after thorax irradiation. Our data suggest that nicaraven attenuates radiation-induced lung metastasis, likely by regulating the inflammatory response after radiation exposure., Cancer Letters, 418, pp.204-210; 2018

ARKIVOC: vol. 2014, no. 4, (issn) 1551-7012, (dlps) 5550190.p008.429, This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 License. Please contact mpub-help@umich.edu to use this work in a way not covered by the license.

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Heparanase promotes tumorigenesis, angiogenesis, and metastasis. Here, we conducted a study based on systematic review and the Cancer Genome Atlas (TCGA) data that examined heparanase expression in clinical samples to determine its prognostic value. According to the meta-analysis and TCGA data, we found that heparanase expression was up-regulated in most breast cancer specimens, and elevated heparanase expression was associated with increased lymph node metastasis, larger tumor size, higher histological grade, and poor survival. These results suggest that targeting heparanase might improve treatments for breast cancer patients.

Speech recognition (SR) systems such as Siri or Google Now have become an increasingly popular human-computer interaction method, and have turned various systems into voice controllable systems(VCS). Prior work on attacking VCS shows that the hidden voice commands that are incomprehensible to people can control the systems. Hidden voice commands, though hidden, are nonetheless audible. In this work, we design a completely inaudible attack, DolphinAttack, that modulates voice commands on ultrasonic carriers (e.g., f > 20 kHz) to achieve inaudibility. By leveraging the nonlinearity of the microphone circuits, the modulated low frequency audio commands can be successfully demodulated, recovered, and more importantly interpreted by the speech recognition systems. We validate DolphinAttack on popular speech recognition systems, including Siri, Google Now, Samsung S Voice, Huawei HiVoice, Cortana and Alexa. By injecting a sequence of inaudible voice commands, we show a few proof-of-concept attacks, which include activating Siri to initiate a FaceTime call on iPhone, activating Google Now to switch the phone to the airplane mode, and even manipulating the navigation system in an Audi automobile. We propose hardware and software defense solutions. We validate that it is feasible to detect DolphinAttack by classifying the audios using supported vector machine (SVM), and suggest to re-design voice controllable systems to be resilient to inaudible voice command attacks., Comment: 15 pages, 17 figures

High-risk human papillomavirus (HPV) is the causative agent of cervical cancer. Integration of the HPV genome into the host genome is a key event in cervical carcinogenesis, with oxidative stress (OS) likely playing a major role in promoting DNA damage, and subsequently, integration. In our current study, we demonstrated a chain of events leading from the induction of OS, to DNA damage, and then to viral integration. Induction of OS by either virus-mediated factors, such as expression of E6*, a splice variant of the E6 oncogene, or by exogenous factors led to DNA damage in normal oral keratinocytes and in cervical keratinocytes containing episomal HPV16. We found that OS increased the integration rate for both foreign DNA and HPV, while antioxidants reduced the integration frequency. We also demonstrated a significant variability in ROS levels in patient-derived cervical specimens, which may reflect differences in susceptibility to cervical cancer between women.

Cardiosphere-derived cells (CDCs), one of the promising stem cell sources for myocardial repair, have been tested in clinical trials and resulted in beneficial effects; however, the relevant mechanisms are not fully understood. In this study, we examined the hypothesis that CDCs favor heart repair by switching the macrophages from a pro-inflammatory phenotype (M1) into a regulatory anti-inflammatory phenotype (M2). Macrophages from mice were cultured with CDCs-conditioned medium or with fibroblasts-conditioned medium as a control. Immunostaining showed that CDCs-conditioned medium significantly enhanced the expression of CD206 (a marker for M2 macrophages), but decreased the expression of CD86 (a marker for M1 macrophages) 3 days after culture. For animal studies, we used an acute myocardial infarction model of mice. We injected CDCs, fibroblasts, or saline only into the border zone of infarction. Then we collected the heart tissues for histological analysis 5 and 14 days after treatment. Compared with control animals, CDCs treatment significantly decreased M1 macrophages and neutrophils but increased M2 macrophages in the infarcted heart. Furthermore, CDCs-treated mice had reduced infarct size and fewer apoptotic cells compared to the controls. Our data suggest that CDCs facilitate heart repair by modulating M1/M2 macrophage polarization and neutrophil recruitment, which may provide a new insight into the mechanisms of stem cell-based myocardial repair., PLOS ONE, 11(10), e0165255; 2016

Sustav ventilacije u rudniku važna je sastavnica podzemnog sustava za vađenje rude. Poznato je da je projekt ventilacijskog sustava od velike važnosti u rudnicima s izvanredno velikim količinama plina te je model ventilacije primarni čimbenik u reguliranju plina kod potpuno mehaniziranih iskopa. Budući da je količina ispuštanja plina posebno velika u potpuno mehaniziranim iskopima s krajnje visokim količinama plina te da U model ventilacije ozbiljno ograničava normalnu proizvodnju, potreban je novi model ventilacije. U ovom je radu primijenjena metoda numeričke simulacije distribucije protoka plina u analizi učinka reguliranja plina u modelima U+L i Y+L. Rezultati pokazuju da je koncentracija plina u U+L modelu ventilacije niža nego u modelu Y+L kod potpuno mehaniziranog iskopa i njegovog gornjeg ugla. Nadalje, glavni čimbenici ventilacije koji utječu na odvod plina kod U+L modela ventilacije optimizirani su ortogonalnim testom i metodom fuzzy evaluacije; tako se učinkovito smanjila koncentracija plina u gornjem uglu i povratnom prolazu za ventilaciju. Nakon implementacije optimalnog rješenja modela ventilacije U+L u iskopu No. 32212(1) rudnika ugljena Rujigou u autonomnoj pokrajini Ningxia Hui u Kini, koncentracija plina u gornjem uglu smanjena je na 0,6 %, što može osigurati normalnu proizvodnju ugljenokopa., A mine ventilation system is an important component of an underground mining system. We all know that the ventilation system design plays an important role in highly gassy mines, and the ventilation pattern is the primary factor in gob gas control in fully mechanized working faces. Because the gas emission rate is notably large in highly gassy fully mechanized working faces and the U ventilation pattern seriously restricts normal production, a new ventilation pattern is required. This paper uses a gas flow distribution numerical simulation method to analyze the gas controlling effect of U+L and Y+L patterns. The results indicate that the gas concentration of the U+L ventilation pattern is lower than that of Y+L pattern in a fully mechanized working face and its upper corner. Furthermore, the main ventilation factors that affect the gas drainage of U+L ventilation pattern are optimized through the orthogonal test and fuzzy evaluation method; it effectively reduces the gas concentration of the upper corner and the return airway. After the implementation of the optimal solution of the U+L ventilation pattern in No. 32212(1) working face of Rujigou coal mine of Ningxia Hui Autonomous Region in China, the gas concentration of the upper corner was reduced to 0,6 %, which can ensure the normal production of the coal mine.

Editorial paper

In this thesis, folic acid-conjugated titanium dioxide-silica (Ti02-Si02) composite nanoparticles and iron oxide-zinc oxide (Fe30 4-Zn0) hybrid nanoparticles were successfully synthesised, and systematically investigated as potential nano-photosensitisers for effective and targeted photokilling of cancerous cells.

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Pharmacology and Physiology, 2011., Pathological cardiac remodeling involves adaptations such as cardiomyocyte hypertrophy and interstitial fibrosis in response to neurohumoral and biomechanical stress, and often precedes cardiac dysfunction and heart failure. Cyclic adenosine 3’,5’-monophosphate (cAMP) and cyclic guanosine 3’,5’-monophosphate (cGMP) are two critical second messengers regulating fundamental cellular processes in the cardiovascular system, from acute effects on muscle contraction/relaxation to chronic effects on gene expression and cell growth/survival. Phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and cGMP, thereby limiting intracellular diffusion of cyclic nucleotides to regulate the amplitude, duration, and compartmentation of cyclic nucleotide signaling. PDEs constitute a superfamily with >60 isoforms that differ in tissue distribution and biochemical properties, and have been selectively targeted by chemical inhibitors. At least six different PDE families have been described in the heart, including PDE1, 2, 3, 4, 5, and 8. The Ca2+/CaM-stimulated PDE1 family consists of three genes: PDE1A, PDE1B and PDE1C, which hydrolyze cAMP and cGMP in vitro, however their function in the heart remains unknown. We hypothesized that PDE1 isoforms may play a pivotal role in the cross-talk of Ca2+/CaM and cGMP signaling to modulate cardiac hypertrophy and remodeling. We first evaluated the regulation of PDE1 expression in animal models of chronic neurohumoral and biomechanical stress induced cardiac hypertrophy. Our initial studies indicated a significant upregulation of PDE1A protein in whole myocardium and cardiomyocytes in isoproterenol (ISO) and angiotensin II infusion and transverse aortic constriction models. We then measured the effects of selective PDE1 inhibition using IC86340. Interestingly, IC86340 treatment abrogated neurohumoral stress induced pathological cardiac hypertrophy both in vivo and in vitro. These effects were recapitulated by PDE1A knockdown in hypertrophic car

Z-source converter as a kind of power converter will be responsible for the energy transmission and load switching and other important functions, the paper focuses on the nonlinear characteristic analysis of Z-source DC/DC converter, in the continuous conduction mode (CCM), take the Z-source converter with peak current control as the research object, establish stroboscopic mapping model for analyzing its bifurcation and chaos characteristic based on system accurate modeling. According to numerical simulation and analysis, estimate parameter range in which Z-source occur bifurcation and chaos under different design. Considering the change of reference current, input voltage and load impedance, the experiment results prove that Z-source converter stroboscopic mapping model is correct for analyzing its nonlinear behavior, which provides a theoretical basis for optimal design and control.

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Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Pharmacology and Physiology, 2011., Cardiac remodeling including hypertrophy and apoptosis following myocardial infarction (MI) leads to congestive heart failure, which is a major cause of morbidity and mortality following MI. Many factors, for instance, reactive oxygen species (ROS), renin-angiotensin signaling (RAS) are reported as regulators in the cardiac remodeling process. Previous studies in our laboratory showed an elevated p90 ribosomal S6 Kinase (RSK) activity in animal and human failing hearts. However, the precise role of p90RSK has not been well studied yet. We proposed that RSK contributes to cardiac injury and pathological cardiac remodeling by regulating local RAS and Na+/H+ exchanger 1 (NHE1) activation. To study this, we used transgenic mice that over express p90RSK (WT-RSK-Tg) or dominant negative form of RSK (DN-RSK-Tg) specifically in cardiac myocytes. First, we demonstrated that RSK up-regulates prorenin and local RAS, which contributes to accelerate cardiac ischemia/reperfusion (I/R) injury. Renin inhibitor aliskiren significantly increases cardiac functional recovery in WT-RSK-Tg mice after I/R. Second, we found that up regulated angiotensin-converting enzyme (ACE) in WT-RSK-Tg hearts, as well as in normal mouse hearts with MI. In cultured cardiomyocyte, Angiotensin II (Ang II) stimulated ACE up regulation is enhanced by over expressing WT-RSK, and blunted by DN-RSK and RSK inhibitor. In addition, MI induced cardiac remodeling and dysfunction is significantly reduced in DN-RSK-Tg. Third, we proved that inhibiting RSK activity by DN-RSK-Tg or RSK inhibitor provides similar cardiac protection in mice with I/R. This is possibly mediated by inhibiting I/R induced NHE1 activation. In conclusion, we found that RSK plays a crucial role in both acute and chronic MI, which may provide new therapeutic approaches for treating cardiac diseases.

Yan Chen, Lei Zhou, Ling Yuan, Zhen-hai Zhang, Xuan Liu, Qingqing WuKey Laboratory of New Drug Delivery System of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, Nanjing, Jiangsu, ChinaBackground: Nanostructured lipid carriers (NLCs) are attractive materials for topical drug delivery, and in a previous study, we demonstrated that NLCs loaded with tripterine enhance its deposition. However, the surface charge of nanoparticles influences percutaneous drug penetration. Therefore, we aimed to evaluate the influence of the surface charge of NLCs on in vitro skin permeation and in vivo pharmacodynamics of tripterine and optimize tripterine-loaded NLCs for the treatment of skin diseases.Methods: Different solid and liquid matrices were selected to prepare cationic, anionic, and neutral NLCs by the solvent evaporation method. The in vitro studies were evaluated by using Franz diffusion cells. The effect of surface-charged NLCs on cellular uptake was appraised across HaCaT and B16BL6 cells. The in vitro and in vivo anticancer activity of surface-charged NLCs was evaluated in B16BL6 cells and melanoma-bearing mice, respectively.Results: The average particle sizes of the cationic, anionic, and neutral NLCs were 90.2 ± 9.7, 87.8 ± 7.4, and 84.5 ± 10.2 nm, respectively; their encapsulation efficiencies were 64.3% ± 5.1%, 67.8% ± 4.4%, and 72.5% ± 4.9%, respectively. In vitro studies showed delayed tripterine release, and the order of skin permeation was cationic NLCs > anionic NLCs > neutral NLCs. Further, in vitro cytotoxicity studies showed that the cationic NLCs had the highest (P < 0.05) inhibition ratio in B16BL6 (melanoma) cells. Moreover, in vivo pharmacodynamic experiments in melanoma-bearing mice indicated that the cationic NLCs had significantly higher (P < 0.05) antimelanoma efficacy than the anionic and neutral NLCs.Conclusion: The surface charge of N

Resveratrol is a natural occurring polyphenol with diverse biological activities in vitro and poor pharmacokinetic profile because of its rapid metabolism in vivo. In this project, polymer conjugate approach was evaluated for masking resveratrol against the metabolism. Various polymer conjugates were prepared and evaluated both in vitro and in vivo. Among those tested, resveratrol-PLA-PEG and resveratrol-PEG ether conjugates were found capable of providing better pharmacokinetics than native resveratrol.