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Background: As precision medicine advances, polygenic scores (PGS) have become increasingly important for clinical risk assessment. Many methods have been developed to create polygenic models with increased accuracy for risk prediction. Our select and shrink with summary statistics (S4) PGS method has previously been shown to accurately predict the polygenic risk of epithelial ovarian cancer. Here, we applied S4 PGS to 12 phenotypes for UK Biobank participants, and compared it with the LDpred2 and a combined S4 + LDpred2 method., Results: The S4 + LDpred2 method provided overall improved PGS accuracy across a variety of phenotypes for UK Biobank participants. Additionally, the S4 + LDpred2 method had the best estimated PGS accuracy in Finnish and Japanese populations. We also addressed the challenge of limited genotype level data by developing the PGS models using only GWAS summary statistics., Conclusions: Taken together, the S4 + LDpred2 method represents an improvement in overall PGS accuracy across multiple phenotypes and populations., (© 2024. The Author(s).)

Common genetic variation throughout the genome together with rare coding variants identified to date explain about a half of the inherited genetic component of epithelial ovarian cancer risk. It is likely that rare variation in the non-coding genome will explain some of the unexplained heritability, but identifying such variants is challenging. The primary problem is lack of statistical power to identifying individual risk variants by association as power is a function of sample size, effect size and allele frequency. Power can be increased by using burden tests which test for association of carriers of any variant in a specified genomic region. This has the effect of increasing the putative effect allele frequency. PAX8 is a transcription factor that plays a critical role in tumour progression, migration and invasion. Furthermore, regulatory elements proximal to target genes of PAX8 are enriched for common ovarian cancer risk variants. We hypothesised that rare variation in PAX8 binding sites are also associated with ovarian cancer risk, but unlikely to be associated with risk of breast, colorectal or endometrial cancer. We have used publicly available, whole-genome sequencing data from the UK 100,000 Genomes Project to evaluate the burden of rare variation in PAX8 binding sites across the genome. Data were available for 522 ovarian cancers, 2,984 breast cancers, 2,696 colorectal cancers, 836 endometrial cancers and 2253 non-cancer controls. Active binding sites were defined using data from multiple PAX8 and H3K27 ChIPseq experiments. We found no association between the burden of rare variation in PAX8 binding sites (defined in several ways) and risk of ovarian, breast or endometrial cancer. An apparent association with colorectal cancer was likely to be a technical artefact as a similar association was also detected for rare variation in random regions of the genome. Despite the null result this study provides a proof-of -principle for using burden testing to identify rare, non-coding germline genetic variation associated with disease. Larger sample sizes available from large-scale sequencing projects together with improved understanding of the function of the non-coding genome will increase the potential of similar studies in the future., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Deploying distributed fiber-optic sensor (DFOS) technology to gather environmental parameters over expansive areas is an essential monitoring strategy in the context of comprehensive searches for anomalous places. This study utilizes a single temperature measurement channel within a commercial Raman-based distributed temperature sensing (RDTS) interrogator and divides it into two separate, uncorrelated paths to enable spatial duplex temperature measurements. The distinction between temperature events corresponding to each path in the dual separate path (DSP) in RDTS can be achieved when temperature events are concurrently occurring in the DSP. Additionally, the RDTS-DSP solution may integrate free space optics (FSO) into its fiber path, which serves to enhance the user-friendliness, scalability, and cost-effectiveness of DFOS technology. An RDTS measurement channel can effectively function as a DSP, thus doubling the RDTS measurement pathway, and can be combined with FSO to significantly improve RDTS performance.

This paper proposes a novel approach to enhance the multichannel fiber optic sensing systems by integrating an Inverse Fast Fourier Transform-based Deep Neural Network (IFFT-DNN) to accurately predict sensor responses despite signals overlapping and crosstalk between sensors. The IFFT-DNN leverages both frequency and time domain information, enabling a comprehensive feature extraction which enhances the prediction accuracy and reliability performance. To investigate the IFFT-DNN's performance, we propose a multichannel water level sensing system based on Free Space Optics (FSO) to measure the water level at multiple points in remote areas. The experimental results demonstrate the system's high precision, with a Mean Absolute Error (MAE) of 0.07 cm, even in complex conditions. Hence, this system provides a cost-effective and reliable remote water level sensing solution, highlighting its practical applicability in various industrial settings.

This study aimed to define the role of heterogeneity of liver parenchymal enhancement on computed tomography (CT) in the survival of patients with hepatocellular carcinoma (HCC) after hepatic resection. The medical records of patients with HCCs and who had undergone hepatic resection were retrospectively reviewed. The standard deviation (SD) of three different enhanced CT scan images was used to estimate the heterogeneity of liver parenchymal enhancement: SD of > 5.6, heterogenous enhancement, and SD of ≤ 5.6, homogeneous enhancement. A total of 57 patients had heterogenous enhancement, and 143 patients had homogeneous enhancement. The patients with heterogenous enhancement had longer disease-free and overall survivals than those with other enhancements (log-rank test, P < 0.001 and P = 0.036). The pathologic exam showed that heterogenous enhancement tended to develop septa in the peritumoral liver tissues. The prevalence of CD8 + cells was significantly higher in the peritumor liver tissues with septa than in those without (0.83% vs. 0.26%, P < 0.001). The peritumoral CD8/Foxp3 ratio was higher in the liver tissues with septa than in those without (1.22 vs. 0.47, P = 0.001), and patients with CD8/Foxp3 of > 0.8 had better overall survival than those with CD8/Foxp3 of ≤ 0.8 (log-rank test, P = 0.028). In conclusion, patients who had undergone hepatic resection with a heterogenous liver parenchymal enhancement tended to develop hepatic septa, which was associated with a higher CD8/Foxp3 ratio and longer survival. Therefore, contrast-enhanced CT scans might be a useful tool to predict the outcome of HCC., Competing Interests: None., (AJCR Copyright © 2024.)

To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5 × 10 -8 ) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (p value <10 -5 ). Fine mapping identified 4,008 CCVs in these regions, of which 1,452 CCVs were located in ovarian cancer-related chromatin marks with significant enrichment in active enhancers, active promoters, and active regions for CCVs from each EOC histotype. Transcriptome-wide association and colocalization analyses across histotypes using tissue-specific and cross-tissue datasets identified 86 candidate susceptibility genes in known EOC risk regions and 32 genes in 23 additional genomic regions that may represent novel EOC risk loci (false discovery rate <0.05). Finally, by integrating genome-wide HiChIP interactome analysis with transcriptome-wide association study (TWAS), variant effect predictor, transcription factor ChIP-seq, and motifbreakR data, we identified candidate gene-CCV interactions at each locus. This included risk loci where TWAS identified one or more candidate susceptibility genes (e.g., HOXD-AS2, HOXD8, and HOXD3 at 2q31) and other loci where no candidate gene was identified (e.g., MYC and PVT1 at 8q24) by TWAS. In summary, this study describes a functional framework and provides a greater understanding of the biological significance of risk alleles and candidate gene targets at EOC susceptibility loci identified by a genome-wide association study., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

We successfully demonstrated an intelligent adaptive beam alignment scheme using a reinforcement learning (RL) algorithm integrated with an 8 × 8 photonic array antenna operating in the 40 GHz millimeter wave (MMW) band. In our proposed scheme, the three key elements of RL: state, action, and reward, are represented as the phase values in the photonic array antenna, phase changes with specified steps, and an obtained error vector magnitude (EVM) value, respectively. Furthermore, thanks to the Q-table, the RL agent can effectively choose the most suitable action based on its prior experiences. As a result, the proposed scheme autonomously achieves the best EVM performance by determining the optimal phase. In this Letter, we verify the capability of the proposed scheme in single- and multiple-user scenarios and experimentally demonstrate the performance of beam alignment to the user's location optimized by the RL algorithm. The achieved results always meet the signal quality requirement specified by the 3rd Generation Partnership Project (3GPP) criterion for 64-QAM orthogonal frequency division multiplexing (OFDM).

While the structure and composition of the scientific manuscript is well known within scientific communities, insider knowledge such as the tricks of the trade and editorial viewpoints of scientific publishing are often less known to early-career research scientists. This article focuses on the key aspects of scientific publishing, including tips for success geared towards senior postdocs and junior faculty. It also highlights important considerations for getting manuscripts published in an efficient and successful manner., (© 2024. The Author(s).)

Social interaction enables the smooth progression of our daily lives. Mounting evidence from recent hyperscanning neuroimaging studies indicates that key components of social behavior can be evaluated using inter-brain oscillations and connectivity. However, mapping out inter-brain networks and developing neurocognitive theories that explain how humans co-create and share information during social interaction remains challenging. In this study, we developed a jigsaw puzzle-solving game with hyperscanning electroencephalography (EEG) signals recorded to investigate inter-brain activities during social interactions involving cooperation and competition. Participants were recruited and paired into dyads to participate in the multiplayer jigsaw puzzle game with 32-channel EEG signals recorded. The corresponding event-related potentials (ERPs), brain oscillations, and inter-brain functional connectivity were analyzed. The results showed different ERP morphologies of P3 patterns in competitive and cooperative contexts, and brain oscillations in the low-frequency band may be an indicator of social cognitive activities. Furthermore, increased inter-brain functional connectivity in the delta, theta, alpha, and beta frequency bands was observed in the competition mode compared to the cooperation mode. By presenting comparable and valid hyperscanning EEG results alongside those of previous studies using traditional paradigms, this study demonstrates the potential of utilizing hyperscanning techniques in real-life game-playing scenarios to quantitatively assess social cognitive interactions involving cooperation and competition. Our approach offers a promising platform with potential applications in the flexible assessment of psychiatric disorders related to social functioning.

This Letter demonstrates the successful use of free-space optics (FSO) as a transition channel for an air segment in transmitting Raman backscattering signals for distributed temperature sensing (DTS). A barrier-free air segment link shaped by an FSO is part of the Raman-based DTS (RDTS) fiber optic transmission route. For this plan, the FSO enables delivery of the RDTS's pulse with the low-loss transmission over the air segment while also returning to the RDTS the varied Raman backscattered signals from the probing temperature variations for signal interpretation. The difference between various temperatures sensed and the referential air temperature remains nearly the same before and after passing the FSO. The viability of this technology provides a crucial basis for tackling the high expense of installing and repairing DTS cables and the challenges associated with doing so owing to topographical restrictions.

This paper introduces a new bidirectional integration approach that combines fiber sensor/free space optics (FSO) communication using an intensity and wavelength division multiplexer (IWDM) techniques-based long-distance fiber Bragg grating (FBG) sensor strain-sensing system. By implementing coarse wavelength division multiplexing (CWDM), the system achieves the simultaneous transmission of optical communication and fiber optical sensor (FOS) sensing signals, resulting in a highly capable, flexible, and cost-effective solution. The proposed FSO transmission technique addresses complex fiber cable installation concerns with topographical limitations. This bidirectional structure ensures the reliability and stability of the long-distance FBG sensor system, supported by extensive research and experimentation. A hybrid stacked gated recurrent units and long short-term memory (SGRU-LSTM) model is proposed to enhance strain measurement accuracy by predicting and measuring the central wavelength of overlapped strain-sensing FBG sensor signals. The results demonstrate the superiority of the proposed model in peak wavelength detection accuracy. The primary benefit of integrating communication and sensing is the significant reduction in construction costs by eliminating the requirement for two individual fiber optic systems, as the integration allows for a single system to fulfill both functions, resulting in more efficient and cost-effective implementation. Overall, this paper contributes to advancing long-distance FBG sensor systems by integrating fiber sensor/FSO communication and deep learning techniques, improving transmission distance, multiplexing capacity, measurement accuracy, system survivability, and cost-effectiveness.

The development of the Internet has changed people's lives and has resulted in a new type of addictive behavior. In the past decade, Internet game addiction has been identified as a mental illness. Considering internet game addiction as the only cause of mental illness is limited in its view, as internet games, social platforms and other internet multimedia are also widely used. Thus, other internet-related behaviors, that maybe addictive, should also be included. Previous neuroimaging studies have reported a role of alteration in brain's inhibitory control mechanism in addiction. However, the results are still diverse with inconsistent findings. In this study, we used an Internet-related stop signal task with EEG signals recorded to study the relationship between internet addiction through brain oscillations and functional connectivity. We also compared the differences in the brain connectivity between addicted and non-addicted participants using phase lag index. We found that the brain connectivity in participants addicted to the internet is significantly greater than that of nonaddicted users.Clinical Relevance- In this study, we assessed brain functional networks of participants with Internet Gaming Disorder and internet addiction.

In this paper, a novel liquid level sensing system is proposed to enhance the capacity of the sensing system, as well as reduce the cost and increase the sensing accuracy. The proposed sensing system can monitor the liquid level of several points at the same time in the sensing unit. Additionally, for cost efficiency, the proposed system employs only one sensor at each spot and all the sensors are multiplexed. In multiplexed systems, when changing the liquid level inside the container, the float position is changed and leads to an overlap or cross-talk between two sensors. To solve this overlap problem and to accurately predict the liquid level of each container, we proposed a deep neural network (DNN) approach to properly identify the water level. The performance of the proposed DNN model is evaluated via two different scenarios and the result proves that the proposed DNN model can accurately predict the liquid level of each point. Furthermore, when comparing the DNN model with the conventional machine learning schemes, including random forest (RF) and support vector machines (SVM), the DNN model exhibits the best performance.

Background: Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort., Methods: Single nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer-related cell types., Results: We identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types., Conclusions: CNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention., (© The Author(s) 2022. Published by Oxford University Press.)

Background: Little is known about the role of global DNA methylation in recurrence and chemoresistance of high grade serous ovarian cancer (HGSOC)., Methods: We performed whole genome bisulfite sequencing and transcriptome sequencing in 62 primary and recurrent tumors from 28 patients with stage III/IV HGSOC, of which 11 patients carried germline, pathogenic BRCA1 and/or BRCA2 mutations., Results: Landscapes of genome-wide methylation (on average 24.2 million CpGs per tumor) and transcriptomes in primary and recurrent tumors showed extensive heterogeneity between patients but were highly preserved in tumors from the same patient. We identified significant differences in the burden of differentially methylated regions (DMRs) in tumors from BRCA1/2 compared to non-BRCA1/2 carriers (mean 659 DMRs and 388 DMRs in paired comparisons respectively). We identified overexpression of immune pathways in BRCA1/2 carriers compared to non-carriers, implicating an increased immune response in improved survival (P = 0.006) in these BRCA1/2 carriers., Conclusion: These findings indicate methylome and gene expression programs established in the primary tumor are conserved throughout disease progression, even after extensive chemotherapy treatment, and that changes in methylation and gene expression are unlikely to serve as drivers for chemoresistance in HGSOC., (© 2022. The Author(s).)

Doxorubicin (Dox) is a widely known chemotherapeutic drug that has been encapsulated into liposomes for clinical use, such as Doxil ® and Myocet ® . Both of these are prepared via remote loading methods, which require multistep procedures. Additionally, their antitumor efficacy is hindered due to the poor drug release from PEGylated liposomes in the tumor microenvironment. In this study, we aimed to develop doxorubicin-loaded lipid-based nanocarriers (LNC-Dox) based on electrostatic interaction using microfluidic technology. The resulting LNC-Dox showed high loading capacity, with a drug-to-lipid ratio (D/L ratio) greater than 0.2, and high efficacy of drug release in an acidic environment. Different lipid compositions were selected based on critical packing parameters and further studied to outline their effects on the physicochemical characteristics of LNC-Dox. Design of experiments was implemented for formulation optimization. The optimized LNC-Dox showed preferred release in acidic environments and better therapeutic efficacy compared to PEGylated liposomal Dox in vivo. Thus, this study provides a feasible approach to efficiently encapsulate doxorubicin into lipid-based nanocarriers fabricated by microfluidic rapid mixing.

Reinforcement learning (RL) is applied to improve the performance of the polarization modulator (PolM)-based W-band radio-over-fiber (RoF) system in this Letter. By controlling the polarization angle of the dual-wavelength laser source in the PolM-based scheme, the RF response can be easily modified and therefore it hugely increases the available bandwidth in the RoF system. In the proposed RL scheme, the state is described as the value of the angle from the polarization controller (PC). We use changing the angle of the polarizer (P) as the actions of the RL agent to optimize the frequency response. The agent also receives a reward from the system and learns from the environment and previous experience. Moreover, the reward is the value of error vector magnitude at each state. Therefore, the proposed scheme of RL is implemented and demonstrated in a multi-channel RoF system, and the results show that an RL agent provides an effective intelligent technique to obtain the best quality of data transmission.

The focus of this paper was designing and demonstrating bus structure FBG sensor networks using intensity wavelength division multiplexing (IWDM) techniques and a gated recurrent unit (GRU) algorithm to increase the capability of multiplexing and the ability to detect Bragg wavelengths with greater accuracy. Several Fiber Bragg grating (FBG) sensors are coupled with power ratios of 90:10 and 80:10, respectively in the suggested experimental setup. We used the latest IWDM multiplexing technique for the proposed scheme, as the IWDM system increases the number of sensors and allows us to alleviate the limited operational region drawback of conventional wavelength division multiplexing (WDM). However, IWDM has a crosstalk problem that causes high-sensor signal measurement errors. Thus, we proposed the GRU model to overcome this crosstalk or overlapping problem by converting the spectral detection problem into a regression problem and considered the sequence of spectral features as input. By feeding this sequential spectrum dataset into the GRU model, we trained the GRU system until we achieved optimal efficiency. Consequently, the well-trained GRU model quickly and accurately identifies the Bragg wavelength of each FBG from the overlapping spectra. The Bragg wavelength detection performance of our proposed GRU model is tested or validated using different numbers of FBG sensors, such as 3-FBG, 5-FBG, 7-FBG, and 10-FBG, separately. As a result, the experiment result proves that the well-trained GRU model accurately identifies each FBG Bragg wavelength, and even the number of FBG sensors increase, as well as the spectra of FBGs, which are partially or fully overlapped. Therefore, to boost the detection efficiency, reliability, and to increase the multiplexing capabilities of FBG sensor networks, the proposed sensor system is better than the other previously proposed methods.

Quantifying the functional effects of complex disease risk variants can provide insights into mechanisms underlying disease biology. Genome-wide association studies have identified 39 regions associated with risk of epithelial ovarian cancer (EOC). The vast majority of these variants lie in the non-coding genome, where they likely function through interaction with gene regulatory elements. In this study we first estimated the heritability explained by known common low penetrance risk alleles for EOC. The narrow sense heritability (h g 2 ) of EOC overall and high-grade serous ovarian cancer (HGSOCs) were estimated to be 5%-6%. Partitioned SNP heritability across broad functional categories indicated a significant contribution of regulatory elements to EOC heritability. We collated epigenomic profiling data for 77 cell and tissue types from Roadmap Epigenomics and ENCODE, and from H3K27Ac ChIP-seq data generated in 26 ovarian cancer and precursor-related cell and tissue types. We identified significant enrichment of risk single-nucleotide polymorphisms (SNPs) in active regulatory elements marked by H3K27Ac in HGSOCs. To further investigate how risk SNPs in active regulatory elements influence predisposition to ovarian cancer, we used motifbreakR to predict the disruption of transcription factor binding sites. We identified 469 candidate causal risk variants in H3K27Ac peaks that are predicted to significantly break transcription factor (TF) motifs. The most frequently broken motif was REST (p value = 0.0028), which has been reported as both a tumor suppressor and an oncogene. Overall, these systematic functional annotations with epigenomic data improve interpretation of EOC risk variants and shed light on likely cells of origin., (Copyright © 2020. Published by Elsevier Inc.)

Neurofibromatosis type 1 (NF1) is an inherited neurological disorder. Approximately 5-13% of NF1 patients may develop a malignant peripheral nerve sheath tumor (MPNST), which is a neurofibrosarcoma transformed from the plexiform neurofibroma or schwannoma. Given the large size and easy metastasis of MPNST, it remains difficult to be cured by either surgical or conventional chemotherapy. In this study, we investigated the possibility of combining photodynamic therapy (PDT) and chemotherapy to treat MPNST by using a dual-effect liposome (named as PL-cDDP-Ce6), in which a chemotherapeutic agent, cisplatin (cDDP), and photosensitizer, chlorine e6 (Ce6) were encapsulated in the same carrier. The cytotoxic effect of PL-cDDP-Ce6 against MPNST cells was significantly higher than cells treated with liposomal cDDP or Ce6 alone or in combination after light irradiation. Treatment with the dual-effect liposomes in mice bearing xenograft MPNST tumor reveals a significant increase in survival rate compared to those treated with liposomal cDDP and Ce6 in combination. Moreover, there is no weight loss or derangements of serum biochemistry. In conclusion, this study demonstrates the clinical potential and advantage of using this liposomal drug for the treatment of MPNST., Competing Interests: The authors declare no conflict of interest in preparing the manuscript. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

In this paper, for an intensity wavelength division multiplexing (IWDM)-based multipoint fiber Bragg grating (FBG) sensor network, an effective strain sensing signal measurement method, called a long short-term memory (LSTM) machine learning algorithm, integrated with data de-noising techniques is proposed. These are considered extremely accurate for the prediction of very complex problems. Four ports of an optical coupler with distinct output power ratios of 70%, 60%, 40%, and 30% have been used in the proposed distributed IWDM-based FBG sensor network to connect a number of FBG sensors for strain sensing. In an IWDM-based FBG sensor network, distinct power ratios of coupler ports can contain distinct powers or intensities. However, unstable output power in the sensor system due to random noise, harsh environments, aging of the equipment, or other environmental factors can introduce fluctuations and noise to the spectra of the FBGs, which makes it hard to distinguish the sensing signals of FBGs from the noise signals. As a result, noise reduction and signal processing methods play a significant role in enhancing the capability of strain sensing. Thus, to reduce the noise, to improve the signal-to-noise ratio, and to accurately measure the sensing signal of FBGs, we proposed a long short-term memory (LSTM) deep learning algorithm integrated with discrete waveform transform (DWT) data smoother (de-noising) techniques. The DWT data de-noising methods are important techniques for analyzing and de-noising the sensor signals, and it further improves the strain sensing signal measurement accuracy of the LSTM model. Thus, after de-noising the sensor data, these data are fed into the LSTM model to measure the sensing signal of each FBG. The experimental results prove that the integration of LSTM with the DWT data de-noising technique achieved better sensing signal measurement accuracy, even in noisy data or environments. Therefore, the proposed IWDM-based FBG sensor network can accurately sense the signal of strain, even in bad or noisy environments; can increase the number of FBG sensors multiplexed in the sensor system; and can enhance the capacity of the sensor system.

Long-circulating PEG-modified liposome has been shown to improve pharmacokinetic properties and reduce systemic toxicity in cancer treatment. However, drug bioavailability from liposome remains a major challenge to the improvement of its therapeutic efficacy. Previously, we designed a PEGylated dual-effect liposome (named as PL-Dox-Ce6) with chlorin e6 incorporated in the lipid bilayer and Doxorubicin encapsulated in the interior. In this study, another dual-effect liposome with cisplatin encapsulated in the interior was further developed. The pharmacokinetics of these two dual-effect liposomes were studied in tumor-bearing mice. Based on the kinetic data of tumor and plasma, light irradiation was applied onto the tumors at different time points after drug administration to compare the therapeutic efficacy. We demonstrated that a single dose of the dual-effect liposomes combined with two doses of light irradiation can completely eradicate over 90% of the tumor in mice alone with significant survival rate and no toxicity. Thus, this study established a platform that utilizes the dual-effect liposome which combines photodynamic therapy and chemotherapy to improve the therapeutic outcomes of tumors.

Transcription factor (TF) binding is determined by sequence as well as chromatin accessibility. Although the role of accessibility in shaping TF-binding landscapes is well recorded, its role in evolutionary divergence of TF binding, which in turn can alter cis-regulatory activities, is not well understood. In this work, we studied the evolution of genome-wide binding landscapes of five major TFs in the core network of mesoderm specification, between Drosophila melanogaster and Drosophila virilis, and examined its relationship to accessibility and sequence-level changes. We generated chromatin accessibility data from three important stages of embryogenesis in both Drosophila melanogaster and Drosophila virilis and recorded conservation and divergence patterns. We then used multivariable models to correlate accessibility and sequence changes to TF-binding divergence. We found that accessibility changes can in some cases, for example, for the master regulator Twist and for earlier developmental stages, more accurately predict binding change than is possible using TF-binding motif changes between orthologous enhancers. Accessibility changes also explain a significant portion of the codivergence of TF pairs. We noted that accessibility and motif changes offer complementary views of the evolution of TF binding and developed a combined model that captures the evolutionary data much more accurately than either view alone. Finally, we trained machine learning models to predict enhancer activity from TF binding and used these functional models to argue that motif and accessibility-based predictors of TF-binding change can substitute for experimentally measured binding change, for the purpose of predicting evolutionary changes in enhancer activity., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Sequence variation within enhancers plays a major role in both evolution and disease, yet its functional impact on transcription factor (TF) occupancy and enhancer activity remains poorly understood. Here, we assayed the binding of five essential TFs over multiple stages of embryogenesis in two distant Drosophila species (with 1.4 substitutions per neutral site), identifying thousands of orthologous enhancers with conserved or diverged combinatorial occupancy. We used these binding signatures to dissect two properties of developmental enhancers: (1) potential TF cooperativity, using signatures of co-associations and co-divergence in TF occupancy. This revealed conserved combinatorial binding despite sequence divergence, suggesting protein-protein interactions sustain conserved collective occupancy. (2) Enhancer in-vivo activity, revealing orthologous enhancers with conserved activity despite divergence in TF occupancy. Taken together, we identify enhancers with diverged motifs yet conserved occupancy and others with diverged occupancy yet conserved activity, emphasising the need to functionally measure the effect of divergence on enhancer activity.

Chitosan hydrogels containing hydroxypropyl methylcellulose (HPMC) and toluidine blue O were prepared and assessed for their mucoadhesive property and antimicrobial efficacy of photodynamic inactivation (PDI). Increased HPMC content in the hydrogels resulted in increased mucoadhesiveness. Furthermore, we developed a simple In Vitro 3D gingival model resembling the oral periodontal pocket to culture the biofilms of Staphylococcus aureus ( S. aureus ), Aggregatibacter actinomycetemcomitans ( A. actinomycetemcomitans ), and Porphyromonas gingivalis ( P. gingivalis ). The PDI efficacy of chitosan hydrogel was examined against periodontal biofilms cultured in this 3D gingival model. We found that the PDI effectiveness was limited due to leaving some of the innermost bacteria alive at the non-illuminated site. Using this 3D gingival model, we further optimized PDI procedures with various adjustments of light energy and irradiation sites. The PDI efficacy of the chitosan hydrogel against periodontal biofilms can significantly improve via four sides of irradiation. In conclusion, this study not only showed the clinical applicability of this chitosan hydrogel but also the importance of the light irradiation pattern in performing PDI for periodontal disease., Competing Interests: The authors declare no conflict of interest.

Prediction of gene expression levels driven by regulatory sequences is pivotal in genomic biology. A major focus in transcriptional regulation is sequence-to-expression modeling, which interprets the enhancer sequence based on transcription factor concentrations and DNA binding specificities and predicts precise gene expression levels in varying cellular contexts. Such models largely rely on the position weight matrix (PWM) model for DNA binding, and the effect of alternative models based on DNA shape remains unexplored. Here, we propose a statistical thermodynamics model of gene expression using DNA shape features of binding sites. We used rigorous methods to evaluate the fits of expression readouts of 37 enhancers regulating spatial gene expression patterns in Drosophila embryo, and show that DNA shape-based models perform arguably better than PWM-based models. We also observed DNA shape captures information complimentary to the PWM, in a way that is useful for expression modeling. Furthermore, we tested if combining shape and PWM-based features provides better predictions than using either binding model alone. Our work demonstrates that the increasingly popular DNA-binding models based on local DNA shape can be useful in sequence-to-expression modeling. It also provides a framework for future studies to predict gene expression better than with PWM models alone., (© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The excretion rates and ecological risk to the environment of three commonly used veterinary antibiotics (VAs), amoxicillin, ciprofloxacin, and doxycycline, in layer hen manure during the application and withdrawal periods were investigated in a study consisting of a control group fed with VA-free basal diet and nine treatment groups consisted of three levels (200 mg/kg, 100 mg/kg, and 50 mg/kg) of amoxicillin (AMX), ciprofloxacin (CIP), or doxycycline (DOC). Each treatment group was replicated seven times with three layer hens per replication. Results of the study showed that the average excretion rates of AMX in the 200, 100, and 50 mg/kg groups were 67.88, 55.82, and 66.15%, respectively, while those for CIP and DOC were 47.84, 51.85, and 44.87% and 82.67, 94.39, and 95.72%, respectively. The concentrations of the above veterinary drugs in manure decreased sharply in the withdrawal period (7, 28, and 10 d, respectively), for AMX, DOC, and CIP. Neither AMX nor DOC was detected in the manure after the withdrawal period. In contrast to AMX and DOC, the excretion rate of CIP was significantly lower and thus had a longer residence time. Ecological risk study, estimated using hazard quotient values, showed that AMX in the 100 and 50 mg/kg groups posed no risk to the environment after d 1 of withdrawal, while CIP in the 50 mg/kg group posed no risk to the environment from d 5 of withdrawal. CIP in the 200 and 100 mg/kg groups required 10 d withdrawal in order to pose no risk to the environment. In contrast, DOC residue during withdrawal in the manure posed no risk to the environment, thus making it more environmentally safe., (© 2016 Poultry Science Association Inc.)

This systematic review and meta-analysis evaluated anti-programmed cell death (PD)-1 immunotherapy (nivolumab or pembrolizumab) for overall efficacy, safety, and effective dose relative to standard chemotherapy or other conventional drugs in the treatment of malignant tumors. We searched the following databases, PubMed, Medline, Embase, Cochrane, Wangfang Data, Weipu, and China National Knowledge Infrastructure, and the reference lists of the selected articles for randomized controlled trials (RCTs) of anti-PD-1 therapies in humans. The outcome measures were overall survival, treatment response, and adverse events. Only four randomized controlled trials met our inclusion criteria. Three of these evaluated responses to nivolumab, whereas one tested pembrolizumab. The result of our analysis suggested that nivolumab may improve the overall response rate in treating melanoma relative to chemotherapy and has few associated adverse events. Similarly, in metastatic melanoma patients, nivolumab had a significant advantage over dacarbazine in terms of 1-year survival, progression-free survival, and objective response rate. Regarding dose levels of nivolumab for patients with metastatic renal cell carcinoma, the outcomes in response to 2 and 10 mg/kg were similar, but both had significant advantages over 0.3 mg/kg. In addition, pembrolizumab showed similar outcomes in response to 2- and 10-mg/kg treatment. Anti-PD-1 immunotherapy appears to be safe and effective for patients with melanoma or metastatic renal cell carcinoma. Our meta-analysis is limited, but additional clinical trials are warranted to verify this preliminary evidence of positive outcomes and before anti-PD-1 therapy can be recommended for routine clinical use., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

A hybrid lightwave transmission system for cable television (CATV)/millimeter-wave (MMW)/baseband (BB) signal transmission based on fiber-wired/fiber-wireless/fiber-visible laser light communication (VLLC) integrations is proposed and demonstrated. For down-link transmission, the light is intensity-modulated with 50-550 MHz CATV signal and optically promoted from 25 GHz radio frequency (RF) signal to 10 Gbps/50 GHz and 20 Gbps/100 GHz MMW data signals based on fiber-wired and fiber-wireless integrations. Good performances of carrier-to-noise ratio (CNR), composite second-order (CSO), composite triple-beat (CTB), and bit error rate (BER) are obtained over a 40-km single-mode fiber (SMF) and a 10-m RF wireless transport. For up-link transmission, the light is successfully intensity-remodulated with 5-Gbps BB data stream based on fiber-VLLC integration. Good BER performance is achieved over a 40-km SMF and a 10-m free-space VLLC transport. Such a hybrid CATV/MMW/BB lightwave transmission system is an attractive alternative, it gives the benefits of a communication link for broader bandwidth and higher transmission rate.

Oxidative stress mediated by photodynamic therapy (PDT) mediates the tumoricidal effect, but has also been shown to induce the expression of prosurvival molecules, such as cyclooxygenase-2 (COX-2), which is involved in tumor recurrences after PDT. However, the molecular mechanism is still not fully understood. In this study, we found that activated p38MAPK could significantly up-regulate the activity and expression of histone acetyltransferase p300 (p300HAT) in A375 and C26 cells treated with ALA-and chlorin e6 (Ce6)-mediated photodynamic treatment. A colony-formation assay showed that PDT-induced cytotoxicity was dramatically elevated in the presence of the p300HAT inhibitor anacardic acid (AA). Further studies showed that increased p300HAT acetylates histone H3 and NF-κB p65 subunit to up-regulate the COX-2 expression, which was reduced by AA or p300HAT shRNA. Using chromatin immunoprecipitation analysis, we found that the augmented acetylation of histone H3 and NF-κB increases their binding to the COX-2 promoter region. These in vitro findings were further verified in mice bearing murine C26 and human A375 tumors treated with liposomal Ce6 mediated PDT. Meanwhile, the combination of PDT and AA resulted in greater tumor regression in BALB/c mice bearing C26 tumors, compared with PDT only or combined with COX-2 inhibitor. Finally, we demonstrated that suppression of the PDT-induced p300HAT activity also resulted in the decreased expression of survivin, restoring caspase-3 activity and sensitizing PDT-treated cells from autophagy to apoptosis due to the Becline-1 cleavage. This study demonstrates for the first time the molecular mechanisms involved in histone modification induced by PDT-mediated oxidative stress, suggesting that HAT inhibitors may provide a novel therapeutic approach for improving PDT response., (Copyright © 2015 Elsevier Inc. All rights reserved.)

A hybrid wireless-over-fiber (WoF) transmission system based on multiple injection-locked Fabry-Perot laser diodes (FP LDs) is proposed and experimentally demonstrated. Unlike the traditional hybrid WoF transmission systems that require multiple distributed feedback (DFB) LDs to support different kinds of services, the proposed system employs multiple injection-locked FP LDs to provide different kinds of applications. Such a hybrid WoF transmission system delivers downstream intensity-modulated 20-GHz microwave (MW)/60-GHz millimeter-wave (MMW)/550-MHz cable television (CATV) signals and upstream phase-remodulated 20-GHz MW signal. Excellent bit error rate (BER), carrier-to-noise ratio (CNR), composite second-order (CSO), and composite triple-beat (CTB) are observed over a 40-km single-mode fiber (SMF) and a 4-m radio frequency (RF) wireless transport. Such a hybrid WoF transmission system has practical applications for fiber-wireless convergence to provide broadband integrated services, including telecommunication, data communication, and CATV services.

A 20-Gbps optical light-based WiFi (LiFi) transport system employing vertical-cavity surface-emitting laser (VCSEL) and external light injection technique with 16-quadrature amplitude modulation (QAM)-orthogonal frequency-division multiplexing (OFDM) modulating signal is proposed. Good bit error rate (BER) performance and clear constellation map are achieved in our proposed optical LiFi transport systems. An optical LiFi transport system, delivering 16-QAM-OFDM signal over a 6-m free-space link, with a data rate of 20 Gbps, is successfully demonstrated. Such a 20-Gbps optical LiFi transport system provides the advantage of a free-space communication link for high data rates, which can accelerate the visible laser light communication (VLLC) deployment.

Prediction of gene expression levels from regulatory sequences is one of the major challenges of genomic biology today. A particularly promising approach to this problem is that taken by thermodynamics-based models that interpret an enhancer sequence in a given cellular context specified by transcription factor concentration levels and predict precise expression levels driven by that enhancer. Such models have so far not accounted for the effect of chromatin accessibility on interactions between transcription factor and DNA and consequently on gene-expression levels. Here, we extend a thermodynamics-based model of gene expression, called GEMSTAT (Gene Expression Modeling Based on Statistical Thermodynamics), to incorporate chromatin accessibility data and quantify its effect on accuracy of expression prediction. In the new model, called GEMSTAT-A, accessibility at a binding site is assumed to affect the transcription factor's binding strength at the site, whereas all other aspects are identical to the GEMSTAT model. We show that this modification results in significantly better fits in a data set of over 30 enhancers regulating spatial expression patterns in the blastoderm-stage Drosophila embryo. It is important to note that the improved fits result not from an overall elevated accessibility in active enhancers but from the variation of accessibility levels within an enhancer. With whole-genome DNA accessibility measurements becoming increasingly popular, our work demonstrates how such data may be useful for sequence-to-expression models. It also calls for future advances in modeling accessibility levels from sequence and the transregulatory context, so as to predict accurately the effect of cis and trans perturbations on gene expression., (Copyright © 2015 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Background and Objective: Long circulating doxorubicin (Dox)-loaded PEGylated liposomes are clinically safer than the free form due to the significant reduction of cardiac toxicity. However, the therapeutic efficacy of the PEGylated liposome could further be improved if poor diffusivity and slow drug release of the liposome in tumor interstitium can be overcome. In this study, a dual-effect liposome triggered by photodynamic effect was developed to improve the therapeutic efficacy of Dox-loaded PEGylated liposomes., Materials and Methods: Dox and chlorin e6 (Ce6) were co-encapsulated in PEGylated liposomes (named as PL-Dox-Ce6). To induce the drug release, photodynamic effect was triggered by the light irradiation of a 662 nm diode laser. The cellular distribution of Dox and Ce6 was examined under confocal microscope. The in vitro and in vivo cytotoxicity of PL-Dox-Ce6 was determined via the colony formation assay and the synergistic C26 tumor model, respectively., Results: The cellular distribution of PL-Dox-Ce6 was in the cytoplasmic area; while under light irradiation, Dox was co-localized with nuclear staining positive signals. The cellular cytotoxicity of PL-Dox-Ce6 was significantly higher than the controls including liposomes encapsulating either Dox (PL-Dox) or Ce6 (PL-Ce6). The in vivo treatment efficacy of PL-Dox-Ce6 determined in the C26 tumor model reveals a significant therapeutic effect compared to that of PL-Ce6 and PL-Dox alone or in combination., Conclusion: This study indicates that this dual-effect PEGylated liposome could provide clinical advantages in the combination regimen of photodynamic therapy and chemotherapy., (© 2015 Wiley Periodicals, Inc.)

Neurofibromatosis type 1 (NF1) is the most common tumor predisposition disorder affecting 1/3500 worldwide. Patients are at risk of developing benign (neurofibromas) and malignant peripheral nerve sheath tumors (MPNST). The AXL receptor tyrosine kinase has been implicated in several kinds of cancers, but so far no studies have investigated the role of AXL in NF1 related tumorigenesis. Recently, the soluble fraction from the extracellular domain of AXL (sAXL) has been found in human plasma, and its level was correlated to poor prognosis in patients with renal cancer. Compared to normal human Schwann cells, a significantly high expression level of AXL was found in three of the four MPNST cell lines and two of the three primary MPNST tissues. Similarly, the level of sAXL in conditioned media corresponded to the protein and mRNA levels of AXL in the MPNST cell lines. Furthermore, in two different human MPNST xenograft models, the human sAXL could be detected in the mouse plasma. Its level was proportionate to the size of the xenograft tumors, while no human sAXL was detect prior to the formation of the tumors. Treatment with a newly developed photodynamic therapy, prevented further tumor growth and resulted in drastically reduced the levels of sAXL compared to that of the control group. Finally, the level of sAXL was significantly increased in patients with plexiform tumors compared to patients with only dermal neurofibromas, further supporting the role of sAXL as a marker for NF1 related tumor burden.

A hybrid cable television (CATV)/microwave (MW)/millimeter-wave (MMW) wavelength-division-multiplexing (WDM) light wave transmission system based on injection-locked Fabry-Perot laser diodes (FP LDs) is proposed and demonstrated. Different from conventional hybrid WDM light wave transmission systems, which need wavelength-selected distributed feedback laser diodes to support various services, the proposed systems employ injection-locked FP LDs to provide multiple applications. Over a 40 km single-mode fiber transport, impressive performances of carrier-to-noise ratio/composite second-order/composite triple-beat/bit error rate are obtained for 550 MHz CATV/20 GHz MW/40 GHz MMW/60 GHz MMW signal transmissions. Such a hybrid WDM light wave transmission system would be attractive for fiber links to provide broadband integrated services.

This work develops and demonstrates a double sideband with optical carrier suppression (DSBCS) modulation scheme for a hybrid wireless and cable television system based on a phase modulator (PM) and a polarization beam splitter (PBS). A carrier suppression ratio greater than 20 dB is achieved between two sidebands. In addition, the values of carrier-to-noise ratio, composite second-order and composite triple beat in various channels after 25 km of transmission are higher than the threshold value, and the power penalty of microwave signal in back-to-back and 25 km transmission perform well. Additionally, the constellation diagram of upstream signal is successfully recovered. Above results demonstrate that the proposed scheme is highly promising for practical applications.

The amount of gene expression data of microarray has grown exponentially. To apply them for extensive studies, integrated analysis of cross-laboratory (cross-lab) data becomes a trend, and thus, choosing an appropriate feature selection method is an essential issue. This paper focuses on feature selection for Affymetrix (Affy) microarray studies across different labs. We investigate four feature selection methods: $(t)$-test, significance analysis of microarrays (SAM), rank products (RP), and random forest (RF). The four methods are applied to acute lymphoblastic leukemia, acute myeloid leukemia, breast cancer, and lung cancer Affy data which consist of three cross-lab data sets each. We utilize a rank-based normalization method to reduce the bias from cross-lab data sets. Training on one data set or two combined data sets to test the remaining data set(s) are both considered. Balanced accuracy is used for prediction evaluation. This study provides comprehensive comparisons of the four feature selection methods in cross-lab microarray analysis. Results show that SAM has the best classification performance. RF also gets high classification accuracy, but it is not as stable as SAM. The most naive method is $(t)$-test, but its performance is the worst among the four methods. In this study, we further discuss the influence from the number of training samples, the number of selected genes, and the issue of unbalanced data sets.

Coherently injection-locked and directly modulated weak-resonant-cavity laser diode (WRC-FPLD) for back-to-back optical 16-quadrature-amplitude-modulation (QAM) and 52-subcarrier orthogonal frequency division multiplexing (OFDM) transmission with maximum bit rate up to 4 Gbit/s at carrier frequency of 2.5 GHz is demonstrated. The WRC-FPLD transmitter source is a specific design with very weak-resonant longitudinal modes to preserve its broadband gain spectral characteristics for serving as a colorless WDM-PON transmitter. Under coherent injection-locking, the relative-intensity noise (RIN) of the injection-locked WRC-FPLD can be suppressed to ?105 dBc/Hz and the error vector magnitude of the received optical OFDM data is greatly reduced with the amplitude error suppressed down 5.5%. Such a coherently injection-locked single-mode WRC-FPLD can perform both the back-to-back and the 25-km-SMF 16-QAM-52-OFDM transmissions with a symbol rate of 20-MSa/s in each OFDM subcarrier. After coherent injection locking, the BER of the back-to-back transmitted 16-QAM-52-OFDM data is reduced to 2.5 × 10(-5) at receiving power of ?10 dBm. After propagating along a 25-km-long SMF, a receiving power sensitivity of ?7.5 dBm is required to obtain a lowest BER of 2.5 × 10(-5), and a power penalty of 2.7 dB is observed when comparing with the back-to-back transmission.

A hybrid CATV/OFDM long-reach PON architecture is proposed and experimentally demonstrated. By multiplexing the OFDM and CATV signals in different frequency bands, the overall network structure is simplified and the available bandwidth for the OFDM signals is increased. Furthermore, by carefully adjusting the driving voltage of the employed CATV transmitter, the overall transmission performance can be optimized by eliminating a large amount of unwanted distortions. Unlike the current fiber optical CATV transport system in which the CATV signals need to be amplified in every 30 ~40 km transmission span, the proposed architecture has successfully extended the transmission span to 60 km. This can practically remove the needs of electrical power provisioning and monitoring between the central office (CO) and each local exchange (LE). Good transmission performances of carrier-to-noise ratio (CNR), composite second-order (CSO), composite triple beat (CTB) and bit error rate (BER) were obtained for the transmitted CATV and OFDM signals. All of these experimental results prove the practice and efficiency of the proposed architecture in providing simplicity and extended reach services to customers.

A combination of an economic multi-band optical carrier generator and a novel optical signal to noise ratio (OSNR) enhancement circuit is proposed and demonstrated for radio over fiber (RoF) transport systems. Different from normal RoF transport systems which a central station (CS) needs multiple dedicate wavelength laser diodes (LDs) to support various base stations (BSs), the proposed scheme can employ a single LD to provide multiple optical carriers for various BSs. To verify this scheme, 8 coherent optical carriers are firstly generated using a single LD and a local oscillator (LO). Subsequently, their OSNR values are optimized by the developed OSNR enhancement circuit. An up to 15 dB OSNR enlargement in those optical carriers is experimentally achieved. To demonstrate the practice of the proposal, a pair of those optical carriers is employed to experimentally achieve frequency up-conversion process in a RoF transport system. Clear eye diagram and error free transmission reveal that with a proper carrier selector the proposed scheme can be employed to support multiple RoF transmissions. Furthermore, this proposal also presents a high possibility to achieve 60 GHz RoF transmission using a 10 GHz LO, a LD and a low frequency external modulator.

A hybrid CATV/16-QAM OFDM in-building network over a combination of single-mode fiber (SMF) and graded-index plastic optical fiber (GI-POF) transport is proposed and experimentally demonstrated with good qualities of service. In this system, a 1556 nm optical signal is directly transmitted along with two fiber spans (20-km SMF + 25-m GI-POF). Without using any wavelength conversion or bridge circuit between SMF and POF connection, error free transmissions with sufficient low bit error rate (BER) values are achieved for 2.5 Gbps/2.5 GHz and 5 Gbps/2.5 GHz OFDM signals; as well as good performances of carrier-to-noise ratio (CNR), composite second-order (CSO), and composite triple beat (CTB) are obtained for CATV one. This proposed network reveals an outstanding one with economy and convenience to be installed., (© 2011 Optical Society of America)

A hybrid community antenna television (CATV) and orthogonal-frequency-division-multiplexing (OFDM) transport system is proposed and experimentally demonstrated to transmit multiple CATV channels and bi-directional radio frequency signals on a single optical carrier. By polarization remodulating an optical CATV signal with downstream OFDM signals and then amplitude remodulating upstream OFDM signals with the hybrid CATV/OFDM signals, this architecture can efficiently utilize only one optical carrier to support optical analog/digital CATV transmission and bi-directional wireless broadband services for each client. Good experimental results prove that this architecture provides a proper wavelength utilization scheme for future multiwavelength optical transport systems.