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During breast cancer metastasis, the developmental process epithelial-mesenchymal (EM) transition is abnormally activated. Transcriptional regulatory networks controlling EM transition are well-studied; however, alternative RNA splicing also plays a critical regulatory role during this process. Alternative splicing was proved to control the EM transition process, and RNA-binding proteins were determined to regulate alternative splicing. A comprehensive understanding of alternative splicing and the RNA-binding proteins that regulate it during EM transition and their dynamic impact on breast cancer remains largely unknown. To accurately study the dynamic regulatory relationships, time-series data of the EM transition process are essential. However, only cross-sectional data of epithelial and mesenchymal specimens are available. Therefore, we developed a pseudotemporal causality-based Bayesian (PCB) approach to infer the dynamic regulatory relationships between alternative splicing events and RNA-binding proteins. Our study sheds light on facilitating the regulatory network-based approach to identify key RNA-binding proteins or target alternative splicing events for the diagnosis or treatment of cancers. The data and code for PCB are available at: http://hkumath.hku.hk/~wkc/PCB(data+code).zip.

For a serial delivery system, the latter 3PL needs to be prepared at the transshipment node in advance to reduce the total delivery time. In this paper, we propose the concept of Connecting Time Spot (CTS) to help 4PL schedule the latter 3PL when to wait at the transshipment node. We study a serial delivery system with a 4PL and two 3PLs, where 4PL designs optimal contracts with two types of CTS (GCTS is derived by system parameter and DCTS is determined by 4PL’s optimization) to induce 3PLs to exert the optimal effort levels. We analyze the effects of CTS on the system profit in the centralized system. For the decentralized system, we particularly investigate the optimal contracts in three penalty modes which are according to the occupancy of the warehouses. The results show that CTS can avoid 3PLs’ idle resources and enhance the system profit for serial delivery both in the centralized system and the decentralized system. Compared with GCTS, DCTS has a better performance in enhancing the system profits. Also, the optimal incentive contracts achieve Pareto improvement for system profits. Interestingly, one 3PL’s delivery penalty mode will not affect the other 3PL’s optimal contracts.

Although tumor immunotherapy has emerged as a promising therapeutic method for oncology, it encounters several limitations, especially concerning low response rates and potential off-targets that elicit side effects. Furthermore, tumor immunogenicity is the critical factor that predicts the success rate of immunotherapy, which can be boosted by the application of nanotechnology. Herein, we introduce the current approach of cancer immunotherapy and its challenges and the general methods to enhance tumor immunogenicity. Importantly, this review highlights the integration of anticancer chemo/immuno-based drugs with multifunctional nanomedicines that possess imaging modality to determine tumor location and can respond to stimuli, such as light, pH, magnetic field, or metabolic changes, to trigger chemotherapy, phototherapy, radiotherapy, or catalytic therapy to upregulate tumor immunogenicity. This promotion rouses immunological memory, such as enhanced immunogenic cell death, promoted maturation of dendritic cells, and activation of tumor-specific T cells against cancer. Finally, we express the related challenges and personal perspectives of bioengineered nanomaterials for future cancer immunotherapy.

FoundationOne®CDx (F1CDx) is a United States (US) Food and Drug Administration (FDA)-approved companion diagnostic test to identify patients who may benefit from treatment in accordance with the approved therapeutic product labeling for 28 drug therapies. F1CDx utilizes next-generation sequencing (NGS)-based comprehensive genomic profiling (CGP) technology to examine 324 cancer genes in solid tumors. F1CDx reports known and likely pathogenic short variants (SVs), copy number alterations (CNAs), and select rearrangements, as well as complex biomarkers including tumor mutational burden (TMB) and microsatellite instability (MSI), in addition to genomic loss of heterozygosity (gLOH) in ovarian cancer. CGP services can reduce the complexity of biomarker testing, enabling precision medicine to improve treatment decision-making and outcomes for cancer patients, but only if test results are reliable, accurate, and validated clinically and analytically to the highest standard available. The analyses presented herein demonstrate the extensive analytical and clinical validation supporting the F1CDx initial and subsequent FDA approvals to ensure high sensitivity, specificity, and reliability of the data reported. The analytical validation included several in-depth evaluations of F1CDx assay performance including limit of detection (LoD), limit of blank (LoB), precision, and orthogonal concordance for SVs (including base substitutions [SUBs] and insertions/deletions [INDELs]), CNAs (including amplifications and homozygous deletions), genomic rearrangements, and select complex biomarkers. The assay validation of >30,000 test results comprises a considerable and increasing body of evidence that supports the clinical utility of F1CDx to match patients with solid tumors to targeted therapies or immunotherapies based on their tumor’s genomic alterations and biomarkers. F1CDx meets the clinical needs of providers and patients to receive guideline-based biomarker testing, helping them keep pace with a rapidly evolving field of medicine.

Metals have been investigated as biomaterials for a wide range of medical applications. At nanoscale, some metals, such as gold nanoparticles, exhibit plasmonics, which have motivated researchers’ focus on biosensor development. At the device level, some metals, such as titanium, exhibit good physical properties, which could allow them to act as biomedical implants for physical support. Despite these attractive features, the non-specific delivery of metallic nanoparticles and poor tissue–device compatibility have greatly limited their performance. This review aims to illustrate the interplay between polymers and metals, and to highlight the pivotal role of polymer–metal composite/nanocomposite healthcare materials in different biomedical applications. Here, we revisit the recent plasmonic engineered platforms for biomolecules detection in cell-free samples and highlight updated nanocomposite design for (1) intracellular RNA detection, (2) photothermal therapy, and (3) nanomedicine for neurodegenerative diseases, as selected significant live cell–interactive biomedical applications. At the device scale, the rational design of polymer–metallic medical devices is of importance for dental and cardiovascular implantation to overcome the poor physical load transfer between tissues and devices, as well as implant compatibility under a dynamic fluidic environment, respectively. Finally, we conclude the treatment of these innovative polymer–metal biomedical composite designs and provide a future perspective on the aforementioned research areas.

This paper reports on the long-term effectiveness of a non-formal co-curricular educational program based on a campus ecogarden at a Hong Kong university in developing pro-sustainability awareness, attitudes and behavior among undergraduate students. This service-based, nature-based experiential learning program, termed the Ecogarden Farmer and Biodiversity Surveyor, has been running at the university since 2015. The program is divided into two consecutive phases: a training phase comprising various learning activities and a successive internship phase consisting of the all-round practical tasks involved in managing the garden. A retrospective evaluation of the program using phenomenographic approach and content analysis was adopted to reveal the diversity of students’ learning experience, as the indicators of the success of the program. Of 112 participants from 4 cohorts, 32 completed online questionnaires, and semi-structured interviews were successfully conducted with twelve participants, three from each of the four cohorts. The results indicated that the program’s outcomes could be categorized into five themes. Most outcomes fit into the theme ‘an increase in knowledge and skill level,’ followed by ‘rise in environmental awareness,’‘facilitation of personal growth,’ and ‘enhancement of career development.’ Many structural experiences revealed may suggest the success of the program. The longer the participants had participated in the program, the more in-depth and diversified reflection of the senior participants relating to personal development were mentioned. This study provides critical insights into the validity of retrospective program evaluation for assessing the long-term impact of EfS programs by introducing a cross-sectional study of different cohorts as a serial time-point sampling strategy.

Abstract Background The next-generation sequencing (NGS) technology has greatly facilitated genomic and transcriptomic studies, contributing significantly in expanding the current knowledge on genome and transcriptome. However, the continually evolving variety of sequencing platforms, protocols and analytical pipelines has led the research community to focus on cross-platform evaluation and standardization. As a NGS pioneer in China, the Beijing Genomics Institute (BGI) has announced its own NGS platform designated as BGISEQ-500, since 2016. The capability of this platform in large-scale DNA sequencing and small RNA analysis has been already evaluated. However, the comparative performance of BGISEQ-500 platform in transcriptome analysis remains yet to be elucidated. The Illumina series, a leading sequencing platform in China’s sequencing market, would be a preferable reference to evaluate new platforms. Methods To this end, we describe a cross-platform comparative study between BGISEQ-500 and Illumina HiSeq4000 for analysis of Arabidopsis thaliana WT (Col 0) transcriptome. The key parameters in RNA sequencing and transcriptomic data processing were assessed in biological replicate experiments, using aforesaid platforms. Results The results from the two platforms BGISEQ-500 and Illumina HiSeq4000 shared high concordance in both inter- (correlation, 0.88–0.93) and intra-platform (correlation, 0.95–0.98) comparison for gene quantification, identification of differentially expressed genes and alternative splicing events. However, the two platforms yielded highly variable interpretation results for single nucleotide polymorphism and insertion–deletion analysis. Conclusion The present case study provides a comprehensive reference dataset to validate the capability of BGISEQ-500 enabling it to be established as a competitive and reliable platform in plant transcriptome analysis.

Pallet management as a backbone of logistics and supply chain activities is essential to supply chain parties, while a number of regulations, standards and operational constraints are considered in daily operations. In recent years, pallet pooling has been unconventionally advocated to manage pallets in a closed-loop system to enhance the sustainability and operational effectiveness, but pitfalls in terms of service reliability, quality compliance and pallet limitation when using a single service provider may occur. Therefore, this study incorporates a decentralisation mechanism into the pallet management to formulate a technological eco-system for pallet pooling, namely Pallet as a Service (PalletaaS), raised by the foundation of consortium blockchain and Internet of things (IoT). Consortium blockchain is regarded as the blockchain 3.0 to facilitate more industrial applications, except cryptocurrency, and the synergy of integrating a consortium blockchain and IoT is thus investigated. The corresponding layered architecture is proposed to structure the system deployment in the industry, in which the location-inventory-routing problem for pallet pooling is formulated. To demonstrate the values of this study, a case analysis to illustrate the human–computer interaction and pallet pooling operations is conducted. Overall, this study standardises the decentralised pallet management in the closed-loop mechanism, resulting in a constructive impact to sustainable development in the logistics industry.

Background: Mannose-binding lectin (MBL) is an innate immune protein with strong biologic plausibility for protecting against influenza virus-related sepsis and bacterial co-infection. In an autopsy cohort of 105 influenza-infected young people, carriage of the deleterious MBL gene MBL2_Gly54Asp(“B”) mutation was identified in 5 of 8 individuals that died from influenza-methicillin-resistant Staphylococcus aureus (MRSA) co-infection. We evaluated MBL2 variants known to influence MBL levels with pediatric influenza-related critical illness susceptibility and/or severity including with bacterial co-infections.Methods: We enrolled children and adolescents with laboratory-confirmed influenza infection across 38 pediatric intensive care units from November 2008 to June 2016. We sequenced MBL2 “low-producer” variants rs11003125(“H/L”), rs7096206(“Y/X”), rs1800450Gly54Asp(“B”), rs1800451Gly57Glu(“C”), rs5030737Arg52Cys(“D”) in patients and biologic parents. We measured serum levels and compared complement activity in low-producing homozygotes (“B/B,” “C/C”) to HYA/HYA controls. We used a population control of 1,142 healthy children and also analyzed family trios (PBAT/HBAT) to evaluate disease susceptibility, and nested case-control analyses to evaluate severity.Results: We genotyped 420 patients with confirmed influenza-related sepsis: 159 (38%) had acute lung injury (ALI), 165 (39%) septic shock, and 30 (7%) died. Although bacterial co-infection was diagnosed in 133 patients (32%), only MRSA co-infection (n = 33, 8% overall) was associated with death (p < 0.0001), present in 11 of 30 children that died (37%). MBL2 variants predicted serum levels and complement activation as expected. We found no association between influenza-related critical illness susceptibility and MBL2 variants using family trios (633 biologic parents) or compared to population controls. MBL2 variants were not associated with admission illness severity, septic shock, ALI, or bacterial co-infection diagnosis. Carriage of low-MBL producing MBL2 variants was not a risk factor for mortality, but children that died did have higher carriage of one or more B alleles (OR 2.3; p = 0.007), including 7 of 11 with influenza MRSA-related death (vs. 2 of 22 survivors: OR 14.5, p = 0.0002).Conclusions:MBL2 variants that decrease MBL levels were not associated with susceptibility to pediatric influenza-related critical illness or with multiple measures of critical illness severity. We confirmed a prior report of higher B allele carriage in a relatively small number of young individuals with influenza-MRSA associated death.

Social networking sites (SNSs) such as Facebook have a potential to become a valuable learning environment. Facebook games with appropriate instructional design may provide players with better learning experiences and outcomes. Using an effective educational Facebook game, we aimed to explore the educational effects of Facebook games as self-directed e-learning environments. We tested our hypotheses on a sample of 73 undergraduates (42 females). The participants completed the Facebook game and self-administered questionnaires over a 3-week period. Path analysis demonstrated that Internet self-efficacy, usability, and fun positively affected perceived learning effectiveness and user satisfaction in a Facebook learning environment. We discussed the research and practical implications of these findings for the future development of self-directed e-learning on SNS.

Three-dimensional virtual environments have gained wide popularity due to improvement in graphic rendering technology and networking infrastructure. Many education institutions have been trying to leverage the potential of 3D virtual environments in their application in education. In this research, we aim to evaluate the students’ perception of virtual environments in teaching and learning activities. We set up a virtual classroom, where a short presentation was delivered to students through virtual projectors in Second Life, the most widely adopted 3D virtual environment. The students filled in a questionnaire after the class. We found that the students gave a statistically higher evaluation to 3D virtual environments in terms of satisfaction and enjoyment, while comparable scores between 3D and traditional learning environment in terms of concentration, perceived usefulness, and learning and understanding were obtained. Our results show that virtual learning environment is of great potential in e-learning. Some recommendations in using the virtual environment for learning activities are given.

Purpose. To review records of 17 patients who sustained a tibial or femoral intra-operative fracture during primary cemented total knee arthroplasty (TKA) Methods. Records of 1346 primary cemented TKAs using the NexGen LPS fluted tibial component performed by a single surgeon were reviewed. 12 tibial and 5 femoral intra-operative fractures occurred in 5 men and 12 women aged 54 to 83 (mean, 71.6) years. No patient had any condition that may predispose to osteoporosis. Results. All 12 tibial fractures occurred during hammering down of the final tibial component. They were vertical crack fractures of the anterior cortex of the medial tibial plateau with minimal displacement and did not extend beyond the tip of the tibial stem. Four of the 5 femoral fractures were avulsion fractures in the coronal plane of the medial femoral condyles and occurred during removal of the intercondylar notch. The remaining femoral fracture involved the medial cortex of the medial femoral condyle and occurred during removal of a large medial femoral condyle osteophyte. All fractures were immediately fixed with 3.5-mm partially threaded AO cancellous screws. All patients achieved bone union and good function. Conclusion. Intra-operative tibial fractures are more common than femoral fractures; fixation with multiple AO screws achieves good outcome.

Genome-wide association studies have been able to identify disease associations with many common variants; however most of the estimated genetic contribution explained by these variants appears to be very modest. Rare variants are thought to have larger effect sizes compared to common SNPs but effects of rare variants cannot be tested in the GWAS setting. Here we propose a novel method to test for association of rare variants obtained by sequencing in family-based samples by collapsing the standard family-based association test (FBAT) statistic over a region of interest. We also propose a suitable weighting scheme so that low frequency SNPs that may be enriched in functional variants can be upweighted compared to common variants. Using simulations we show that the family-based methods perform at par with the population-based methods under no population stratification. By construction, family-based tests are completely robust to population stratification; we show that our proposed methods remain valid even when population stratification is present.

This article examines the role of university students during the anti-extradition movement in Hong Kong, analyzing their strategy to mobilize schools' physical, symbolic, and interpersonal resources, and how the authorities reacted by restricting and redefining key resources. Universities have served as a safe space since police officers traditionally are not allowed to enter them. Some schools are also strategically located to allow for more disruptive protests. Since Confucianism venerates the moral value of learning, universities are perceived as a hallowed symbol of intellectual conscience, justifying students' defiance. Universities are commonly seen as warm families whose leaders are obliged to protect students. Finally, universities sustain a rich network of cross-mobilization. The regime restricts access to resources by tightening campus control and reshuffling university leadership, and redefined the symbolic meanings by discrediting higher education. We find interpersonal relationships constitute the most resilient resource because they are embedded in everyday life common identities.

Primary sclerosing cholangitis is a rare cause of cholestasis caused by progressive inflammation and fibrosis of both intrahepatic and extrahepatic bile ducts leading to multifocal ductal strictures. Herein, we report a case of primary sclerosing cholangitis and inflammatory bowel disease. The concomitant diagnosis of these two diseases is not typical. The management includes the treatment of inflammatory bowel disease and potential complications of primary sclerosing cholangitis, including dominant strictures of bile duct, portal hypertension, gallbladder diseases, cholangiocarcinoma, and colonoscopic surveillance.

Background: Mannose-binding lectin (MBL) is an innate immune protein with strong biologic plausibility for protecting against influenza virus-related sepsis and bacterial co-infection. In an autopsy cohort of 105 influenza-infected young people, carriage of the deleterious MBL gene MBL2_Gly54Asp("B") mutation was identified in 5 of 8 individuals that died from influenza-methicillin-resistant Staphylococcus aureus (MRSA) co-infection. We evaluated MBL2 variants known to influence MBL levels with pediatric influenza-related critical illness susceptibility and/or severity including with bacterial co-infections. Methods: We enrolled children and adolescents with laboratory-confirmed influenza infection across 38 pediatric intensive care units from November 2008 to June 2016. We sequenced MBL2 "low-producer" variants rs11003125("H/L"), rs7096206("Y/X"), rs1800450Gly54Asp("B"), rs1800451Gly57Glu("C"), rs5030737Arg52Cys("D") in patients and biologic parents. We measured serum levels and compared complement activity in low-producing homozygotes ("B/B," "C/C") to HYA/HYA controls. We used a population control of 1,142 healthy children and also analyzed family trios (PBAT/HBAT) to evaluate disease susceptibility, and nested case-control analyses to evaluate severity. Results: We genotyped 420 patients with confirmed influenza-related sepsis: 159 (38%) had acute lung injury (ALI), 165 (39%) septic shock, and 30 (7%) died. Although bacterial co-infection was diagnosed in 133 patients (32%), only MRSA co-infection (n = 33, 8% overall) was associated with death (p < 0.0001), present in 11 of 30 children that died (37%). MBL2 variants predicted serum levels and complement activation as expected. We found no association between influenza-related critical illness susceptibility and MBL2 variants using family trios (633 biologic parents) or compared to population controls. MBL2 variants were not associated with admission illness severity, septic shock, ALI, or bacterial co-infection diagnosis. Carriage of low-MBL producing MBL2 variants was not a risk factor for mortality, but children that died did have higher carriage of one or more B alleles (OR 2.3; p = 0.007), including 7 of 11 with influenza MRSA-related death (vs. 2 of 22 survivors: OR 14.5, p = 0.0002). Conclusions: MBL2 variants that decrease MBL levels were not associated with susceptibility to pediatric influenza-related critical illness or with multiple measures of critical illness severity. We confirmed a prior report of higher B allele carriage in a relatively small number of young individuals with influenza-MRSA associated death.

Motivation Single cell RNA sequencing (scRNA-seq) technique enables the transcriptome profiling of hundreds to ten thousands of cells at the unprecedented individual level and provides new insights to study cell heterogeneity. However, its advantages are hampered by dropout events. To address this problem, we propose a Blockwise Accelerated Non-negative Matrix Factorization framework with Structural network constraints (BANMF-S) to impute those technical zeros. Results BANMF-S constructs a gene-gene similarity network to integrate prior information from the external PPI network by the Triadic Closure Principle and a cell-cell similarity network to capture the neighborhood structure and temporal information through a Minimum-Spanning Tree. By collaboratively employing these two networks as regularizations, BANMF-S encourages the coherence of similar gene and cell pairs in the latent space, enhancing the potential to recover the underlying features. Besides, BANMF-S adopts a blocklization strategy to solve the traditional NMF problem through distributed Stochastic Gradient Descent method in a parallel way to accelerate the optimization. Numerical experiments on simulations and real datasets verify that BANMF-S can improve the accuracy of downstream clustering and pseudo-trajectory inference, and its performance is superior to seven state-of-the-art algorithms. Availability All data used in this work are downloaded from publicly available data sources, and their corresponding accession numbers or source URLs are provided in Supplementary File Section 5.1 Dataset Information. The source codes are publicly available in Github repository https://github.com/jiayingzhao/BANMF-S. [ABSTRACT FROM AUTHOR]

A vision care-based community service subject is offered to general university students for fulfillment of a service-learning compulsory credit requirement. Here, a professional health subject is taught in a way that caters to generalist learners. Students gain basic skills they can apply to provide vision screenings for the needy population. All enrolled undergraduates had no background in eye health-related subjects. The teaching was not content-driven, requiring students' direct recall of facts. Rather, the teaching focused on Socratic teaching of logical theories and applications. The objective was to increase awareness of current eye care problems using case examples. Students learned to appreciate ways to promote active outreach services. Through activities and project work, students learned and practiced strong teamwork and direct application of knowledge in community-based eye care services. This learning experience demonstrates emergence of authentic practice from theory.