Network Modeling Identifies Molecular Functions Targeted by miR-204 to Suppress Head and Neck Tumor Metastasis

Due to the large number of putative microRNA gene targets predicted by sequence-alignment databases and the relative low accuracy of such predictions which are conducted independently of biological context by design, systematic experimental identification and validation of every functional microRNA target is currently challenging. Consequently, biological studies have yet to identify, on a genome scale, key regulatory networks perturbed by altered microRNA functions in the context of cancer. In this report, we demonstrate for the first time how phenotypic knowledge of inheritable cancer traits and of risk factor loci can be utilized jointly with gene expression analysis to efficiently prioritize deregulated microRNAs for biological characterization. Using this approach we characterize miR-204 as a tumor suppressor microRNA and uncover previously unknown connections between microRNA regulation, network topology, and expression dynamics. Specifically, we validate 18 gene targets of miR-204 that show elevated mRNA expression and are enriched in biological processes associated with tumor progression in squamous cell carcinoma of the head and neck (HNSCC). We further demonstrate the enrichment of bottleneckness, a key molecular network topology, among miR-204 gene targets. Restoration of miR-204 function in HNSCC cell lines inhibits the expression of its functionally related gene targets, leads to the reduced adhesion, migration and invasion in vitro and attenuates experimental lung metastasis in vivo. As importantly, our investigation also provides experimental evidence linking the function of microRNAs that are located in the cancer-associated genomic regions (CAGRs) to the observed predisposition to human cancers. Specifically, we show miR-204 may serve as a tumor suppressor gene at the 9q21.1–22.3 CAGR locus, a well established risk factor locus in head and neck cancers for which tumor suppressor genes have not been identified. This new strategy that integrates expression profiling, genetics and novel computational biology approaches provides for improved efficiency in characterization and modeling of microRNA functions in cancer as compared to the state of art and is applicable to the investigation of microRNA functions in other biological processes and diseases

Fabrication And Study Of Microstructure, Solid-Electrolyte Interphase, And Phase Evolution Of Nanoporous Metals Used As Li-Ion Battery Alloy Anodes

There is an urgent need to increase national use of clean, renewable energy. While resources such as solar energy are highly intermittent, renewable energy adoption can be extended by dramatically increasing the energy density of Li-ion battery (LIB) technology used to store renewable energy by replacing graphite with high-capacity nanostructured alloy anodes. However, there are many challenges to utilizing these materials in commercial LIBs, including: (1) limited sustainable and scalable nanomaterial fabrication methods, and (2) their poor cycling performance. In this work, we seek to better understand and help mitigate these two challenges. To address the first challenge, we demonstrate a methodology for fabrication of nanoporous Au (NP-Au) through electrolytic dealloying of a Au-Ag parent alloy with simultaneous recovery of the sacrificial Ag material. This sustainable electrolytic dealloying method is generalized to a procedure that can be used to fabricate a wide array of nanoporous metals including nanoporous Al (NP-Al), a promising high-capacity alloy anode material. We find that NP-Al fabricated through this methodology is nearly oxide-free and consists of a hierarchical, bimodal morphology with the smaller ligaments having a structure size of 10-20 nm. While NP-Al alloy anodes exhibit enhanced performance compared to bulk Al, NP-Al still has a short cycle life, prompting the need to explore the various morphological evolutions that occur during cycling that give rise to this poor performance. We address the second challenge by studying the solid-electrolyte interphase (SEI), microstructure, and phase evolutions that occur when cycling nanoporous alloy anodes. Using transmission electron microscopy (TEM), we find that the SEI formed on a NP-Au model anode becomes increasingly thick during lithiation and fractures during delithiation. Next, we investigate the microstructural evolution of NP-Au during cycling using TEM and small-angle X-ray scattering. The nanoporous structure degrades during lithiation as the ligaments expand and pulverize to form nanoparticles which become trapped in the SEI. During delithiation, SEI containing these particles fractures and a fine porous structure forms on the ligaments. From these insights, we develop a model for the degradation that occurs during cycling. The last morphology evolution process explored is the phase transformation pathways that occur in nanoporous alloy anodes compared to bulk alloy anodes. By comparing the voltage profile shape of bulk and nanoporous Ag (NP-Ag) model alloy anodes with X-ray diffraction data and the calculated Ag open circuit voltage, we can determine the phase transformation pathways that occur during cycling. While bulk Ag follows the pathway expected by the phase diagram, the NP-Ag alloy anode forms a non-equilibrium solid solution during lithiation. We develop models of the complex core-shell phase morphologies expected from both of these pathways. Lastly, we explore NP-Al as a candidate material for an alternative energy application: a water-reactive metal used to produce hydrogen gas on-demand to generate clean electricity using a fuel cell. From our conclusions, we suggest future work and show preliminary results for a fully electrochemical (de)alloying alloy anode fabrication process, and an operando TEM investigation of alloy anode degradation processes

Technology acceptance and m-commerce in an operational environment

Purpose – To provide a case study in the implementation of mobile technologies in an operations management environment, and viewed through a model for technology acceptance. Design/methodology/approach – This is an assessment of the technology acceptance model(TAM) through action research, a practical implementation based upon understandings developed in the TAM. Findings – Provides fresh data to further develop the TAM, shedding light on some of the factors expounded within TAM, and their relationships. Research limitations/implications – This is not the empirical research required to fully validate the TAM, but is useful in terms of investigating its various features within a detailed case study. It is also useful in terms of the project management implications for the implementation of new technologies. Practical implications – Useful for those looking at the practical implementation of mobile technologies in an operations environment, and highlights the role of technology acceptance in the project management process. Originality/value – This paper fulfils an important role in helping to validate the TAM developed by other researchers

Aphid Resistance in Medicago truncatula Involves Antixenosis and Phloem-Specific, Inducible Antibiosis, and Maps to a Single Locus Flanked by NBS-LRR Resistance Gene Analogs

Aphids and related insects feed from a single cell type in plants: the phloem sieve element. Genetic resistance to Acyrthosiphon kondoi Shinji (bluegreen aphid or blue alfalfa aphid) has been identified in Medicago truncatula Gaert. (barrel medic) and backcrossed into susceptible cultivars. The status of M. truncatula as a model legume allows an in-depth study of defense against this aphid at physiological, biochemical, and molecular levels. In this study, two closely related resistant and susceptible genotypes were used to characterize the aphid-resistance phenotype. Resistance conditions antixenosis since migratory aphids were deterred from settling on resistant plants within 6 h of release, preferring to settle on susceptible plants. Analysis of feeding behavior revealed the trait affects A. kondoi at the level of the phloem sieve element. Aphid reproduction on excised shoots demonstrated that resistance requires an intact plant. Antibiosis against A. kondoi is enhanced by prior infestation, indicating induction of this phloem-specific defense. Resistance segregates as a single dominant gene, AKR (Acyrthosiphon kondoi resistance), in two mapping populations, which have been used to map the locus to a region flanked by resistance gene analogs predicted to encode the CC-NBS-LRR subfamily of resistance proteins. This work provides the basis for future molecular analysis of defense against phloem parasitism in a plant model system

Rethinking North–South Research Partnerships Amidst Global Uncertainties: Leveraging Lessons Learned from UK GCRF Projects during COVID-19

International research and development projects (or grand challenge projects) consist of multicultural, multi-country, multi-sectoral, and multi-stakeholder initiatives aimed at poverty reduction. They are usually conceived as partnerships between actors in the global north–south. The COVID-19 pandemic was a major unexpected disruption to ongoing projects and challenged their already complex management. The aim of this paper is to present evidence on how international development projects were impacted by COVID-19 with a particular focus on the relationship between research institutions in the north and south. We conducted a mixed-methods research study, combining a reflective exercise with the co-author team and a survey with principal investigators, project managers, and capacity development leads drawn from 31 Global Challenges Research Fund (GCRF) projects funded through the UK government’s Official Development Assistance (ODA) and focused on social–ecological system research. The survey contained closed- and open-ended questions in order to (i) demonstrate how those involved in managing projects adapted to risks, including both threats and opportunities, presented by the COVID-19 pandemic, and (ii) consider the implications for tailoring adaptive management approaches in international research projects amidst uncertainties, with a special focus on enhancing equities in global north–south partnerships. The paper offers the following recommendations on designing, planning, and implementing international research and development projects: (i) devolve project management in order to enhance project resilience and improve north–south equities; (ii) allocate dedicated resources to enable equitable north–south research partnerships; (iii) rely more on hybrid and agile approaches for managing a project’s life cycle; and (iv) improve resource flexibility, transparency, and communication through enhanced funder–implementer collaboration

Simultaneous monitoring of three key neuronal functions in primary neuronal cultures

The coupling of Ca2+ influx to synaptic vesicle (SV) recycling in nerve terminals is essential for neurotransmitter release and thus neuronal communication. Both of these parameters have been monitored using fluorescent reporter dyes such as fura-2 and FM1-43 in single central nerve terminals. However, their simultaneous monitoring has been hampered by the proximity of their fluorescence spectra, resulting in significant contamination of their signals by bleedthrough. We have developed an assay that simultaneously monitors both SV recycling and changes in intracellular free Ca2+ ([Ca2+]i) in cultured neurons using the reporter dyes FM4-64 and fura-2AM. By monitoring both fura-2 and FM4-64 emission in the far red range, we were able to visualize functionally independent readouts of both SV recycling and [Ca2+]i independent of fluorescence bleedthrough. We were also able to incorporate an assay of cell viability without any fluorescence bleedthrough from either fura-2 or FM4-64 signals, using the dye SYTOX Green. We propose that this assay of three key neuronal functions could be simply translated into a high content screening format for studies investigating small molecule inhibitors of these processes