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Targeting the CBM complex causes Treg cells to prime tumours for immune checkpoint therapy.
Solid tumours are infiltrated by effector T cells with the potential to control or reject them, as well as by regulatory T (Treg) cells that restrict the function of effector T cells and thereby promote tumour growth1. The anti-tumour activity of effector T cells can be therapeutically unleashed, and is now being exploited for the treatment of some forms of human cancer. However, weak tumour-associated inflammatory responses and the immune-suppressive function of Treg cells remain major hurdles to broader effectiveness of tumour immunotherapy2. Here we show that, after disruption of the CARMA1-BCL10-MALT1 (CBM) signalosome complex, most tumour-infiltrating Treg cells produce IFNγ, resulting in stunted tumour growth. Notably, genetic deletion of both or even just one allele of CARMA1 (also known as Card11) in only a fraction of Treg cells-which avoided systemic autoimmunity-was sufficient to produce this anti-tumour effect, showing that it is not the mere loss of suppressive function but the gain of effector activity by Treg cells that initiates tumour control. The production of IFNγ by Treg cells was accompanied by activation of macrophages and upregulation of class I molecules of the major histocompatibility complex on tumour cells. However, tumour cells also upregulated the expression of PD-L1, which indicates activation of adaptive immune resistance3. Consequently, blockade of PD-1 together with CARMA1 deletion caused rejection of tumours that otherwise do not respond to anti-PD-1 monotherapy. This effect was reproduced by pharmacological inhibition of the CBM protein MALT1. Our results demonstrate that partial disruption of the CBM complex and induction of IFNγ secretion in the preferentially self-reactive Treg cell pool does not cause systemic autoimmunity but is sufficient to prime the tumour environment for successful immune checkpoint therapy
Communicating quality audit indicators for inbound tourism: a qualitative insight from Malaysian travel agencies
Quality assurance is fundamental to all business activities in the tourism sector as it is advantageous to market recognition and competitiveness. Awareness of the importance of quality assurance certifications is already in place in Malaysia however it is still under-researched. Thus, this study aims to investigate how local travel agency operators perceive suitable levels of quality audit indicators for inbound travel agencies. A semi-structured interview was conducted to explore the views and experiences of key industry players from five travel agencies involved in both inbound and outbound tourism businesses in the country. A content analysis of data acknowledged the industry's increased awareness of quality service delivery and the importance of rationalising key quality audit indicators in assuring the lifelong survival of inbound Malaysian travel agencies. Also found was the need for systematic monitoring of the inbound travel agency's certification plan that continually reflects the demands of the clientèle and uplifts national productivity as outlined in the initiatives undertaken by the Tourism Productivity Nexus, an industry-led establishment under the Malaysia Productivity Blueprint 2016-2020. The study finally outlines specific entrepreneurial strategies that will enhance productivity operations at the enterprise level
Genome editing in potato via CRISPR-Cas9 ribonucleoprotein delivery
Clustered regularly interspaced short palindromic repeats and CRISPR-associated protein-9 (CRISPR-Cas9) can be used as an efficient tool for genome editing in potato (Solanum tuberosum). From both a scientific and a regulatory perspective, it is beneficial if integration of DNA in the potato genome is avoided. We have implemented a DNA-free genome editing method, using delivery of CRISPR-Cas9 ribonucleoproteins (RNPs) to potato protoplasts, by targeting the gene encoding a granule bound starch synthase (GBSS, EC 2.4.1.242). The RNP method was directly implemented using previously developed protoplast isolation, transfection and regeneration protocols without further adjustments. Cas9 protein was preassembled with RNA produced either synthetically or by in vitro transcription. RNP with synthetically produced RNA (cr-RNP) induced mutations, i.e. indels, at a frequency of up to 9%, with all mutated lines being transgene-free. A mutagenesis frequency of 25% of all regenerated shoots was found when using RNP with in vitro transcriptionally produced RNA (IVT–RNP). However, more than 80% of the shoots with confirmed mutations had unintended inserts in the cut site, which was in the same range as when using DNA delivery. The inserts originated both from DNA template remnants from the in vitro transcription, and from chromosomal potato DNA. In 2–3% of the regenerated shoots from the RNP-experiments, mutations were induced in all four alleles resulting in a complete knockout of the GBSS enzyme function.Fil: Andersson, Mariette. Swedish University Of Agricultural Sciences; SueciaFil: Turesson, Helle. Swedish University Of Agricultural Sciences; SueciaFil: Olsson, Niklas. Swedish University Of Agricultural Sciences; SueciaFil: Fält, Ann Sofie. Swedish University Of Agricultural Sciences; SueciaFil: Ohlsson, Pia. Swedish University Of Agricultural Sciences; SueciaFil: Gonzalez, Matías Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; Argentina. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Buenos Aires Sur. Estación Experimental Agropecuaria Balcarce; ArgentinaFil: Samuelsson, Mathias. Lyckeby Starch AB; SueciaFil: Hofvander, Per. Swedish University Of Agricultural Sciences; Sueci
Development and characterisation of acoustofluidic devices using detachable electrodes made from PCB.
Acoustofluidics has been increasingly applied in biology, medicine and chemistry due to its versatility in manipulating fluids, cells and nano-/micro-particles. In this paper, we develop a novel and simple technology to fabricate a surface acoustic wave (SAW)-based acoustofluidic device by clamping electrodes made using a printed circuit board (PCB) with a piezoelectric substrate. The PCB-based SAW (PCB-SAW) device is systematically characterised and benchmarked with a SAW device made using the conventional photolithography process with the same specifications. Microparticle manipulations such as streaming in droplets and patterning in microchannels were demonstrated in the PCB-SAW device. In addition, the PCB-SAW device was applied as an acoustic tweezer to pattern lung cancer cells to form three or four traces inside the microchannel in a controllable manner. Cell viability of ∼97% was achieved after acoustic manipulation using the PCB-SAW device, which proved its ability as a suitable tool for acoustophoretic applications.The authors would gratefully acknowledge the financial support from EPSRC (EP/P002803/1, EP/P018998/1), EPSRC IAA, Welcome Trust, Global Challenges Research Fund (GCRF), the Royal Society (IEC\NSFC\170142, IE161019), and the Natural Science Foundation of China (NSFC) (Grant No. 51811530310)
Deepen electronic health record diffusion beyond breadth: game changers and decision drivers
Cloud computing, financial incentive and patient-centered care are the game changers that deepen EHR diffusion beyond breadth. Based on the innovation diffusion theory (IDT), technology-organization-environment (TOE) framework and alignment literature, this study examines how these changes shape business requirement, service value and society need that drive different phases of EHR diffusion in terms of planning, adoption, usage and upgrade. A longitudinal analysis with the USA National Ambulatory Medical Care Survey (NAMCS) reveals the impacts of different drivers on EHR diffusion. In addition to quantitative results, interview observations corroborate the relationships among game changers, decision drivers and EHR diffusion. The findings provide healthcare providers, system vendors and policy-makers the insights on the best practices of promoting EHR diffusion for long-term success
The Role of Information and Communication Technology (ICT) in the 2015 Presidential Election of Nigeria
The use of ICT in elections has been attracting a lot of interests in the country and has been a subject for discussion in various media during the past years after elections. The paper based method of voting during elections in Nigeria comes with a lot of problems such as delay in voting, multiple voting, result manipulations, invalid votes and delay in declaring results. This paper investigated the feasibility of ICT implementation in Nigeria by assessing the role played by ICT in the 2015 elections. It relied on documentary method for the generation of data. Using the diffusion of innovation theory, the research concluded that ICT has reinforced the legitimacy of Nigerians in the democratic process as majority after the elections believed that their votes counted and as such their will could be respected in future elections. Thus, it is recommended that the innovation of ICT shouldn’t only be welcomed but also incorporated into the Nigeria’s electoral system as a lasting solution to electoral fraud. The Electoral Act, 2010 (as amended) should be amended to include the use of the card reader for biometric verification of voters for the purpose of accreditation in future elections. Keywords: E-participation, ICT, Innovation Diffusion Theory (IDT), Nigeria, 2015 Presidential elections
Numerical and experimental investigations of interdigital transducer configurations for efficient droplet streaming and jetting induced by surface acoustic waves
Surface acoustic wave (SAW) based technologies have recently been explored for various sensing and microfluidic applications, and numerous experimental studies and numerical modelling of SAW streaming and liquid-solid interactions have been performed. However, the large deformation of droplet interface actuated by SAWs has not been widely explored, mainly due to the complex physics of SAW-droplet interactions and interfacial phenomena. In this paper, a computational interface tracking method is developed based on the couple level set the volume of fluid (CLSVOF) approach to simulate the interactions between liquid and acoustic waves and deformation of the liquid-air surface. A dynamic contact angle boundary condition is developed and validated by experimental results to simulate the three-phase contact line dynamics. The modified CLSVOF method is then used to study the droplet jetting and internal streaming behaviours by analyzing the energy terms within the liquid medium. Furthermore, by applying the numerical model, effects of configurations and positions of two interdigital transducers (IDTs) on droplet actuation have been investigated to achieve efficient mixing, separation, and jetting. Results show that two perfectly aligned IDTs are optimal for mixing applications. In contrast, two offset IDTs are optimal for concentration and separation applications. The maximum jetting velocity and minimum jetting time are achieved by using a pair of aligned IDTs, whereas by using the two offset IDTs, effective liquid mixing and jetting are observed which can be used in bioprinting applications
Acoustic Microfluidic Separation Techniques and Bioapplications: A Review
Microfluidic separation technology has garnered significant attention over the past decade where particles are being separated at a micro/nanoscale in a rapid, low-cost, and simple manner. Amongst a myriad of separation technologies that have emerged thus far, acoustic microfluidic separation techniques are extremely apt to applications involving biological samples attributed to various advantages, including high controllability, biocompatibility, and non-invasive, label-free features. With that being said, downsides such as low throughput and dependence on external equipment still impede successful commercialization from laboratory-based prototypes. Here, we present a comprehensive review of recent advances in acoustic microfluidic separation techniques, along with exemplary applications. Specifically, an inclusive overview of fundamental theory and background is presented, then two sets of mechanisms underlying acoustic separation, bulk acoustic wave and surface acoustic wave, are introduced and discussed. Upon these summaries, we present a variety of applications based on acoustic separation. The primary focus is given to those associated with biological samples such as blood cells, cancer cells, proteins, bacteria, viruses, and DNA/RNA. Finally, we highlight the benefits and challenges behind burgeoning developments in the field and discuss the future perspectives and an outlook towards robust, integrated, and commercialized devices based on acoustic microfluidic separation
Increasing the Knowledge of Opioid Use Disorder and Medication Assisted Treatment for Advanced Practice Registered Nurses in Georgia
The national opioid crisis has had devastating effects on the United States (US) healthcare system with the financial burden totaling more than $2 trillion from 2015 to 2018 (White House Government, 2020) and the physical burden of 128 overdose-related deaths daily (Centers for Disease Control, 2020). According to the Centers for Disease Control (CDC), some of these deaths result from deficits in education of healthcare providers about pain management treatment (CDC, 2020). Improved education for healthcare providers has resulted in a significant decline in the total number of opioid prescriptions from 2016 to 2019, which suggests that successful containment of the opioid epidemic begins with the prescriber (White House Government, 2020). This paper will describe an online training module’s effectiveness in educating Advanced Practice Registered Nurses (APRNs) about medications used to treat opioid use disorder (OUD)
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