Delivery Methods Research Articles

Effect of Lubricated Liquid Carbon Dioxide (LCO2 + MQL) on Grinding of AISI 4140 Steel

This paper investigates the potential of utilizing lubricated liquid carbon dioxide (LCO2 + MQL) as an alternative to conventional flood cooling in grinding operations. This approach could facilitate a transition towards fossil-free production, which is a significant challenge in industry. The alternative cooling–lubrication method relies on pre-mixed LCO2 and oil and a single-channel minimum quantity lubrication (MQL) delivery method, which has already demonstrated potential in machining with geometrically defined cutting edges. However, this method has been less explored in grinding. This study primarily evaluates the grindability of AISI 4140 steel, examining surface roughness, residual stresses, microhardness, grinding forces, and specific energy for different cooling–lubrication methods. The results indicate that LCO2 + MQL is capable of attaining surface roughness and microhardness that is comparable to that of conventional flood cooling, especially in the case of less aggressive, finish grinding. Nevertheless, the presence of higher tensile residual stresses in rough grinding suggests that the cooling capability may be insufficient. While the primary objective was to evaluate the technological viability of LCO2 + MQL in terms of grindability, a supplementary cost-effectiveness analysis (CEA) was also conducted to assess the economic feasibility of LCO2 + MQL in comparison to conventional flood cooling. The CEA showed that the costs of both the cooling–lubrication methods are very similar. In conclusion, this study offers insights into the technological and economic viability of LCO2 + MQL as a sustainable cooling–lubrication method for industrial grinding processes.

Drone Integration in Last-Mile Delivery Operations

Purpose: This research examines the integration of drone technology into last-mile delivery operations, focusing on its impact on supply chain efficiency, cost reduction, and sustainability. The study explores operational challenges, such as air traffic management, payload limitations, regulatory compliance, and public perception, providing a comprehensive understanding of how drones can reshape last-mile logistics. Methodology: The study employs a multi-faceted approach, combining historical analysis, in-depth case studies, and scenario planning to assess the impact of drone technology on last-mile delivery efficiency, cost optimization, and accessibility. Data is gathered from industry reports, interviews with logistics professionals, and regulatory documents. Thematic analysis is conducted to identify critical patterns, while scenario-based modeling offers insight into the potential outcomes of various integration strategies. A comparative evaluation of existing last-mile delivery methods against drone-based delivery models is also provided. Findings: The research reveals that drone technology offers significant potential for enhancing last-mile delivery efficiency, particularly in urban areas and remote locations, aligning with findings from studies like those by Murray & Chu (2015). However, the study identifies considerable obstacles, including regulatory challenges, limited payload capacities, and public acceptance issues. Solutions such as airspace regulation frameworks, collaborative logistics networks, and advanced battery technologies are highlighted as critical enablers for successful drone integration. Contribution to Theory, Policy and Practice: This study contributes to the growing body of knowledge on drone technology's role in logistics by providing a comprehensive framework for businesses and policymakers to navigate the complexities of drone integration. It recommends actionable steps for integrating drones into last-mile delivery, bridging the gap between theoretical innovation and practical application. It provides policy recommendations for regulatory bodies to develop airspace management systems that support drone operations. For practitioners, the research offers a strategic guide to overcoming operational challenges, facilitating the adoption of drones as a sustainable solution for last-mile delivery.

Prospects for Long-Distance Cascaded Liquid—Gaseous Hydrogen Delivery: An Economic and Environmental Assessment

As an important energy source to achieve carbon neutrality, green hydrogen has always faced the problems of high use cost and unsatisfactory environmental benefits due to its remote production areas. Therefore, a liquid-gaseous cascade green hydrogen delivery scheme is proposed in this article. In this scheme, green hydrogen is liquefied into high-density and low-pressure liquid hydrogen to enable the transport of large quantities of green hydrogen over long distances. After long-distance transport, the liquid hydrogen is stored and then gasified at transfer stations and converted into high-pressure hydrogen for distribution to the nearby hydrogen facilities in cities. In addition, this study conducted a detailed model evaluation of the scheme around the actual case of hydrogen energy demand in Chengdu City in China and compared it with conventional hydrogen delivery methods. The results show that the unit hydrogen cost of the liquid-gaseous cascade green hydrogen delivery scheme is only 51.58 CNY/kgH2, and the dynamic payback periods of long- and short-distance transportation stages are 13.61 years and 7.02 years, respectively. In terms of carbon emissions, this scheme only generates indirect carbon emissions of 2.98 kgCO2/kgH2 without using utility electricity. In sum, both the economic and carbon emission analyses demonstrate the advantages of the liquid-gaseous cascade green hydrogen delivery scheme. With further reductions in electricity prices and liquefication costs, this scheme has the potential to provide an economically/environmentally superior solution for future large-scale green hydrogen applications.

MRNA vaccines: A powerful tool in cancer treatment

As an emerging immunotherapy, cancer vaccine is a method of introducing tumor antigens, genes encoding tumor antigens, immune cells and molecules into the body to activate specific immune responses to kill tumors. In April 2010, the world's first related drug, previz, was approved for marketing in United States. The drug extracts peripheral blood mononuclear cells from patients' autoimmune cells, activates them in vitro and then infuses them back into the treatment of asymptomatic or mildly symptomatic hormone-refractory advanced prostate cancer. mRNA vaccines have attracted much attention because of their high efficacy, specificity, versatility, ability to develop rapidly on a large-scale, low-cost production potential and safety. The mRNA vaccines and nano-agent delivery technology are considered to have great potential in cancer immunotherapy. In recent years, developments in the design and delivery methods of mRNA vaccines have accelerated the development and use of mRNA vaccinations against cancer in clinical settings. This review introduces optimization strategies of mRNA vaccinations against cancer, including coding and non-coding region optimization, and emphasizes mRNA vaccine delivery systems. Multiple nanoparticle vectors have currently been developed to improve mRNA stability and administration efficiency. At the same time, we discuss the applications of cancer therapy with mRNA vaccinations, its limitations and future challenges.

Evaluation of transplant drench and foliar insecticide applications for wireworm (Coleoptera: Elateridae) management in sweetpotato.

The revocation of chlorpyrifos tolerances in 2022 left sweetpotato growers without their most important tool to combat a complex of soil-borne root pests that includes wireworms (Coleoptera: Elateridae). Since then, growers have reported increased root damage despite a rapid pivot to pyrethroid-based management systems to replace mechanically incorporated preplant chlorpyrifos broadcast sprays. Our goal was to evaluate the efficacy of alternative insecticide chemistries and application methods to expand the portfolio of management options for wireworms, specifically Conoderus spp. and Melanotus communis (Gyllenhal). We tested (i) insecticidal transplant water drenches and (ii) a foliar spray program targeting adult elaterids. We found that incorporating insecticides into transplant water reduced wireworm damage when compared to untreated transplant water. Our treatments included a recently registered meta-diamide, broflanilide, which represents a promising path to diversify active ingredients and shift away from an overreliance on preplant and post-directed pyrethroid soil sprays. Foliar spray plots had less damage than plots that did not receive foliar sprays. One benefit of adult-focused management is the availability of effective monitoring tools such as sex pheromones and blacklight trapping. Developing a robust adult monitoring program would enable more precise applications of foliar insecticides versus season-long prophylactic soil sprays targeting larvae. Our results demonstrated a significant benefit to both alternative delivery methods. These management alternatives could expand treatment options beyond traditional preplant and post-directed pyrethroid sprays.

Exploring Innovations in Transdermal Drug Delivery: Microneedle Technologies and the Latest in Patent Developments

Introduction/Objective: Microneedle technology has emerged as a promising approach for drug delivery, offering advantages such as improved patient compliance and enhanced therapeutic efficacy. This review aims to provide a comprehensive overview of recent advancements in microneedle- based drug delivery systems, emphasizing their potential to overcome limitations associated with traditional transdermal drug delivery methods. The objective is to synthesize existing knowledge, identify key trends, and highlight potential applications of microneedle technology in various medical fields. Methods: A systematic approach was employed to select and analyse relevant studies on microneedle technology. Databases were searched for peer-reviewed articles published and patents or patent applications worldwide within the last decade, focusing on innovations in microneedle materials, design, fabrication techniques, and applications. Studies were evaluated based on their methodology, outcomes, and relevance to current trends in drug delivery. Key data were extracted and synthesized to provide an integrated perspective on the state of microneedle technology. Results: The review highlights significant progress in microneedle technology; innovations in materials, fabrication techniques, and applications. Advancements include biodegradable microneedles, vaccine drug delivery systems, and integration with biosensors. Innovations led to improved drug bioavailability and reduced side effects. Challenges such as scalability, standardization, and regulatory considerations were also identified. Conclusion: In conclusion, microneedle technology has evolved significantly, offering a versatile platform for controlled drug delivery and various medical applications. The diversity in design and fabrication methods allows customization for specific therapeutic or diagnostic needs, with numerous patents filed for microneedle innovations, reflecting the intense research and development in this field.

Delivery Aspects for Implementing siRNA Therapeutics for Blood Diseases.

Hematological disorders result in significant health consequences, and traditional therapies frequently entail adverse reactions without addressing the root cause. A potential solution for hematological disorders characterized by gain-of-function mutations lies in the emergence of small interfering RNA (siRNA) molecules as a therapeutic option. siRNAs are a class of RNA molecules composed of double-stranded RNAs that can degrade specific mRNAs, thereby inhibiting the synthesis of underlying disease proteins. Therapeutic interventions utilizing siRNA can be tailored to selectively target genes implicated in diverse hematological disorders, including sickle cell anemia, β-thalassemia, and malignancies such as lymphoma, myeloma, and leukemia. The development of efficient siRNA silencers necessitates meticulous contemplation of variables such as the RNA backbone, stability, and specificity. Transportation of siRNA to specific cells poses a significant hurdle, prompting investigations of diverse delivery approaches, including chemically modified forms of siRNA and nanoparticle formulations with various biocompatible carriers. This review delves into the crucial role of siRNA technology in targeting and treating hematological malignancies and disorders. It sheds light on the latest research, development, and clinical trials, detailing how various pharmaceutical approaches leverage siRNA against blood disorders, mainly concentrating on cancers. It outlines the preferred molecular targets and physiological barriers to delivery while emphasizing the growing potential of various therapeutic delivery methods. The need for further research is articulated in the context of overcoming the shortcomings of siRNA in order to enrich discussions around siRNA's role in managing blood disorders and aiding the scientific community in advancing more targeted and effective treatments.

Advances in glial cell line-derived neurotrophic factor

Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor with significant research value due to its profound effects on dopaminergic, cholinergic, and motor neurons. Initially identified for its neuroprotective role in dopaminergic neurons, GDNF has been found to support various neuronal populations and plays a crucial role in neural development, maintenance, and repair. This review provides a comprehensive overview of the molecular characteristics, tissue distribution, physiological function of GDNF and its protective effect on a series of diseases, emphasizing its potential therapeutic applications. Meanwhile, this study discusses the challenges in delivering GDNF across the blood-brain barrier and explores current strategies to enhance its clinical efficacy, including the use of gene therapy and innovative delivery methods. In summary, the review underscores the promise of GDNF as a therapeutic agent for neurodegenerative diseases and nerve injuries, highlighting the need for further research to translate these findings into clinical practice.

The Role of Language in Remote Healthcare Triage: AMeta-Aggregative Review.

To provide an overview of evidence on the role of language in remote healthcare services prioritisation, from now on termed triage. This study synthesises literature, to better understand how language affects triage interactions, aiming to improve these processes. We conducted a meta-aggregative review. A systematic search in Scopus from inception to September 2023 identified 437 studies on language in remote healthcare triage, of which 23 were included. Information was selected using both inductive and deductive coding, focusing on six linguistic features of interaction that have been described in the literature on studies using conversation analysis: turn-taking organisation, overall structure, sequence organisation, turn design, lexical choice, and epistemological and other forms of asymmetry. The process followed the RAMESES Publication Standards for Meta-narrative Reviews. Two main findings emerged. First, all six linguistic features are present in triage conversations, indicating that language involves more than just what is said. It also matters, for example, how and when a question is asked. Second, computerised decision support systems (CDSS) significantly affect conversation flow and dynamics. Language in triage involves more than literal speech and is heavily influenced by CDSS. Our study suggests that quality assessments of triage conversations should consider not only what is said but cover all relevant aspects of language. The influence of computerised decision support systems (CDSS) on linguistic features highlights the need for systems to be adaptable, to improve conversation quality and better addressing caller needs rather than focusing on one-size-fits-all questions. This review highlights the complex role of language in triage conversations and its impact on interaction. It calls for a broader view of language in quality assessments, recognising that both call-takers and callers contribute to call quality. Insights from this review can help developers enhance question types, sequence, and delivery methods of computerised decision support systems. Finally, education for call-takers in healthcare sectors may be improved based on our findings. No patient or public contribution.

Tunable, self-contained gene dosage control via proteolytic cleavage of CRISPR-Cas systems.

Gene therapy holds great therapeutic potential. Yet, controlling cargo expression in single cells is limited due to the variability of delivery methods. We implement an incoherent feedforward loop based on proteolytic cleavage of CRISPR-Cas activation or inhibition systems to reduce gene expression variability against the variability of vector delivery. We demonstrate dosage control for activation and inhibition, post-delivery tuning, and RNA-based delivery, for a genome-integrated marker. We then target the RAI1 gene, the haploinsufficiency and triplosensitivity of which cause two autism-related syndromes, Smith-Magenis-Syndrome (SMS) and Potocki-Lupski-Syndrome, respectively. We demonstrate dosage control for RAI1 activation in HEK293s, Neuro-2As, and mouse cortical neurons via AAVs and lentiviruses. Finally, we activate the intact RAI1 copy in SMS patient-derived cells to an estimated two-copy healthy range, avoiding the harmful three-copy regime. Our circuit paves the way for viable therapy in dosage-sensitive disorders, creating precise and tunable gene regulation systems for basic and translational research.

Impact of the method of delivery and feeding practice on the gut microbiome of infants in the postnatal period

BACKGROUND: The increasing frequency of cesarean sections and artificial feeding creates a predisposition to allergic diseases, obesity, and diabetes mellitus. Pathogenesis of these involves changes in the gut microbiome of infants. AIM: The aim of this study was to evaluate the impact of the method of delivery and feeding practice on the gut microbiome of infants. MATERIALS AND METHODS: This study included 103 infants aged 4-6 weeks (group 1: 39 infants born vaginally and breastfed; group 2: 10 infants born vaginally and formula-fed; group 3: 31 infants born by caesarean section and breastfed; group 4: 23 infants born by caesarean section and formula-fed), each of whom had stool collected for 16S ribosomal RNA gene sequencing. RESULTS: We found differences in the relative abundance of Akkermansia spp. [34.07 (29.29–38.85)% in group 4 and 0.01 (0.01–0.02)% in group 1; p = 0.011], Bifidobacterium spp. [30.68 (21.65–39.41)% in group 1 and 17.08 (9.86–21.68)% in group 4, (p = 0.002); 31.46 (24,30–52.97)% in group 3 and 17.08 (9.86–21.68)% in group 4 (p = 0.001)], and Enterococcus spp. [4.69 (1.01–8.59)% in group 3 and 0.58 (0.12–1.87)% in group 1 (p = 0.003); 4.29 (2.07–6.96)% in group 4 and 0.58 (0.12–1.87)% in group 1 (p = 0.001)]. The coefficient of correlation adaptometry was maximum for groups of infants who were breastfed. Analysis of the morbidity of infants in the first year of life revealed differences in the incidence of acute respiratory viral infections between infants in groups 1 and 4 (17.9 and 78.3%, respectively; p = 0.0064), as well as groups 3 and 4 (32.2 and 78.3%, respectively; p = 0.018). CONCLUSIONS: The relative abundance of Bifidobacterium spp. depends on feeding practice to a greater extent than on the method of delivery. The method of delivery affects the relative abundance of opportunistic bacteria such as Enterococcus spp. Correlation analysis demonstrated the role of breastfeeding as a mechanism for “learning” and maturing the immune system of children.

Age-Related Macular Degeneration (AMD): Pathophysiology, Drug Targeting Approaches, and Recent Developments in Nanotherapeutics

The most prevalent reason for vision impairment in aging inhabitants is age-related macular degeneration (AMD), a posterior ocular disease with a poor understanding of the anatomic, genetic, and pathophysiological progression of the disease. Recently, new insights exploring the role of atrophic changes in the retinal pigment epithelium, extracellular drusen deposits, lysosomal lipofuscin, and various genes have been investigated in the progression of AMD. Hence, this review explores the incidence and risk factors for AMD, such as oxidative stress, inflammation, the complement system, and the involvement of bioactive lipids and their role in angiogenesis. In addition to intravitreal anti-vascular endothelial growth factor (VEGF) therapy and other therapeutic interventions such as oral kinase inhibitors, photodynamic, gene, and antioxidant therapy, as well as their benefits and drawbacks as AMD treatment options, strategic drug delivery methods, including drug delivery routes with a focus on intravitreal pharmacokinetics, are investigated. Further, the recent advancements in nanoformulations such as polymeric and lipid nanocarriers, liposomes, etc., intended for ocular drug delivery with pros and cons are too summarized. Therefore, the purpose of this review is to give new researchers an understanding of AMD pathophysiology, with an emphasis on angiogenesis, inflammation, the function of bioactive lipids, and therapy options. Additionally, drug delivery options that focus on the development of drug delivery system(s) via several routes of delivery can aid in the advancement of therapeutic choices.

Synthesis and Characterization of Acacia-Stabilized Doxorubicin-Loaded Gold Nanoparticles for Breast Cancer Therapy.

The targeted delivery of drugs is vital in breast cancer treatment due to its ability to produce long-lasting therapeutic effects with minimal side effects. This study reports the successful development of doxorubicin hydrochloride (DOX)-loaded colloidal gold nanoparticles stabilized with acacia gum (AG). Optimization studies varied AG concentrations (0.25% to 3% w/v) to determine optimal conditions for nanoparticle synthesis. The resulting acacia stabilized gold nanoparticles (AGNPs) were characterized using various techniques including high-resolution transmission electron microscopy (HR-TEM), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), ultraviolet-visible spectroscopy, Fourier-transform infrared spectroscopy (FT-IR), field emission scanning electron microscopy (FE-SEM), and selected area electron diffraction (SAED). In vitro drug release studies demonstrated a higher release rate of DOX in sodium acetate buffer (pH 5.0) compared to phosphate buffer saline (pH 7.4), suggesting an enhanced therapeutic efficacy in acidic tumor environments. Cytotoxicity of DOX-AGNPs and free DOX was assessed in human breast cancer cells (MDA-MB-231). The DOX-AGNPs exhibited significantly greater cytotoxicity, indicating enhanced efficacy in targeting cancer cells. This enhancement suggests that adsorbing DOX on the surface of gold nanoparticles can improve drug delivery and effectiveness, potentially reducing side effects compared to pure DOX and traditional delivery methods. Stability tests conducted over six months at 25±1°C showed significant changes in particle size and PDI, suggesting limited stability under these conditions. Overall, the acacia-stabilized gold nanoparticles synthesized in this study exhibit promising characteristics for drug delivery applications, particularly in cancer therapy, with effective drug loading, controlled release, and favorable physicochemical properties.

Analysis of in-store crowdshipping in a stochastic dynamic pickup-and-delivery system

AbstractTo meet the increasing demands of home delivery resulting from the proliferation of internet shopping and compounded by the rising expectation of fast fulfillment (often within hours of request), companies seek new delivery methods supported by information and communication technologies. In this study, we consider a dispatching platform with delivery capacity consisting of a dedicated fleet of vehicles complemented by crowdsourced couriers. We consider the crowdsourced couriers to be in-store customers who, upon checking out of the store, declare themselves available to deliver one or more requests from e-shoppers. The role of the collaborative platform is to aggregate e-shopper orders from the participating businesses and then manage the routing for the pickup of the corresponding products at the physical stores and the subsequent deliveries to the e-shoppers’ locations. We model this dynamic stochastic pickup-and-delivery problem as a Markov decision process to represent the uncertainty in the e-shopper requests and in-store crowdshipper appearances. We adapt a real-time insertion method enhanced with a cost function approximation to account for differences in the temporal availability of the dedicated vehicles and in-store crowdshippers. We conduct computational experiments to demonstrate the conditions under which in-store crowdshippers provide a cost benefit.

Revolutionizing Cardiac Care: The Role of Gene Therapy in Treating Cardiomyopathy

Gene therapy presents a method for addressing types of cardiomyopathies that play a substantial role in heart failure. This innovative approach, leveraging technologies such as clustered regularly interspaced short palindromic repeats/Cas9 for modifying genomes, holds promise for lasting treatments or potential cures that go beyond therapies. It is essential to grasp the workings of gene therapy, including gene silencing, clustered regularly interspaced short palindromic repeats genome editing, and enhancing sarcomere function to effectively apply it to treating cardiomyopathy. Examining current trials will shed light on the advancements and accomplishments in this field while also addressing the obstacles, uncertainties, and opportunities ahead. Delving into the possibilities of gene therapy involves exploring targets and inventive delivery methods that underscore the evolving landscape of research in this domain hinting at a future brimming with opportunities to transform care. The progress made in using gene therapy to treat cardiomyopathies represents the progress of medicine in driving forward scientific innovation to provide more precise and enduring solutions for patients. Continuously refining gene therapy techniques and deepening our knowledge of genetics are factors that will shape the future direction of cardiac care. The potential of gene therapy does not just benefit individuals with cardiomyopathy but also represents a move toward effective treatments for various genetic conditions. This signifies a step in the pursuit of holistic healthcare solutions.

Provision of digital health interventions for young people with ADHD in primary care: findings from a survey and scoping review

BackgroundPeople with attention-deficit hyperactivity disorder (ADHD) are at risk of negative health outcomes, with risks reduced through evidence-based treatments. Therefore, ensuring continued access to treatment for young people with ADHD, especially as they transition from child to adult services, is a priority. Currently many young people with ADHD are unable to access adequate care, with negative consequences for patients and their communities. Preliminary evidence suggests digital health interventions (DHIs) may act as an effective adjunct to usual care, helping overcome barriers to access, and improving outcomes by increasing understanding of ADHD as a long-term condition. The aim of this mixed methods study is to explore the healthcare information preferences of people with lived experience of ADHD in the primary care context and considers these in the light of the emerging body of literature on DHIs for ADHD. To explore this, a descriptive summary of cross-sectional survey responses was compared and discussed in the context of DHIs identified in a scoping review.ResultsDigital apps, followed by support groups, were deemed the most useful information resource types by survey respondents, but were the least currently used/provided. Over 40% participants indicated a preference for signposting to all resource types by their general practitioner (GP), suggesting that GPs are credible sources for ADHD healthcare information. The scoping review identified nine studies of DHI for ADHD, consisting of games, symptom monitoring, psychoeducation, and medication reminders, with limited evidence of effectiveness/implementation.ConclusionsPeople with ADHD state a preference for digital apps as an adjunct to usual care. However, these are currently the least provided information resource in primary care, indicating a key area for future development. The limited evidence base on DHIs for ADHD suggests combining digital apps and support networks, and utilising multimodal delivery methods may also enhance the delivery of healthcare information.

Recent Insights and Clinical Status on Novel Mefenamic Acid Nanocarriers for the Treatment of Rheumatoid Arthritis

Abstract: Joint structure and performance can be compromised by the systemic inflammatory disorder rheumatoid arthritis, which destroys articular cartilage and erodes periarticular bone. However, due to their systemic processes, short half-lives, and poor bioavailability, the anti-inflammatory medicines and biological agents now utilized for the treatment of rheumatoid arthritis (RA) are unable to preferentially target inflamed joints. Anti-inflammatory medicines have made use of nanoparticle-mediated drug delivery methods. The role that inflammation plays in the genesis of disease has had far-reaching repercussions, including its ability to influence the development of disorders as diverse as inflammatory bowel disorder, RA, and osteoarthritis. In the treatment of RA, nanomaterials have the potential to both increase the absorption of the medication and selectively target the damaged joint tissue. Designer nanoparticles now have the ability to engage more thoroughly with their biological targets and a wider variety of diseases. These nanoparticles have a comparable size range and surface properties that can be modified. In this review, we have discussed the progress that has been made and the hurdles that remain in the use of nanomaterials in the treatment of RA, specifically in relation to mefenamic acid.

CRISPR-Cas9 guided RNA-based model for the silencing of spinal bulbar muscular atrophy: A functional genetic disorder.

This study explores a novel therapeutic approach for spinal bulbar muscular atrophy (SBMA), a neurodegenerative disorder caused by a mutation in the Androgen Receptor (AR) gene. The aim is to investigate the potential of CRISPR-Cas9 technology in targeting the mutant AR gene to inhibit its production. The objectives include assessing the accuracy and efficacy of CRISPR-Cas9 guided RNAs in silencing the mutant gene and evaluating the feasibility of this approach as a treatment for SBMA. Computational and in-silico approaches are used to evaluate the feasibility of using CRISPR-Cas9 technology for treating SBMA. Computational analysis is used to design CRISPR-Cas9 guided RNAs targeting the mutant AR gene, assessing their on-target and off-target scores, GC content, and structural accuracy. In-silico simulations predict the potential therapeutic outcomes of the CRISPR-Cas9 approach in an artificial environment. Three guided RNA (gRNA) sequences were designed using the CHOPCHOP tool, targeting specific regions of the AR gene with high efficiency and 100% match. These gRNAs demonstrated effective targeting with minimal off-target scores and optimal GC content. Additionally, lentiCRISPR v2 plasmids were designed for the delivery of CRISPR materials, enabling high-efficiency multiplex genome editing of the AR gene. Thermodynamic ensemble predictions indicated favorable secondary structure stability of the designed gRNAs, further supporting their suitability for gene editing. The evaluation of designed gRNAs confirmed their strong binding ability to the target sequences, validating their potential as effective tools for genome editing. The study highlights the potential of CRISPR-Cas9 technology for targeting the Androgen Receptor gene associated with spinal bulbar muscular atrophy (SBMA). The findings support the feasibility of this approach for gene editing and suggest further exploration in preclinical and clinical settings. Recommendations include continued research to optimize CRISPR-Cas9 delivery methods and enhance specificity for therapeutic applications in SBMA.

Tumour reoxygenation after intratumoural hydrogen peroxide (KORTUC) injection: a novel approach to enhance radiosensitivity

BackgroundKORTUC (0.5% hydrogen peroxide (H2O2) in 1% sodium-hyaluronate) releases cytotoxic levels of H2O2 in tissues after intratumoural injection. High levels of tumour control after radiotherapy plus KORTUC are reported in breast cancer patients. Here, we use human xenograft models to test the hypothesis that oxygen microbubbles released post-KORTUC are effective in modifying the hypoxic tumour microenvironment.Methods and materialsPimonidazole and Image-iT™ Red (live hypoxia marker) were utilised to assess dose-dependent changes in hypoxia post-H2O2 in HCT116 and LICR-LON-HN5 spheroids. Using a dual 2-nitroimidazole-marker technique and phospho-ATM we evaluated changes in hypoxia and reactive oxygen species (ROS) respectively, in HCT116 and LICR-LON-HN5 xenografts following intratumoural KORTUC.ResultsA significant reduction in Image-iT™ Red fluorescence was observed in spheroids 1 h post-H2O2 at ≥1.2 mM, maintained at 24 h. Ultrasound demonstrated sustained release of oxygen microbubbles within tumours, 1 h post-KORTUC. Hypoxia markers demonstrated significant tissue reoxygenation in both models post-KORTUC and significantly increased phospho-ATM foci reflecting increased ROS production.ConclusionIntratumoural KORTUC represents a novel oxygen delivery method, which can be exploited to enhance radiation response. If efficacy is confirmed in the ongoing phase 2 breast trial it could improve treatment of several tumour types where hypoxia is known to affect radiotherapy outcomes.

Exploring the Differences in Types of Commodities and Delivery Methods among Online Shoppers during the Early Stage of the COVID-19 Pandemic

During the early phases of the COVID-19 pandemic, the temporary limitations to in-store shopping during the lockdown period generated a significant increase in online shopping. During that period, the total spending amount and the number of online purchases increased across the whole population, although with rather heterogeneous patterns among various groups of consumers. This research examines the factors that can help explain the differences between users and non-users of online shopping in the U.S.A. during April and May 2020 to help understand the barriers to home-based shopping accessibility. The study uses data collected in the first survey wave of a longitudinal mobility study to analyze individual commodities and delivery options chosen for goods purchased online. Binomial logistic regression and Poisson regression models reveal differences in adopting e-shopping across various delivery channels, the frequency of purchase, and shipping used across commodities. In addition, a latent class cluster analysis identifies three heterogeneous groups of shoppers whose members differ mainly in income, age, education, neighborhood type, and technology attitudes. The results also highlight several differences in usage across crowdshipping markets and novel delivery options, such as in-store or locker pickup. The results also show variation in home-based accessibility across numerous factors during the pandemic.