A Computational Approach for Designing Synthetic Riboswitches for Next-Generation RNA Therapeutics.

Riboswitches are naturally occurring regulatory segments of RNA molecules that modulate gene expression in response to specific ligand binding. They serve as a molecular 'switch' that controls the RNA's structure and function, typically influencing the synthesis of proteins. Riboswitches are unique because they directly interact with metabolites without the need for proteins, making them attractive tools in synthetic biology and RNA-based therapeutics. In synthetic biology, riboswitches are harnessed to create biosensors and genetic circuits. Their ability to respond to specific molecular signals allows for the design of precise control mechanisms in genetic engineering. This specificity is particularly useful in therapeutic applications, where riboswitches can be synthetically designed to respond to disease-specific metabolites, thereby enabling targeted drug delivery or gene therapy. Advancements in designing synthetic riboswitches for RNA-based therapeutics hinge on sophisticated computational techniques, which are described in this chapter. The chapter concludes by underscoring the potential of computational strategies in revolutionizing the design and application of synthetic riboswitches, paving the way for advanced RNA-based therapeutic solutions.

Bacterial Living Therapeutics with Engineered Protein Secretion Circuits to Eliminate Breast Cancer Cells.

Cancer therapy can be limited by potential side effects, and bacteria-based living cancer therapeutics have gained scientific interest in recent years. However, the full potential of bacteria as therapeutics has yet to be explored due to engineering challenges. In this study, we present a bacterial device designed to specifically target and eliminate breast cancer cells. We have engineered Escherichia coli (E. coli) to bind to HER2 receptors on breast cancer cells while also secreting a toxin, HlyE, which is a pore-forming protein. The binding of E. coli to HER2 is facilitated by a nanobody expressed on the bacteria's surface via the Ag43 autotransporter protein system. Our findings demonstrate that the nanobody efficiently binds to HER2+ cells in vitro, and we have utilized the YebF secretion tag to secrete HlyE and kill the target cancer cells. Overall, our results highlight the potential of our engineered bacteria as an innovative strategy for breast cancer treatment.

Emerging role of MAPK signaling in glycosphingolipid-associated tumorigenesis.

Glycosphingolipids (GSLs) are a type of amphipathic lipid molecules consisting of hydrophobic ceramide backbone bound to carbohydrate moiety clustered in the cell surface microdomains named 'lipid rafts' and are known to participate in cell-cell communication as well as intra-cellular signaling, thereby facilitating critical normal cellular processes and functions. Over the past several decades, various GSLs have been reported to be aberrantly expressed in different cancers, many of which have been associated with their prognosis. The wide implication of MAPK signaling in controlling tumor growth, progression, and metastasis through activation of an upstream signaling cascade, often originating in the cell membrane, justifies the rationale for its plausible influence on MAPK signaling. This review highlights the role of GSLs and their metabolites in regulating different signaling pathways towards modulation of tumor cell growth, migration, and adhesion by interacting with various receptors [epidermal growth factor receptor (EGFR), and platelet derived growth factor receptor (PDGFR), and other receptor tyrosine kinases (RTKs)] leading to activation of the MAPK pathway. Furthermore, GSLs can influence the activity and localization of downstream signaling components in the MAPK pathway by regulating the activation state of kinases, which in turn, regulate the activity of MAPKs. Additionally, this review further consolidates the GSL-mediated modulation of MAPK pathway components through the regulation of gene expression. Finally, recent findings on GSL-MAPK crosstalk will be explored in this article for the identification of potential anti-cancer therapeutic targets.

Serious Games as a Therapeutic Tool in Pediatric Urology: A Review of Current Applications and Future Directions.

This paper examines the use of serious games that integrate engaging gameplay with educational and therapeutic benefits with a particular focus on their application in urology. The study reviews both domestic and international cases to evaluate the current practices and implications of these digital therapies. While serious games have been widely utilized in the treatment of pediatric cancer and psychiatric disorders-areas that require long-term care and management-their application in urology, in particular pediatric urology, has been limited. Although digital therapies like serious games are still emerging in the field of urology, they hold promise as effective supplements to traditional treatments while offering new options for managing a range of urological conditions. Pediatric conditions such as bedwetting, urinary incontinence, and dysuria, which often benefit from long-term training and habit formation, are particularly well-suited to this approach. By helping pediatric patients better understand and manage their symptoms, serious games can play a supportive role in the treatment process and have shown positive medical outcomes. This paper reviews the definitions and therapeutic effects of serious games, analyzes their current use in the medical field, and argues for their increased application in treating pediatric urinary conditions.

2024 update of the recommendations of the French Society of Rheumatology for the diagnosis and management of patients with rheumatoid arthritis.

The French Society of Rheumatology recommendations for managing rheumatoid arthritis (RA) has been updated by a working group of 21 rheumatology experts, 4 young rheumatologists and 2 patient association representatives on the basis of the 2023 version of the European Alliance of Associations for Rheumatology (EULAR) recommendations and systematic literature reviews. Two additional topics were addressed: people at risk of RA development and RA-related interstitial lung disease (RA-ILD). Four general principles and 19 recommendations were issued. The general principles emphasize the importance of a shared decision between the rheumatologist and patient and the need for comprehensive management, both drug and non-drug, for people with RA or at risk of RA development. In terms of diagnosis, the recommendations stress the importance of clinical arthritis and in its absence, the risk factors for progression to RA. In terms of treatment, the recommendations incorporate recent data on the cardiovascular and neoplastic risk profile of Janus kinase inhibitors. With regard to RA-ILD, the recommendations highlight the importance of clinical screening and the need for high-resolution CT scan in the presence of pulmonary symptoms. RA-ILD management requires collaboration between rheumatologists and pulmonologists. The treatment strategy is based on controlling disease activity with methotrexate or targeted therapies (mainly abatacept or rituximab). The prescription for anti-fibrotic treatment should be discussed with a pulmonologist with expertise in RA-ILD.

Use of technetium-99m-pyrophosphate single-photon emission computed tomography/computed tomography in monitoring therapeutic changes of RNA interference therapeutics in patients with hereditary transthyretin amyloid cardiomyopathy.

BACKGROUND: RNA interference therapeutics reduce transthyretin production; however, their effect on hereditary transthyretin amyloid cardiomyopathy (ATTR-CA) remains unclear. We aimed to investigate alterations in technetium-99 m (99mTc)-pyrophosphate (PYP) single-photon emission computed tomography/computed tomography (SPECT/CT) outcomes in patients receiving patisiran or vutrisiran. METHODS: We retrospectively identified individuals with hereditary ATTR-CA who received patisiran or vutrisiran. First and second 99mTc-PYP SPECT/CT data, including visual grading, planar heart to contralateral lung (H/CL) ratio, and volumetric heart to lung (H/L) ratio were assessed. RESULTS: Eight patients with hereditary ATTR-CA were enrolled. Cohort A included four patients who underwent their first 99mTc-PYP SPECT/CT imaging at the initiation of small interfering RNA (siRNA) treatment, while cohort B comprised four patients who had been receiving siRNA treatment before their first 99mTc-PYP SPECT/CT imaging (median duration 1281 days). Overall, there were numerical reductions in planar H/CL ratio (1.7 ± 0.2 to 1.6 ± 0.1, p = 0.050) and a significant improvement in volumetric H/L ratio (4.0 ± 0.9 to 3.5 ± 0.4, p = 0.035). Although without significance, subgroup analysis showed more pronounced changes in cohort A for both planar H/CL ratio and volumetric H/L ratio (-20.1 ± 12.6% and -17.1 ± 11.4%) compared to cohort B (-3.3 ± 11.2% and -4.3 ± 12.7%). CONCLUSION: Our results demonstrated a significant decrease in volumetric H/L ratio in hereditary ATTR-CA patients receiving RNA interference therapeutics.

Engineering growth factor ligands and receptors for therapeutic innovation.

Growth factors signal through engagement and activation of their respective cell surface receptors to choreograph an array of cellular functions, including proliferation, growth, repair, migration, differentiation, and survival. Because of their vital role in determining cell fate and maintaining homeostasis, dysregulation of growth factor pathways leads to the development and/or progression of disease, particularly in the context of cancer. Exciting advances in protein engineering technologies have enabled innovative strategies to redesign naturally occurring growth factor ligands and receptors as targeted therapeutics. We review growth factor protein engineering efforts, including affinity modulation, molecular fusion, the design of decoy receptors, dual specificity constructs, and vaccines. Collectively, these approaches are catapulting next-generation drugs to treat cancer and a host of other conditions.

Radioactive Iodine Treatment of Graves' Disease: Predictors of Time Interval Greater than 90 Days for Treatment Success.

Objective: Radioactive iodine (RAI) is often used for treating Graves' disease. We study predictors for a time interval greater than 90 days between RAI treatment and success. Methods: This was a retrospective study of 106 patients with Graves' disease seen at a public hospital in suburban New York City. Predictor variables were from demographics, prior treatment history, iodine 131 RAI treatment, and thyroid function prior to RAI treatment. Results: There were 62.3% that had a time interval greater than 90 days between RAI treatment and success. Only the thyroid function prior to RAI treatment variable of free thyroxine (FT4) had statistically significantly increased odds for time interval greater than 90 days between RAI treatment and success (OR:1.28, 95% CI:1.02, 1.61, p = 0.03). Demographics, prior treatment history, and iodine 131 RAI treatment variables were not significantly associated with time interval greater than 90 days between RAI treatment and success. Conclusion: Thyroid function measured by FT4 was significantly associated with time interval greater than 90 days between RAI treatment and success. We suggest that the thyroid function variable of FT4 levels at initial diagnosis is most helpful for understanding the prognosis and success rate for using RAI treatment in patients with Graves' disease.

Claudins: from gatekeepers of epithelial integrity to potential targets in hepato-pancreato-biliary cancers.

Claudins, a family of tetraspan transmembrane proteins, are critical to the integrity of tight junctions in epithelia and endothelia, influencing cellular processes such as development, differentiation, and apoptosis. Abnormal claudin expression is associated with various malignancies, particularly affecting tissue architecture and potentially facilitating tumor invasion and metastasis. In this comprehensive review, we explore the multifaceted functions of claudins: their expression, specific roles in cancer with a focus on hepato-pancreato-biliary malignancies and highlight their potential as therapeutic targets. We discuss current claudin-targeted therapies, including monoclonal antibodies, antibody-drug conjugates, bispecific T-cell engager and chimeric antigen receptor T-cell therapies. These approaches show promise in pre-clinical and clinical studies, particularly in hepato-pancreato-biliary cancers with large unmet needs. Despite these early signs of efficacy, challenges remain in effectively targeting these proteins due to their structural resemblance and overlapping functions.

Alternative splicing dysregulation across tissue and therapeutic approaches in a mouse model of myotonic dystrophy type 1.

Myotonic dystrophy type 1 (DM1), the leading cause of adult-onset muscular dystrophy, is caused by a CTG repeat expansion. Expression of the repeat causes widespread alternative splicing (AS) defects and downstream pathogenesis, including significant skeletal muscle impacts. The HSA LR mouse model plays a significant role in therapeutic development. This mouse model features a transgene composed of approximately 220 interrupted CTG repeats, which results in skeletal muscle pathology that mirrors DM1. To better understand this model and the growing number of therapeutic approaches developed with it, we performed a meta-analysis of publicly available RNA sequencing data for AS changes across three widely examined skeletal muscles: quadriceps, gastrocnemius, and tibialis anterior. Our analysis demonstrated that transgene expression correlated with the extent of splicing dysregulation across these muscles from gastrocnemius (highest), quadriceps (medium), to tibialis anterior (lowest). We identified 95 splicing events consistently dysregulated across all examined datasets. Comparison of splicing rescue across seven therapeutic approaches showed a range of rescue across the 95 splicing events from the three muscle groups. This analysis contributes to our understanding of the HSA LR model and the growing number of therapeutic approaches currently in preclinical development for DM1.

The gut microbiota: emerging biomarkers and potential treatments for infertility-related diseases.

Infertility is a disease of impaired fertility. With socioeconomic development, changes in human lifestyles, and increased environmental pollution, the problem of low human fertility has become increasingly prominent. The incidence of global infertility is increasing every year. Many factors lead to infertility, and common female factors include tubal factors, ovulation disorders, endometriosis, and immune factors. The gut microbiota is involved in many physiological processes, such as nutrient absorption, intestinal mucosal growth, glycolipid metabolism, and immune system regulation. An altered gut flora is associated with female infertility disorders such as polycystic ovary syndrome (PCOS), endometriosis (EMs), and premature ovarian failure (POF). Dysbiosis of the gut microbiota directly or indirectly contributes to the development of female infertility disorders, which also affect the homeostasis of the gut microbiota. Identifying the etiology and pathogenesis of infertility in patients is the focus of reproductive medicine physicians. We studied the developmental mechanism between the gut microbiota and PCOS, EMs, and POF from a new perspective, providing new ideas for diagnosing and treating female infertility diseases and specific reference values for eugenics.

Skin-permeable gold nanoparticles with modifications azelamide monoethanolamine ameliorate inflammatory skin diseases.

BACKGROUND: Traditional topical drug delivery for treating inflammatory skin diseases suffers from poor skin penetration and long-term side effects. Metal nanoparticles show promising application in topical drug delivery for inflammatory skin diseases. METHODS: Here, we synthesized a new type of nanoparticles, azelamide monoethanolamine-functionalized gold nanoparticles (Au-MEA NPs), based on citrate-capped gold nanoparticles (Au-CA NPs) via the ligand exchange method. The physical and chemical properties of Au-CA NPs and Au-MEA NPs were characterized. In vivo studies were performed using imiquimod-induced psoriasis and LL37-induced rosacea animal models, respectively. For in vitro studies, a model of cellular inflammation was established using HaCaT cells stimulated with TNF-α. In addition, proteomics, gelatin zymography, and other techniques were used to investigate the possible therapeutic mechanisms of the Au-MEA NPs. RESULTS: We found that Au-MEA NPs exhibited better stability and permeation properties compared to conventional Au-CA NPs. Transcutaneously administered Au-MEA NPs exerted potent therapeutic efficacy against both rosacea-like and psoriasiform skin dermatitis in vivo without overt signs of toxicity. Mechanistically, Au-MEA NPs reduced the production of pro-inflammatory mediators in keratinocytes by promoting SOD activity and inhibiting the activity of MMP9. CONCLUSION: Au-MEA NPs have the potential to be a topical nanomedicine for the effective and safe treatment of inflammatory skin diseases.

Aptamers: precision tools for diagnosing and treating infectious diseases.

Infectious diseases represent a significant global health challenge, with bacteria, fungi, viruses, and parasitic protozoa being significant causative agents. The shared symptoms among diseases and the emergence of new pathogen variations make diagnosis and treatment complex. Conventional diagnostic methods are laborious and intricate, underscoring the need for rapid, accurate techniques. Aptamer-based technologies offer a promising solution, as they are cost-effective, sensitive, specific, and convenient for molecular disease diagnosis. Aptamers, which are single-stranded RNA or DNA sequences, serve as nucleotide equivalents of monoclonal antibodies, displaying high specificity and affinity for target molecules. They are structurally robust, allowing for long-term storage without substantial activity loss. Aptamers find applications in diverse fields such as drug screening, material science, and environmental monitoring. In biomedicine, they are extensively studied for biomarker detection, diagnostics, imaging, and targeted therapy. This comprehensive review focuses on the utility of aptamers in managing infectious diseases, particularly in the realms of diagnostics and therapeutics.

Clinical Use of Mental Health Digital Therapeutics in a Large Health Care Delivery System: Retrospective Patient Cohort Study and Provider Survey.

Background: While the number of digital therapeutics (DTx) has proliferated, there is little real-world research on the characteristics of providers recommending DTx, their recommendation behaviors, or the characteristics of patients receiving recommendations in the clinical setting. Objective: The aim of this study was to characterize the clinical and demographic characteristics of patients receiving DTx recommendations and describe provider characteristics and behaviors regarding DTx. Methods: This retrospective cohort study used electronic health record data from a large, integrated health care delivery system. Demographic and clinical characteristics of adult patients recommended versus not recommended DTx by a mental health provider between May 2020 and December 2021 were examined. A cross-sectional survey of mental health providers providing these recommendations was conducted in December 2022 to assess the characteristics of providers and recommendation behaviors related to DTx. Parametric and nonparametric tests were used to examine statistical significance between groups. Results: Of 335,250 patients with a mental health appointment, 53,546 (16%) received a DTx recommendation. Patients recommended to DTx were younger, were of Asian or Hispanic race or ethnicity, were female, were without medical comorbidities, and had commercial insurance compared to those without a DTx recommendation (P<.001). More patients receiving a DTx recommendation had anxiety or adjustment disorder diagnoses, but less had depression, bipolar, or psychotic disorder diagnoses (P<.001) versus matched controls not recommended to DTx. Overall, depression and anxiety symptom scores were lower in patients recommended to DTx compared to matched controls not receiving a recommendation, although female patients had a higher proportion of severe depression and anxiety scores compared to male patients. Provider survey results indicated a higher proportion of nonprescribers recommended DTx to patients compared to prescribers (P=.008). Of all providers, 29.4% (45/153) reported using the suggested internal electronic health record-based tools (eg, smart text) to recommend DTx, and of providers recommending DTx resources to patients, 64.1% (98/153) reported they follow up with patients to inquire on DTx benefits. Only 38.4% (58/151) of respondents report recommending specific DTx modules, and of those, 58.6% (34/58) report following up on the impact of these specific modules. Conclusions: DTx use in mental health was modest and varied by patient and provider characteristics. Providers do not appear to actively engage with these tools and integrate them into treatment plans. Providers, while expressing interest in potential benefits from DTx, may view DTx as a passive strategy to augment traditional treatment for select patients.

Platelet factors ameliorate thoracic aortic aneurysm and dissection by inhibiting the FGF-FGFR cascade activation in aortic-endothelial cell.

Thoracic aortic aneurysm and dissection (TAAD) is closely associated with vascular endothelial dysfunction. Platelet factor 4 (PF4) is crucial for maintaining vascular endothelial cell homeostasis. However, whether PF4 can influence the progression of TAAD remains unknown. In the present study, we constructed a liposome-encapsulated PF4 nanomedicine and verified its effect on BAPN-induced TAAD in vivo. We found that liposome PF4 nanoparticles (Lipo-PF4), more effectively than PF4 alone, inhibited the formation of TAAD. In vitro, PF4 improved endothelial cell function under pathological conditions by inhibiting migratory and angiogenic abilities of human aortic endothelial cells (HAECs). Mechanically, PF4 inhibited the development of TAAD and improved HAECs function by combining with heparin sulfate and blocking fibroblast growth factor-fibroblast growth factor receptor (FGF-FGFR) signaling. Taken together, we developed a nano-drug (Lipo-PF4) that effectively ameliorates the progression of TAAD by improving endothelial function. Lipo-PF4 is expected to be a therapeutic option for TAAD in the future.

Effectiveness of surfing on psychological health in military members: a systematic review.

INTRODUCTION: Surfing, a leisure activity known for its positive physical and mental health effects, has emerged as a potential therapeutic intervention. This study aims to systematically review the available evidence on the effects of surfing on mental health in active military personnel and veterans. METHODS: Studies were searched across four electronic databases (MEDLINE/PubMed, Web of Science, SportDiscus and Scopus) until May 2024. The methodological quality of the included studies was assessed using the Physiotherapy Evidence Database, Methodological Index for Non-Randomized Studies and the Quality Assessment Tool for Before-After Studies with No Control Group scales. RESULTS: A total of seven studies met the inclusion criteria and were included. Depression and anxiety symptoms (n=7), positive affect (n=5) and pain (n=3) were the main outcomes analysed. Overall, the studies reviewed generally reported beneficial effects of surfing on depression, anxiety and positive affect. However, none of the four studies that examined pain as an outcome observed any positive effects of surfing. CONCLUSION: There is evidence indicating that surfing may positively influence the management of anxiety, depression and overall positive affect among military personnel. Nonetheless, it cannot be definitively concluded that surfing provides superior benefits compared with other forms of exercise.