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Protein-protein interactions (PPIs) are fundamental to understanding biological systems as protein complexes are the active molecular modules critical for carrying out cellular functions. Dysfunctional PPIs have been associated with various diseases including cancer. Systems-wide PPI analysis not only sheds light on pathological mechanisms, but also represents a paradigm in identifying potential therapeutic targets. In recent years, cross-linking mass spectrometry (XL-MS) has emerged as a powerful tool for defining endogenous PPIs of cellular networks. While proteome-wide studies have been performed in cell lysates, intact cells and tissues, applications of XL-MS in clinical samples have not been reported. In this study, we adopted a DSBSO-based in vivo XL-MS platform to map interaction landscapes from two breast cancer patient-derived xenograft (PDX) models. As a result, we have generated a PDX interaction network comprising 2,557 human proteins and identified interactions unique to breast cancer subtypes. Interestingly, most of the observed differences in PPIs correlated well with protein abundance changes determined by TMT-based proteome quantitation. Collectively, this work has demonstrated the feasibility of XL-MS analysis in clinical samples, and established an analytical workflow for tissue cross-linking that can be generalized for mapping PPIs from patient samples in the future to dissect disease-relevant cellular networks.

We report the development of a 384-well formatted NanoBRET assay to characterize molecular glues of 14-3-3/client interactions in living cells. The seven isoforms of 14-3-3 are dimeric hub proteins with diverse roles including transcription factor regulation and signal transduction. 14-3-3 interacts with hundreds of client proteins to regulate their function and is therefore an ideal therapeutic target when client selectivity can be achieved. We have developed the NanoBRET system for three 14-3-3σ client proteins CRAF, TAZ, and estrogen receptor α (ERα), which represent three specific binding modes. We have measured stabilization of 14-3-3σ/client complexes by molecular glues with EC50 values between 100 nM and 1 μM in cells, which align with the EC50 values calculated by fluorescence anisotropy in vitro. Developing this NanoBRET system for the hub protein 14-3-3σ allows for a streamlined approach, bypassing multiple optimization steps in the assay development process for other 14-3-3σ clients. The NanoBRET system allows for an assessment of PPI stabilization in a more physiologically relevant, cell-based environment using full-length proteins. The method is applicable to diverse protein-protein interactions (PPIs) and offers a robust platform to explore libraries of compounds for both PPI stabilizers and inhibitors.

Macroautophagy/autophagy is an essential catabolic process that targets a wide variety of cellular components including proteins, organelles, and pathogens. ATG7, a protein involved in the autophagy process, plays a crucial role in maintaining cellular homeostasis and can contribute to the development of diseases such as cancer. ATG7 initiates autophagy by facilitating the lipidation of the ATG8 proteins in the growing autophagosome membrane. The noncanonical isoform ATG7(2) is unable to perform ATG8 lipidation; however, its cellular regulation and function are unknown. Here, we uncovered a distinct regulation and function of ATG7(2) in contrast with ATG7(1), the canonical isoform. First, affinity-purification mass spectrometry analysis revealed that ATG7(2) establishes direct protein-protein interactions (PPIs) with metabolic proteins, whereas ATG7(1) primarily interacts with autophagy machinery proteins. Furthermore, we identified that ATG7(2) mediates a decrease in metabolic activity, highlighting a novel splice-dependent function of this important autophagy protein. Then, we found a divergent expression pattern of ATG7(1) and ATG7(2) across human tissues. Conclusively, our work uncovers the divergent patterns of expression, protein interactions, and function of ATG7(2) in contrast to ATG7(1). These findings suggest a molecular switch between main catabolic processes through isoform-dependent expression of a key autophagy gene.

AbstractPurposeMaterials and MethodsResultsConclusion\nIMPLICATIONS FOR REHABILITATIONStroke research Priority Setting Partnerships identified a need for interventions that address wellbeing and communication. This paper outlines the development of a communication and wellbeing intervention for delivery in the virtual world, EVA Park, for people with aphasia called Virtual Elaborated Semantic Feature Analysis.The Medical Research Council framework for developing complex interventions was followed to combine evidence (literature review), underpinning theory (semantic processing theories, framework for situated language use and learning theories) and involvement with stakeholders (four people with aphasia and three speech and language therapists) in an intervention that addresses word finding, situated language and wellbeing.Evidence for the semantic word interventions and situated conversation interventions was synthesised. Theory underpinning the proposed intervention included Hebbian learning, the hub and spokes model of semantic processing, semantic spreading activation theory, the framework for situated language use and learning theories. Stakeholders with aphasia identified intervention content, an acceptable intervention regimen and gave feedback on a taster session. Speech therapists advised how the intervention could be implemented in clinical practice.Virtual Elaborated Semantic Feature Analysis is a user-informed, theory-based complex aphasia intervention that is expected to improve word finding, word use in situated conversation and wellbeing.When consulted on acceptable therapy regimens for an aphasia therapy in a virtual world, a lived experience advisory group preferred a distributed regimen (4 days a week over 8 weeks) over a more intense regimen (5 days a week over 6 weeks).Individual word retrieval activities and group conversation activities were equally prioritised by the lived experience advisory group.It is more challenging to retrieve a word in a conversation context, therefore word retrieval practiced in conversations was valued by the lived experienced advisory group.A simulated, supported, virtual space for communication practice, such as groups in the EVA Park virtual world, provides a social context for learning and experiencing success with limited loss of face.When consulted on acceptable therapy regimens for an aphasia therapy in a virtual world, a lived experience advisory group preferred a distributed regimen (4 days a week over 8 weeks) over a more intense regimen (5 days a week over 6 weeks).Individual word retrieval activities and group conversation activities were equally prioritised by the lived experience advisory group.It is more challenging to retrieve a word in a conversation context, therefore word retrieval practiced in conversations was valued by the lived experienced advisory group.A simulated, supported, virtual space for communication practice, such as groups in the EVA Park virtual world, provides a social context for learning and experiencing success with limited loss of face. [ABSTRACT FROM AUTHOR]

Background: Proton pump inhibitors (PPIs) are widely prescribed drugs that have been associated with increased prostate cancer (PCa) cell proliferation in vitro and worse oncological outcomes in vivo. However, data on their influence on PSA levels in the general population are lacking. Methods: We extracted individual participant data from the 2001–2010 cycles of the National Health and Nutrition Examination Survey (NHANES), in which PSA levels were measured in all male participants aged 40 years or older. The association of PPI use with total PSA levels and free/total PSA ratio was evaluated through multivariable linear regression analyses, adjusted for potential confounders. Results: A total of 7366 subjects were included (median age: 53 years; median serum PSA: 0.9 ng/mL), of whom 746 were receiving PPI treatment at the time of the study. After adjustment for potential confounders, ongoing PPI use was associated with lower total PSA levels (-0.24 ng/mL, 95%CI: [-0.37,-0.11], p < 0.001), while no significant association with free/total PSA ratio was found (p = 0.881). A significant effect modification was observed according to age, with the association being limited to older participants (≥ 60 years) at stratified analyses. Conclusions: Contrary to the available data in the context of PCa, we found no evidence of increased PSA levels in PPI users with no prostate malignancy. Instead, PPI use was associated with a decrease of total PSA in older adults. This adds knowledge on how PPIs may influence PSA in population-based screening programs. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BC) is a malignant tumor characterized by a high incidence rate and is the leading cause of cancer-related deaths among women worldwide. This study aims to identify key genes and potential prognostic biomarkers using a bioinformatics approach. Methods: Three microarray datasets, GSE86374, GSE120129, and GSE29044, were downloaded from the GEO database. GEO2R and Venn diagram software were employed to identify differentially expressed genes (DEGs), while DAVID was utilized for functional enrichment analysis. Subsequently, STRING and Cytoscape were used to construct the protein–protein interaction (PPI) network among the DEGs. UALCAN, GEPIA, and the Kaplan–Meier plotter were employed for prognostic analysis. Following this, the correlations and alterations of key genes were examined using cBioPortal. Finally, immunohistochemistry (IHC) was performed to validate the expression levels of the key genes. Results: A total of 323 differentially expressed genes (DEGs) were identified. From the protein–protein interaction (PPI) network, 37 hub genes were selected. Validation using UALCAN, GEPIA, and Kaplan–Meier plotters revealed that three key genes—RACGAP1, SPAG5, and KIF20A—were significantly overexpressed and associated with poor prognosis in breast cancer (BC), as well as advanced tumor staging. The correlations and alterations of these key genes, as demonstrated on cBioPortal, indicated that their alterations co-occurred. Experimental verification through immunohistochemistry (IHC) confirmed that the proteins of these key genes were highly expressed in tumor tissues. Conclusions: The key genes identified in this study can enhance our understanding of the molecular mechanisms underlying breast cancer (BC). Additionally, these genes may serve as potential sensitive biomarkers for patients with BC. [ABSTRACT FROM AUTHOR]

Protein interactions are crucial for understanding biological functions and disease mechanisms, but predicting these remains a complex task in computational biology. Increasingly, Deep Learning models are having success in interface prediction. This study presents PIPENN-EMB which explores the added value of using embeddings from the ProtT5-XL protein language model. Our results show substantial improvement over the previously published PIPENN model for protein interaction interface prediction, reaching an MCC of 0.313 vs. 0.249, and AUROC 0.800 vs. 0.755 on the BIO_DL_TE test set. We furthermore show that these embeddings cover a broad range of 'hand-crafted' protein features in ablation studies. PIPENN-EMB reaches state-of-the-art performance on the ZK448 dataset for protein-protein interface prediction. We showcase predictions on 25 resistance-related proteins from Mycobacterium tuberculosis. Furthermore, whereas other state-of-the-art sequence-based methods perform worse for proteins that have little recognisable homology in their training data, PIPENN-EMB generalises to remote homologs, yielding stable AUROC across all three test sets with less than 30% sequence identity to the training dataset, and even to proteins with less than 15% sequence identity. [ABSTRACT FROM AUTHOR]

Transcatheter aortic valve replacement (TAVR) has rapidly displaced surgical aortic valve replacement (SAVR). However, certain post-TAVR complications persist, with cardiac conduction abnormalities (CCA) being one of the major ones. The elevated pressure exerted by the TAVR stent onto the conduction fibers situated between the aortic annulus and the His bundle, in proximity to the atrioventricular (AV) node, may disrupt the cardiac conduction leading to the emergence of CCA. In this study, an in silico framework was developed to assess the CCA risk, incorporating the effect of a dynamic beating heart and preprocedural parameters such as implantation depth and preexisting cardiac asynchrony in the new onset of post-TAVR CCA. A self-expandable TAVR device deployment was simulated inside an electromechanically coupled beating heart model in five patient scenarios, including three implantation depths and two preexisting cardiac asynchronies: (i) a right bundle branch block (RBBB) and (ii) a left bundle branch block (LBBB). Subsequently, several biomechanical parameters were analyzed to assess the post-TAVR CCA risk. The results manifested a lower cumulative contact pressure on the conduction fibers following TAVR for aortic deployment (0.018 MPa) compared to nominal condition (0.29 MPa) and ventricular deployment (0.52 MPa). Notably, the preexisting RBBB demonstrated a higher cumulative contact pressure (0.34 MPa) compared to the nominal condition and preexisting LBBB (0.25 MPa). Deeper implantation and preexisting RBBB cause higher stresses and contact pressure on the conduction fibers leading to an increased risk of post-TAVR CCA. Conversely, implantation above the MS landmark and preexisting LBBB reduces the risk. [ABSTRACT FROM AUTHOR]

Intrinsically disordered proteins (IDPs) include two types of proteins: partial disordered regions (IDRs) and wholly disordered proteins (WDPs). Extensive studies focused on the proteins with IDRs, but less is known about WDPs because of their difficult-to-form folded tertiary structure. In this study, we developed a bioinformatics method for screening more than 50 amino acids in the genome level and found a total of 27 categories, including 56 WDPs, in Arabidopsis. After comparing with 56 randomly selected structural proteins, we found that WDPs possessed a more wide range of theoretical isoelectric point (PI), a more negative of Grand Average of Hydropathicity (GRAVY), a higher value of Instability Index (II), and lower values of Aliphatic Index (AI). In addition, by calculating the FCR (fraction of charged residue) and NCPR (net charge per residue) values of each WDP, we found 20 WDPs in R1 (FCR < 0.25 and NCPR < 0.25) group, 15 in R2 (0.25 ≤ FCR ≤ 0.35 and NCPR ≤ 0.35), 19 in R3 (FCR > 0.35 and NCPR ≤ 0.35), and two in R4 (FCR > 0.35 and NCPR > 0.35). Moreover, the gene expression and protein-protein interaction (PPI) network analysis showed that WDPs perform different biological functions. We also showed that two WDPs, SIS (Salt Induced Serine rich) and RAB18 (a dehydrin family protein), undergo the in vitro liquid-liquid phase separation (LLPS). Therefore, our results provide insight into understanding the biochemical characters and biological functions of WDPs in plants. [ABSTRACT FROM AUTHOR]

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated inflammatory condition of the esophagus characterized by eosinophilic infiltration, and hallmark symptoms of esophageal dysfunction such as dysphagia and food impaction. Over the past three decades, EoE has been recognized as a distinct clinical entity, distinguished from gastroesophageal reflux disease (GERD) through advancements in diagnostic techniques, particularly endoscopy with biopsy. The rising global prevalence of EoE reflects enhanced diagnostic awareness, evolving criteria, and environmental along with lifestyle changes. The etiology of EoE is multifactorial, involving genetic predispositions, immune dysregulation, the gut microbiome, and environmental triggers, including dietary allergens and aeroallergens. Key mechanisms include a type 2 helper T-cell (Th2)-driven immune response, epithelial barrier dysfunction, and genetic variants such as CAPN14 and TSLP. Chronic inflammation leads to tissue remodeling, fibrosis, and esophageal narrowing, contributing to disease progression and complications. Management strategies have evolved to include dietary elimination, proton pump inhibitors, topical corticosteroids, biologics, and endoscopic interventions for fibrostenotic complications. Emerging therapies targeting cytokines such as interleukin (IL)-4, IL-5, and IL-13, alongside novel diagnostic tools like the esophageal string test and Cytosponge, offer promising avenues for improved disease control and non-invasive monitoring. Long-term surveillance combining endoscopic and histological evaluations with biomarkers and non-invasive tools is critical to optimizing outcomes and preventing complications. Future research should address gaps in understanding the role of the esophageal microbiome, refine therapeutic approaches, and develop personalized strategies to improve disease management and patient quality of life. [ABSTRACT FROM AUTHOR]

While platform protection insurance (PPI) is extensively employed as an insurance policy in many sharing platforms, research on its influence on the tourism supply chain is lacking. At this point, the quality of online tourism services has taken the brunt of consumer complaints, and new solutions are desperately needed. So, would PPI's involvement increase the quality of online tourism services? In this paper, by constructing an online tourism supply chain consisting of a Tourism Supplier (TS), an Online Tourism agency (OTA), and consumers, we study the conditions of PPI introduction and its impact on online tourism service quality and analyze the behavioral decisions of online tourism supply chain subjects. The study found that in the tourism market with a small amount of demand change, OTA is more willing to introduce PPI, and TS is more inclined to improve service quality, which then lowers the service cost of TS and the level of disclosure of information, the stronger the willingness of OTA to introduce PPI, and the introduction of PPI in the lower PPI penetration rate of the tourism market has a more promotive effect on the TS with lower service cost. [ABSTRACT FROM AUTHOR]

Background: Proton pump inhibitor (PPI) drugs are widely used and are among the most significant achievements of modern pharmacology. Their primary purpose is treating and preventing gastric acid-related disorders. Migraine and PPI intake are prevalent, and many people are affected by both. In the last few years, a potential link between PPI intake and the development of headaches—especially migraine–has come to increased attention. In this review, we critically examine the scientific data concerning the co-occurrence of these two entities. Findings: There seems to be a possible link between the use of PPIs and the occurrence of headache, especially migraine, suggesting a pathophysiological connection on several levels. Moreover, PPI use is only partially without side effects, even if these may not occur immediately. Whether the relation is causative or merely co-existential is currently not yet clear. The influence of genetics, environment, gut microbiome, medication intake and evolution of headache is multidirectional. Conclusion: A relation between the prevalence of migraine and the use of PPIs on a population and personal level seems likely. Although PPIs have many advantages, they should be prescribed with caution, especially in patients who suffer from headaches and migraine. In this narrative review, we aim to critically evaluate existing data and offer a potential approach to accurately identify any connections and interactions, leading to a better understanding of how these conditions may influence each other. [ABSTRACT FROM AUTHOR]

Lymphocytic esophagitis (LE) is an uncommon subtype of esophagitis defined by persistent esophageal inflammation characterized by a high count of intraepithelial lymphocytes with scarce granulocytes. Although LE can present with atypical features such as chest pain, its clinical presentation can mimic that of gastroesophageal reflux disease or eosinophilic esophagitis, highlighting the importance of biopsy in diagnosing LE. Studies are still limited in understanding the pathophysiology behind this disease warranting further research. A 47-year-old female patient sought medical care with a chief complaint of recurrent substernal chest pain for the past year. An esophagogastroduodenoscopy was performed and showed patchy linear esophageal erosions and mucosal edema in the middle third of the esophagus with mild erythema. Biopsies revealed intraepithelial lymphocytosis with more than 40 lymphocytes per high-power field, corroborating a diagnosis of LE. Patient reported improvement after receiving high dose of proton pump inhibitor (PPI) on her first follow-up, advised to follow a low-acid diet and an annual endoscopy to monitor her response to treatment. Lymphocytic esophagitis often presents with symptoms that overlap with other esophageal diseases explaining the possible errors in underdiagnosing it as reason behind non-cardiac chest pain. This case plays an instrumental role in changing the way physicians translate unexplained chest pain, adding LE to their list of differential diagnosis as prompt detection slows us to start management with PPIs quicker and lessen the burden of symptoms on the patient. Standardized treatment approaches and further studies are required to clarify the connection between LE and non-cardiac chest discomfort. [ABSTRACT FROM AUTHOR]

Barley leaf stripe, a disease mainly caused by Pyrenophora graminea (P. graminea) infection, severely affects barley yield and quality and is one of the most widespread diseases in barley production. However, little is known about the underlying molecular mechanisms of leaf stripe resistance. In this study, the transcript expression profiles of normal and infected leaves of resistant Tibetan hulless barley (Hordeum vulgare L. var. nudum Hook. f.) variety Kunlun 14 and susceptible variety Z1141 were analyzed by RNA sequencing (RNA-seq). The results showed a total of 7,669 and 5,943 differentially expressed genes (DEGs) were found in resistant and susceptible Kunlun 14 and Z1141, respectively, with 8,916 DEGs found between Kunlun 14 and Z1141. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of the 8,916 DEGs identified many significantly enriched categories and pathways, of which a plant–pathogen interaction pathway, containing a total of 102 genes (100 known genes and two novel genes), was found, that was very important for the study of the leaf stripe resistance mechanism. Using RNA-seq, small RNA sequencing (miRNA-seq) combined with degradome sequencing (degradome-seq), four pairs associated with leaf-stripe miRNAs and target genes were obtained, namely Hvu-miR168-5p and Argonaute1 (HvAGO1), Hvu-novel-52 and growth-regulating factor 6 (HvGRF6), Hvu-miR6195 and chemocyanin-like protein (CLP), and Hvu-miR159b and gibberellin-dependent MYB (GAMYB). Transformation of the important target gene HvAGO1 into Arabidopsis verified that HvAGO1 could against Botrytis cinerea. Then RNA-seq and miRNA-seq of Arabidopsis transformed with overexpressed of HvAGO1 were performed. Based on the above research results, we constructed a Protein-Protein Interaction (PPI) network of barley leaf stripe resistance. This study lays the foundation for the study of the barley leaf stripe resistance mechanism and provides new targets for the genetic improvement of disease-resistant barley varieties. [ABSTRACT FROM AUTHOR]

Background: Involving parents in decisions about the care of their infant is common practice in most neonatal intensive care units. However, involvement is less common in neonatal research and a gap appears to exist in understanding the process of patient and public involvement. The aim of this study was to explore parents and researchers' experiences of patient and public involvement in a neonatal research project. Methods: A qualitative design was employed, consisting of two focus group interviews, one dyadic interview, and four individual interviews with parents and researchers. The interviews followed a semi-structured guide specific to both parents and researchers. Data were analysed using content analysis as described by Graneheim and Lundman. Results: A total of nine parents and four researchers participated in the study. Seven themes were consolidated into three core concepts: Embracing the ethos and pathos of patient and public involvement, Finding the path to maximise meaningful involvement, and Becoming skilled in engaging patients and the public in research. The core concepts highlighted both similarities and differences, as well as challenges and facilitators, of the experiences of the patient and public involvement process. Conclusion: Patient and public involvement in research was a mutually beneficial process, facilitating learning and reflective opportunities for parents and researchers. However, there were challenges that emphasised the need for rapport building between parents and researchers, valuing everyone's unique perspective and expertise, with clear communication and well-defined roles and goals. These insights offer a contribution for future patient and public involvement in health research. Plain English summary: It is usual practice to involve parents in decisions about their babies care in neonatal intensive care units, but their involvement in research is less common. Although patient and public involvement in research is increasing, there is a lack of strategies to ensure meaningful involvement. This qualitative study used interviews, to explore how parents and researchers experienced patient and public involvement in a research project about couplet care in a neonatal intensive care unit. Nine parents and four researchers participated and the analysis revealed several themes that describes their experiences. These themes were consolidated into three main concepts: (1) Embracing the ethos and pathos of patient and public involvement, which focuses on the emotional and ethical aspects of involvement, (2) Finding the path to maximize meaningful involvement, which addresses the strategies and methods to ensure effective involvement, and (3) Becoming skilled in engaging patient and the public in research, which emphasizes the need for developing skills and knowledge for better involvement practices. These core concepts provide a comprehensive understanding of how to enhance involvement, not only in the neonatal setting, but research in general. [ABSTRACT FROM AUTHOR]

The transient receptor potential melastatin type 6 (TRPM6) is a divalent cation channel pivotal for gatekeeping Mg2+ balance. Disturbance in Mg2+ balance has been associated with the chronic use of proton pump inhibitors (PPIs) such as omeprazole. In this study, we investigated if TRPM6 plays a role in mediating the effects of short-term (4 days) omeprazole treatment on intestinal Mg2+ malabsorption using intestine-specific TRPM6 knockout (Vill1-TRPM6−/−) mice. To do this, forty-eight adult male C57BL/6 J mice (50% TRPM6fl/fl and 50% Vill1-TRPM6−/−) were characterized, and the distal colon of these mice was subjected to RNA sequencing. Moreover, these mice were exposed to 20 mg/kg bodyweight omeprazole or placebo for 4 days. Vill1-TRPM6−/− mice had a significantly lower 25Mg2+ absorption compared to control TRPM6fl/fl mice, accompanied by lower Mg2+ serum levels, and urinary Mg2+ excretion. Furthermore, renal Slc41a3, Trpm6, and Trpm7 gene expressions were higher in these animals, indicating a compensatory mechanism via the kidney. RNA sequencing of the distal colon revealed a downregulation of the Mn2+ transporter Slc30a10. However, no changes in Mn2+ serum, urine, and feces levels were observed. Moreover, 4 days omeprazole treatment did not affect Mg2+ homeostasis as no changes in serum 25Mg2+ and total Mg2+ were seen. In conclusion, we demonstrate here for the first time that Vill1-TRPM6−/− mice have a lower Mg2+ absorption in the intestines. Moreover, short-term omeprazole treatment does not alter Mg2+ absorption in both Vill1-TRPM6−/− and TRPM6fl/fl mice. This suggests that TRPM6-mediated Mg2+ absorption in the intestines is not affected by short-term PPI administration. [ABSTRACT FROM AUTHOR]

Purpose: Pulpitis is one of the most common oral inflammatory diseases. There are many limitations in the traditional methods of diagnosing pulpitis. By replacing new diagnostic ways based on biomarkers, it is possible to quickly and accurately identify this disease. Biological indicators have greatly helped not only in the screening of infectious diseases but also in early and appropriate treatment. In this research, differentially expressed genes (DEGs) related to pulpitis were analyzed, and prognostic biomarkers were introduced. Materials and Methods: In this in silico study, we applied the GSE77459 dataset as the gene expression profile of pulpitis. Web tool, GEO2R was used to separate up-regulated and down-regulated DEGs. |logFC|>2 and adjusted p-value < 0.05 was set as the cutoff criterion. For the pathway enrichment study of obtained genes, EnrichR was implemented. After constructing a protein-protein interaction (PPI) network, hub genes that are involved in pulpitis were selected. Finally, functionally grouped networks by ClueGO software (v2.5.10) were generated. Results: GEO2R analysis of the GSE77459 dataset showed 672 up-regulated genes and 239 down-regulated genes with GB_ACC code. Based on Cytoscape Results:, the 15 top hubba nodes were ranked including PTPRC, ITGAM, CCL2, ICAM1, MMP9, CXCL8, TLR2, CD86, CXCR4, IL1A, CD44, CCL3, ITGAX, CXCL10, and CCR7. Functionally grouped networks determined that these genes were mainly enriched in chemokine-mediated signaling pathway, morphogenesis of endothelium, and neuroinflammatory response Conclusion In our research, 15 genes were introduced as diagnostic biomarkers in pulpitis and their functionally grouped networks were constructed. However, the obtained Results need to be validated using in vitro and in vivo methods. [ABSTRACT FROM AUTHOR]

Abstract Gene context-essentiality assessment supports precision oncology opportunities. The variability of gene effects inference from loss-of-function screenings across models and technologies limits identifying robust hits. We propose a computational framework named PRODE that integrates gene effects with protein–protein interactions to generate neighborhood-informed essential (NIE) and neighborhood-informed context essential (NICE) scores. It outperforms the canonical gene effect approach in recovering missed essential genes in shRNA screens and prioritizing context-essential hits from CRISPR-KO screens, as supported by in vitro validations. Applied to Her2 + breast cancer tumor samples, PRODE identifies oxidative phosphorylation genes as vulnerabilities with prognostic value, highlighting new therapeutic opportunities.

Abstract Background Breast cancer (BC) is a malignant tumor characterized by a high incidence rate and is the leading cause of cancer-related deaths among women worldwide. This study aims to identify key genes and potential prognostic biomarkers using a bioinformatics approach. Methods Three microarray datasets, GSE86374, GSE120129, and GSE29044, were downloaded from the GEO database. GEO2R and Venn diagram software were employed to identify differentially expressed genes (DEGs), while DAVID was utilized for functional enrichment analysis. Subsequently, STRING and Cytoscape were used to construct the protein–protein interaction (PPI) network among the DEGs. UALCAN, GEPIA, and the Kaplan–Meier plotter were employed for prognostic analysis. Following this, the correlations and alterations of key genes were examined using cBioPortal. Finally, immunohistochemistry (IHC) was performed to validate the expression levels of the key genes. Results A total of 323 differentially expressed genes (DEGs) were identified. From the protein–protein interaction (PPI) network, 37 hub genes were selected. Validation using UALCAN, GEPIA, and Kaplan–Meier plotters revealed that three key genes—RACGAP1, SPAG5, and KIF20A—were significantly overexpressed and associated with poor prognosis in breast cancer (BC), as well as advanced tumor staging. The correlations and alterations of these key genes, as demonstrated on cBioPortal, indicated that their alterations co-occurred. Experimental verification through immunohistochemistry (IHC) confirmed that the proteins of these key genes were highly expressed in tumor tissues. Conclusions The key genes identified in this study can enhance our understanding of the molecular mechanisms underlying breast cancer (BC). Additionally, these genes may serve as potential sensitive biomarkers for patients with BC.

Abstract Background Involving parents in decisions about the care of their infant is common practice in most neonatal intensive care units. However, involvement is less common in neonatal research and a gap appears to exist in understanding the process of patient and public involvement. The aim of this study was to explore parents and researchers’ experiences of patient and public involvement in a neonatal research project. Methods A qualitative design was employed, consisting of two focus group interviews, one dyadic interview, and four individual interviews with parents and researchers. The interviews followed a semi-structured guide specific to both parents and researchers. Data were analysed using content analysis as described by Graneheim and Lundman. Results A total of nine parents and four researchers participated in the study. Seven themes were consolidated into three core concepts: Embracing the ethos and pathos of patient and public involvement, Finding the path to maximise meaningful involvement, and Becoming skilled in engaging patients and the public in research. The core concepts highlighted both similarities and differences, as well as challenges and facilitators, of the experiences of the patient and public involvement process. Conclusion Patient and public involvement in research was a mutually beneficial process, facilitating learning and reflective opportunities for parents and researchers. However, there were challenges that emphasised the need for rapport building between parents and researchers, valuing everyone’s unique perspective and expertise, with clear communication and well-defined roles and goals. These insights offer a contribution for future patient and public involvement in health research.

The recent assembly and annotation of the 26 maize nested association mapping (NAM) population founder inbreds have enabled large-scale pan-genomic comparative studies. These studies have expanded our understanding of agronomically important traits by integrating pan-transcriptomic data with trait-specific gene candidates from previous association mapping results. In contrast to the availability of pan-transcriptomic data, obtaining reliable protein-protein interaction (PPI) data has remained a challenge due to its high cost and complexity. We generated predicted PPI networks for each of the 26 genomes using the established STRING database. The individual genome-interactomes were then integrated to generate core- and pan-interactomes. We deployed the PPI clustering algorithm ClusterONE to identify numerous PPI clusters that were functionally annotated using gene ontology (GO) functional enrichment, demonstrating a diverse range of enriched GO terms across different clusters. Additional cluster annotations were generated by integrating gene co-expression data and gene description annotations, providing additional useful information. We show that the functionally annotated PPI clusters establish a useful framework for protein function prediction and prioritization of candidate genes of interest. Our study not only provides a comprehensive resource of predicted PPI networks for 26 maize genomes, but also offers annotated interactome clusters for predicting protein functions and prioritizing gene candidates. The source code for the Python implementation of the analysis workflow and a standalone web application for accessing the analysis results are available at https://github.com/eporetsky/PanPPI.

Infrastructure development in Sub-Saharan Africa (SSA) requires diversified financing strategies to address a significant funding shortfall that cannot be met by domestic resources alone. This research evaluates the contributions of external financing—namely Official Development Assistance (ODA), Foreign Direct Investment (FDI), and Private Participation in Infrastructure (PPI)—in complementing domestic efforts to advance infrastructure in SSA. It examines their influence, alongside governance, on the development of physical and social infrastructure components. Employing methodologies such as Panel-Corrected Standard Errors (PCSE) and System Generalized Method of Moments (SGMM) across 43 SSA economies from 2000 to 2022, the analysis reveals that FDI substantially enhances physical infrastructure development but does not significantly impact social infrastructure. In contrast, ODA is shown to have a negative direct effect on overall infrastructure development, whereas PPI shows no significant direct influence. However, when considering indirect effects mediated by governance, all external financing sources positively affect both types of infrastructure, except for PPI’s influence on social infrastructure. Theoretically, this study reinforces the critical roles of economic growth, institutional quality, and external financing in supporting infrastructure development, as suggested by related theories. The study recommends that SSA authorities should focus on attracting more foreign investment, particularly in physical infrastructure projects, and encourage a broader diversification of external financing sources beyond FDI alone. Moreover, enhancing governance practices is essential for effective resource allocation and utilization. The study also advocates for improved public spending efficiency through enhanced project prioritization and governance reforms to foster sustainable infrastructure development in the region.

Abstract Objective Dual‐antiplatelet therapy (DAPT) and proton pump inhibitor (PPI) are frequently prescribed after percutaneous coronary intervention (PCI) with drug-eluting stents (DES) placement. However, studies that evaluate the optimal PPI when used as primary prevention in patients without a history of peptic ulcer disease or upper gastrointestinal bleeding (UGIB), particularly in the context of DAPT involving prasugrel, are lacking. This study aimed to assess the efficacy and safety of PPI use in preventing UGIB in this patient population. Methods This study included patients who underwent PCI with coronary stent placement for acute coronary syndrome or stable angina at our institution from January 2015 to December 2020. Eligible patients started DAPT with aspirin and prasugrel and concomitantly received PPI therapy (lansoprazole or esomeprazole), with a follow-up period of two years. The primary endpoint was UGIB incidence, diagnosed during follow-up, serving as an efficacy measure. Secondary endpoints included the assessment of major bleeding (as defined by the Thrombolysis in Myocardial Infarction major bleeding criteria) and clinically relevant non-major bleeding events. Safety outcomes focused on adverse event incidence attributable to PPI use. Results Among the 165 patients analyzed, 109 and 56 were included in the lansoprazole and esomeprazole groups, respectively, with cumulative incidence of UGIB at 96 weeks of 0.9% (1/109) and 3.6% (2/56). No significant differences in terms of major bleeding events or other bleeding outcomes were observed between the two groups. Adverse events related to PPI use were reported as diarrhea/soft stools in 7 (6%) cases and thrombocytopenia in 1 (1%) case in the lansoprazole group, whereas no such events were observed in the esomeprazole group. No clinically significant hematologic or biochemical abnormalities were reported. Conclusion This study evaluated the efficacy and safety of PPIs in combination with DAPT, including prasugrel, following PCI, and suggests that lansoprazole and esomeprazole may offer comparable efficacy in preventing UGIB.

Abstract Background To address the research-practice gap, knowledge translation is a crucial step in which co-creation, including patient and public involvement (PPI), is key. We performed a knowledge translation project in co-creation with all stakeholders as equal partners in the design and decision-making process. The project was based on scientific knowledge of a large research program on development of children and young adults with cerebral palsy (CP). It aimed to synthesize the knowledge on development of children and youth with CP, and to develop tools that are useful for health care professionals, persons with CP, and families. This paper describes the knowledge translation process applied in the project, specifically how the ‘key principles’ employed to ensure co-creation were operationalised, including reflections on the process and lessons learned. Main body Three key principles were defined to guarantee involvement of all stakeholders as equal partners in the design and decision-making process: a shared vision on collaboration and partnership, transparency: open and honest communication, and co-creation as a stepwise, iterative process. These key principles are based on literature and earlier experiences. They are described in more detail and are illustrated with examples from the knowledge translation project. The iterative co-creation process can be regarded as a cyclical process, including planning, conducting, reflection, evaluation, and refining the product and the process. This means that there was a continuous learning cycle in which we learned from the challenges and successes, now and then taking a step back. Based on our reflections the most important lessons learned are summarized. Conclusion The key principles were helpful in this knowledge translation process. Reflecting on these principles during the joint journey secured co-creation with all stakeholders as equal partners in the design and decision-making process. By sharing experiences, key principles, examples and lessons learned we intend to advance knowledge in PPI, and to inspire others.

Cailing E,1,&ast; Rongying Wang,1,&ast; Zudong Meng,1 Yulin Zou1,2 1Department of Dermatology, Renmin Hospital, Hubei University of Medicine, Shiyan, People’s Republic of China; 2Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen, Göttingen, Germany&ast;These authors contributed equally to this workCorrespondence: Yulin Zou, Email zouyl1007@qq.comBackground: Psoriasis, a chronic and recurrent inflammatory skin disease, current treatments can only alleviate its symptoms. There is still no complete cure. Although increasing research supports the therapeutics to be better, the common mechanism of its occurrence is still not fully elucidated. Our study is about further explore the molecular mechanism of the occurrence of this disease.Methods: The gene expression profiles of psoriasis (GSE151177, GSE41664, GSE30999) were downloaded from the Gene Expression Omnibus (GEO) database. After identifying the common differentially expressed genes (DEGs) of psoriasis using R software, three kinds of analyses were performed, namely WGCNA, GWAS Analysis, Drug Target Prediction.Results: A total of 14 common DEGs was selected for subsequent analyses. Our Drug Target Prediction analysis revealed that the expression profiles influenced by certain drugs, including methotrexate, budesonide, amino purvalanol-a, and selumetinib, exhibited negative correlations with the disease-perturbed expression profiles. Finally, It was found that S100A4, JAML, TRAF3IP3, MIAT, IL7R, and KLRB1 were prominently expressed in the immune pathway related to allograft rejection. In the metabolic pathway, oxidative phosphorylation showed high expression levels, while the reactive oxygen species pathway was notably expressed in the signaling pathways domain.Conclusion: Our study reveals the potential drugs and pathogenesis of psoriasis. These potential pathway and hub genes may provide new ideas for further mechanism research.Keywords: psoriasis, hub genes, bioinformatics, PPI, inflammation

Abstract Background We conducted an NIHR-funded evidence synthesis project, reviewing evidence relating to interventions for perceptual disorders following stroke. This related paper describes how people with lived experience of stroke-related perceptual disorders contributed to and influenced the project, and identifies lessons for future review projects. Methods We planned our patient and public involvement and engagement (PPIE) activities within a study protocol, described according to the domains of the ACTIVE framework; these were founded on principles for good practice in PPIE. Activities occurred across the lifespan of the project, consisting primarily of group discussions and voting to determine if there was consensus. To assess impact and individual experiences, we sought feedback using an evaluation form after each discussion, and conducted an online meeting at the end of the project to allow further reflection. Results We recruited five people to a Lived Experience Group, including two stroke survivors and three carers. Members attended one face-to-face meeting during the development of the review. Subsequent activities were all held online due to the COVID-19 pandemic; with six online meetings, plus email interactions. Positive impacts of the Lived Experience Group on the reviews included clear definitions of key terms, selection of outcome measures, agreement on implications of review findings, and identification of research recommendations. Key challenges identified related to the complexity of the topic and challenges in the use of new online technology as a consequence of the COVID-pandemic. Conclusions A number of lessons were learned during this project. Specific recommendations for future PPIE are to ensure that those involved have an opportunity to get to know one another, and to provide optional sessions to increase familiarity with online meeting software, clear explanations of the purpose of involvement and specific feedback after each activity. These lessons should be considered when planning the PPIE within future reviews.

Das Verschreibungsvolumen von Protonenpumpeninhibitoren (PPI) ist nach wie vor hoch, obwohl in der Literatur zunehmend darauf hingewiesen wird, dass in Relation zu den Leitlinienempfehlungen eine übermäßige Verschreibung erfolgt. Über die Situation in Deutschland liegen keine sehr aktuellen Daten vor. Ziel dieser Studie war es, die tatsächliche Menge an verschriebenen und rezeptfreien PPIs in Deutschland zu ermitteln. Basierend auf mehreren großen IQVIA-Datenbanken zeigen wir, dass zwischen November 2020 und Oktober 2021 insgesamt 2,87 Milliarden PPI-Tabletten verkauft wurden, wobei die meisten Wirkstoffe in den größten Packungen und Stärken verordnet wurden. Darüber hinaus nahm der rezeptfreie PPI-Markt in einem Zeitraum von drei Jahren durchschnittlich um 14% pro Jahr zu. Die Ergebnisse dieser Studie lassen auf die beträchtliche Größe des PPI-Marktes in Deutschland aufgrund von Verschreibungen schließen sowie auf eine konsistente Zunahme der rezeptfreien PPI-Käufe und einen Anstieg der Verschreibungen in der jüngsten Zeit.

Abstract Background Incorporating patient and public involvement (PPI) in research is crucial for ensuring the relevance and success of studies, yet it remains significantly underutilised in surgical research. Main body This commentary presents insights from our neurosurgical research team’s experience with establishing and working with a PPI group called “Science for Tomorrow’s Neurosurgery” on research regarding novel intra-operative optical imaging techniques. Through collaboration with patient-focused charities, we have successfully incorporated patient perspectives into our work at each stage of the research pipeline, whilst adhering to core PPI principles, such as reciprocal relationships, co-learning, partnerships, and transparency. Conclusion We highlight the specific value added to our work in terms of participant recruitment, research ethics and results dissemination.

Introduction: Co-production involves researchers, practitioners and people with lived experience working in a collaborative manner, with shared power. The potential benefits of co-production are well documented. However, there is little research describing the experience of having been involved in co-production from the perspective of Experts By Lived Experience (EBLE). The aim of the present study is to explore the experiences of EBLE of obsessive-compulsive disorder (OCD) on their involvement in co-producing a blended intervention to prevent relapse for OCD. Methods: Five EBLE took part in semi-structured interviews enquiring about their experiences of co-producing a relapse prevention intervention. Reflexive thematic analysis was used to analyse the data. Results: Four themes were developed: (1) Welcome but unexpected therapeutic benefits; (2) The parameters of a safe space; (3) Genuine co-production brings meaningful change; and (4) Navigating the challenging terrain of co-production. Conclusions: Overall, EBLE reported their involvement in the co-production process to have had positive impacts on both the development of the intervention and their own personal recovery journey. EBLE valued the safety created within the group, and the importance this had for allowing them to speak open and honestly about their experiences and the difficulties that can arise with the nature of the work. [ABSTRACT FROM AUTHOR]

Objective: This study aims to investigate the role of the neurodegenerative disease gene C19orf12 in the H1299 cell line and to analyze the potential impact of its pathogenic mutant (p.Ala63Pro). Methods: The expression levels of C19orf12 in various cell lines, including Hela, A549, U2OS, and H1299, were analyzed using Reverse Transcription Quantitative PCR (RT-qPCR) and West- ern Blot. An shRNA lentiviral expression vector targeting C19orf12 was constructed, and C19orf12 was knocked down in the H1299 cell line. Data-independent acquisition (DIA) proteomics was utilized to analyze the effect of C19orf12 knockdown on the cellular protein expression profile. Differentially expressed proteins were subjected to protein-protein interaction (PPI) network analysis, and the MCODE tool was used to identify key protein interaction sub-networks. Finally, immunofluorescence and coimmunoprecipitation were performed to analyze the subcellular localization and interaction changes of the C19orf12 mutant proteins. Results: C19orf12 was expressed at relatively high levels in H1299 cells and its knockdown significantly inhibited cell growth. Proteomic analysis identified 216 significantly differentially expressed proteins, with 132 upregulated and 84 downregulated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that these differentially expressed proteins were mainly involved in pathways related to neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and Huntington's disease, as well as mitochondrial oxidative phosphorylation, lipid metabolism, and heart disease-related pathways. The pathogenic mutant of C19orf12 (p.Ala63Pro) lost the ability to interact with multiple key proteins. Conclusion: C19orf12 plays a key role in cell growth, mitochondrial oxidative phosphorylation, lipid metabolism, and cardiac disease, and its mutation can lead to alterations in protein interaction networks. [ABSTRACT FROM AUTHOR]

Metallic foams have become a cutting-edge solution for many thermal management problems. These are of interest by thermal research community because of the cellular structure and have gas-filled pores inside a metal matrix. Due to the uniqueness in their structure, they exhibit good performance in boiling heat transfer because of the properties such as higher specific surface area, large number of nucleation sites, wettability characteristics, and capillary action. The boiling heat transfer over metal foam is a complex phenomenon, greatly affected by the thickness, porosity, and pores per inch (PPI) of metal foam along with the thermo-physical properties of the foam and boiling liquid. By thoroughly examining recent research investigations, the paper explains the impact of open-cell metal foams on pool boiling of different liquids such as water, refrigerants, organic liquids, and dielectric liquids. This paper reviews the complexity and various influencing factors involved in flow boiling through metal foam in tubes. It also highlights findings that show metal foam significantly enhances jet impingement boiling heat transfer. Moreover, the discussion on gradient metal foams, offering insights into their potential to enhance boiling heat transfer. The comprehensive review also encompasses numerical modeling studies, such as the lattice Boltzmann method, contributing to a deeper understanding of the intricate flow and heat transfer characteristics within channels filled with metal foam. [ABSTRACT FROM AUTHOR]

Background Proton pump inhibitors (PPIs) are often prescribed to manage corticosteroid-induced gastrointestinal toxicity during glioblastoma (GBM) treatment, but were recently identified as strong inducers of aldehyde dehydrogenase-1A1 (ALDH1A1). ALDH1A1 is a primary metabolic enzyme impacting the outcome of chemotherapy, including temozolomide. High expression of ALDH1A1 is associated with poor prognosis in multiple cancers, suggesting PPIs may have a negative impact on survival. Methods Real-world data on GBM patients was annotated from electronic medical records (EMR) according to the prospective observational study, XCELSIOR (NCT03793088). Patients with known IDH1/2 mutations were excluded. Causal effects on survival were analyzed using a multivariate, time-varying Cox Proportional Hazard (CPH) model with stratifications including MGMT methylation status, age, sex, duration of corticosteroid use, extent of resection, starting standard-of-care, and PPI use. Results EMR data from 554 GBM patients across 225 cancer centers was collected, with 72% of patients receiving care from academic medical centers. Patients treated with PPIs (51%) had numerically lower median overall survival (mOS) and 2-year OS rates in the total population and across most strata, with the greatest difference for MGMT-methylated patients (mOS 29.2 vs. 40.1 months). In a time-varying multivariate CPH analysis of the above strata, PPIs caused an adverse effect on survival (HR 1.67 [95% CI: 1.15–2.44], P  = .007). Conclusions Evidence from a nationwide cancer registry has suggested PPIs have a negative impact on OS for GBM patients, particularly those with MGMT promoter methylation. This suggests PPIs should be avoided for prophylactic management of gastrointestinal toxicity in patients with GBM receiving chemoradiotherapy. [ABSTRACT FROM AUTHOR]

Background and Aim: Helicobacter pylori infection is one of the most common bacterial infections affecting humans, causing gastroduodenal and extraintestinal diseases. Treatment of the infection remains challenging for the clinicians, and different factors are involved in the failure of the therapeutic approach. The importance of the intensity of acid secretion inhibition remains an unclear issue. The aim of this study is to assess whether 80 mg/day esomeprazole‐based 10‐day sequential therapy (esomeprazole‐ST) achieved different eradication rates when compared to 80 mg/day pantoprazole‐based analogous regimen (pantoprazole‐ST). Methods: This was a retrospective observational study where data of consecutive patients referred by their physicians to our unit to perform an upper gastrointestinal endoscopy were analyzed. Results: Overall, 1,327 patients were available for the analysis: 599 and 728 patients received pantoprazole‐ST and esomeprazole‐ST, respectively. Eradication rate was significantly higher in patients receiving esomeprazole‐ST (92.6%, 95% CI: 91–94.5) than pantoprazole‐ST (89.3%, 95% CI: 86.7–91.7; difference: 3.3%; 95% CI: 0.2–6.5; P = 0.037). Even after a multivariate analysis, the esomeprazole‐ST achieved a significantly higher eradiation (OR: 1.44; 95% CI: 1.1–2.17). Conclusions: This study showed that esomeprazole‐ST achieved significantly higher H. pylori cure rates than pantoprazole‐ST. Prospective and well‐designed trials are demander to confirm this prelaminar finding. [ABSTRACT FROM AUTHOR]

Introduction: Proton pump inhibitors (PPIs) are anti-ulcer drugs that have reportedly been used inappropriately in therapeutic settings, raising the risk of adverse effects, drug interactions, and costs. Aim: This study aimed to evto evaluate the inappropriate use of PPI medication and which category of PPIs frequently was used for patients in Bangladeshi hospitals. Material and Methods: A one month cross-sectional study was carried out in a tertiary care hospital to evaluate the kinds of PPI prescriptions, their appropriateness, and their tendency to be utilized among patients. Results: Among 298 patients interviewed,140 patients used PPIs inappropriately. The most common reasons for inappropriate use included gastric appetite (29.59%, 29 individuals) and nausea. Other reasons included (15%) no clear indication, (20%) gastric discomfort, (13.57%) asthma, and (8.57%) infections. Esomeprazole was the most prescribed PPI, used by 41% of patients, followed by omeprazole at 32%. Nearly 44% of the 140 patients exhibited a strong tendency to use PPIs. Conclusion: Important steps must be taken to ensure that PPIs are used properly, to increase knowledge, and implement educational TV programs that can reduce the risk of drug interactions, side effects, and unnecessary expenses. [ABSTRACT FROM AUTHOR]