Research Square最新文献

{"title":"Effective xanthine oxidase inhibitor urate lowering therapy in gout is linked to an emergent serum protein interactome of complement activation and inflammation modulators","authors":"Concepcion Sanchez, Anaamika Campeau, R. Liu-Bryan, Ted R Mikuls, James R O'Dell, David J Gonzalez, R. Terkeltaub","doi":"10.21203/rs.3.rs-4278877/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4278877/v1","url":null,"abstract":"Abstract Background Urate-lowering treatment (ULT) to target with xanthine oxidase inhibitors (XOIs) paradoxically causes early increase in gouty arthritis flares. Because delayed reduction in flare burden is mechanistically unclear, we tested for ULT inflammation responsiveness markers. Methods Unbiased proteomics analyzed blood samples (baseline, 48 weeks ULT) in two, independent ULT out trial cohorts (n = 19, n = 30). STRING-db and multivariate analyses supplemented determinations of altered proteins via Wilcoxon matched pairs signed rank testing in XOI ULT responders. Mechanistic studies characterized proteomes of cultured XOI-treated murine bone marrow macrophages (BMDMs). Results At 48 weeks ULT, serum urate normalized in all gout patients, and flares declined, with significantly altered proteins (p < 0.05) in clustering and proteome networks in sera and peripheral blood mononuclear cells. Serum proteome changes included decreased complement C8 heterotrimer C8A and C8G chains and chemokine PPBP/CXCL7, and increased urate crystal phagocytosis inhibitor sCD44. In both cohorts, a treatment-emergent serum interactome included key gouty inflammation mediators (C5, IL-1B, CXCL8, IL6). Last, febuxostat inhibited complement activation pathway proteins in cultured BMDMs. Conclusions Reduced gout flares are kinked with a XOI-treatment emergent complement- and inflammation-regulatory serum protein interactome. Serum and leukocyte proteomes could help identify onset of anti-inflammatory responsiveness to ULT in gout. Trial Registration ClinicalTrials.gov Identifier: NCT02579096, posted October 19, 2015","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140994470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Virtual Screening of Molecules via Neural Fingerprint-based Deep Learning Technique","authors":"Rivaaj Monsia, Sudeep Bhattacharyya","doi":"10.21203/rs.3.rs-4355625/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4355625/v1","url":null,"abstract":"Abstract A machine learning-based drug screening technique has been developed and optimized using convolutional neural network-derived fingerprints. The optimization of weights in the neural network-based fingerprinting technique was compared with fixed Morgan fingerprints in regard to binary classification on drug-target binding affinity. The assessment was carried out using six different target proteins using randomly chosen small molecules from the ZINC15 database for training. This new architecture proved to be more efficient in screening molecules that less favorably bind to specific targets and retaining molecules that favorably bind to it. Scientific contribution We have developed a new neural fingerprint-based screening model that has a significant ability to capture hits. Despite using a smaller dataset, this model is capable of mapping chemical space similar to other contemporary algorithms designed for molecular screening. The novelty of the present algorithm lies in the speed with which the models are trained and tuned before testing its predictive capabilities and hence is a significant step forward in the field of machine learning-embedded computational drug discovery.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140996230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Applying Metabolomics and Aptamer-based Proteomics to Determine Pathophysiologic Differences in Decompensated Cirrhosis Patients Hospitalized with Acute Kidney Injury","authors":"Giuseppe Cullaro, Andrew S. Allegretti, Kavish R. Patidar, Elizabeth C. Verna, Jennifer C. Lai","doi":"10.21203/rs.3.rs-4344179/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4344179/v1","url":null,"abstract":"Abstract Methods A case-control study of 97 patients hospitalized at our institution. We performed aptamer-based proteomics and metabolomics on serum biospecimens obtained within 72 hours of admission. We compared the proteome and metabolome by the AKI phenotype (i.e., HRS-AKI, ATN) and by AKI recovery (decrease in sCr within 0.3 mg/dL of baseline) using ANCOVA analyses adjusting for demographics and clinical characteristics. We completed Random Forest (RF) analyses to identify metabolites and proteins associated with AKI phenotype and recovery. Lasso regression models were developed to highlight metabolites and proteins could improve diagnostic accuracy. Results: ANCOVA analyses showed no metabolomic or proteomic differences by AKI phenotype while identifying differences by AKI recovery status. Our RF and Lasso analyses showed that metabolomics can improve the diagnostic accuracy of both AKI diagnosis and recovery, and aptamer-based proteomics can enhance the diagnostic accuracy of AKI recovery. Discussion: Our analyses provide novel insight into pathophysiologic pathways, highlighting the metabolomic and proteomic similarities between patients with cirrhosis with HRS-AKI and ATN while also identifying differences between those with and without AKI recovery.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140996978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Undergarment Needs and Challenges for Breast Cancer Survivors: A Qualitative Study","authors":"Yen-Tung Liu, Novera H. Khan, Krista M. Nicklaus, Marie Karen Bravo Moix, Chi Liu, Gregory P. Reece, Ashleigh M. Francis, Margaret J. Roubaud, Mia K. Markey","doi":"10.21203/rs.3.rs-4307935/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4307935/v1","url":null,"abstract":"Abstract Purpose Breast cancer surgery, even with reconstruction, can make it difficult for patients to find a bra that fits properly, is comfortable, and meets their aesthetic standards. We explored breast cancer survivors’ experiences with bras over time to identify preferences, needs, and challenges throughout their journeys. Methods Fifteen women who had undergone mastectomy and either delayed or immediate breast reconstruction participated in the study. Focus groups were conducted to explore the participants’ current experiences with bras. They were also prompted to recall their experiences before mastectomy and immediately after reconstruction. The discussion included bra materials, styles, construction techniques, color, quality, and price. Results Thematic analysis generated five major themes: “Sense of normalcy and personal well-being,” “Struggles immediately following surgery,” “Transitions in bra experiences and preference,” “Practicality with outfit,” and “Association between quality and price”. Conclusion Breast cancer survivors' well-being is linked to their experiences with bras and the associated purchasing process, and bra needs change throughout the cancer care journey. Survivors’ experiences with bras impact their sense of normalcy and sense of control over significant bodily changes arising from cancer and its treatment. The study underscores the importance of future research on examining the relationship between survivors' quality of life and garment experiences, including factors such as color choices, closure options, and adjustability for individual needs.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140996731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thermo-ring basis for heat unfolding-induced inactivation in TRPV1.","authors":"Guangyu Wang","doi":"10.21203/rs.3.rs-3280283/v1","DOIUrl":"10.21203/rs.3.rs-3280283/v1","url":null,"abstract":"<p><p>Transient receptor potential vanilloid-1 (TRPV1) is a capsaicin receptor and employs the use-dependent desensitization to protect mammals from noxious heat damage in response to repeated or constant heat stimuli. However, the underlying structural factor or motif has not been resolved precisely. In this computational study, the graph theory-based grid thermodynamic model was used to reveal how the temperature-dependent noncovalent interactions as identified in the 3D structures of rat TRPV1 could develop a well-organized fluidic grid-like mesh network, featuring various topological grids constrained as the thermo-rings that range in size from the biggest to the smallest to govern distinct structural and functional traits of the channel in response to varying temperature degrees. Following the findings that the heat unfolding of three specific biggest grids, one in the closed state and two in the open state, was respectively responsible for the reversible activation at 43 °C and thermal inactivation from 56 °C to 61 °C, a random smaller grid was further identified for the irreversible inactivation and the relevant use-dependent desensitization from the pre-open closed state between 43 °C and 61 °C. Thus, these two distinct inactivation pathways of TRPV1 may be involved in protecting mammals against noxious heat damages.</p>","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10479453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10213335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The MTIST platform: a microbiome time series inference standardized test","authors":"Jonas Schluter, Grant A. Hussey, João Valeriano, Chenzhen Zhang, Alexis Sullivan, David Fenyö","doi":"10.21203/rs.3.rs-4343683/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4343683/v1","url":null,"abstract":"Abstract The human gut microbiome is a promising therapeutic target, but interventions are hampered by our limited understanding of microbial ecosystems. Here, we present a platform to develop, evaluate, and score approaches to learn ecological interactions from microbiome time series data. The microbiome time series inference standardized test (MTIST) comprises: a simulation framework for the in silico generation of microbiome study data akin to what is obtained with quantitative next-generation sequencing approaches, a compilation of a large curated data set generated by the simulation framework representing 648 simulated microbiome studies containing 18,360 time series, with a total of 2,182,800 species abundance measurements, and a scoring method to rank ecological inference algorithms. We use the MTIST platform to rank five implementations of microbiome inference approaches, revealing that while all algorithms performed well on ecosystems with few species (3 and 10), all algorithms failed to infer most interaction in a large ecosystem with 100 member species. However, we do find that the strongest interactions within a large ecosystem are inferred with higher success by all algorithms. Finally, we use the MTIST platform to compare different microbiome study designs, characterizing tradeoffs between samples per subject and number of subjects. Interestingly, we find that when only few samples can be collected per subject, ecological inference is most successful when these samples are collected with highest feasible temporal frequency. Taken together, we provide a computational tool to aid the development of better microbiome ecosystem inference approaches, which will be crucial towards the development of reliable and predictable therapeutic approaches that target the microbiome ecosystem.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141000117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emotional and Psychological Experiences of Nursing students caring for Dying Patients: A phenomenology study at Mulago National Hospital, Uganda","authors":"Asha K. Nabirye, I. Munabi, A. Mubuuke, Sarah Kiguli","doi":"10.21203/rs.3.rs-4323878/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4323878/v1","url":null,"abstract":"Abstract Introduction: Caring for dying patients is associated with psychological trauma, strong emotions and enormous stress for nursing staff and nursing students who are relied on by patients and relatives in such difficult situations. Although nurses have an ability of self-control and calm approach towards death, there are still some emotions they need to “work through”. Research studies have documented limited exposure of nursing students to end-of-life care and inadequate understanding of the psychological and emotional experiences they encounter during clinical placements. This study explored the psychological and emotional experiences of Ugandan student nurses on caring for the dying patients at Mulago national referral hospital during clinical placement. Methods A qualitative phenomenological study was conducted among fifteen undergraduate nursing students of Makerere University in clinical placement at Mulago hospital. An In-depth interview guide was used to gather data on nursing students’ emotional and psychological experiences and coping mechanisms. Data was audio recorded, verbatim transcribed and thematically analyzed using Atlas. ti version 6 software. Results The nursing students emotional and psychological experiences when caring for dying patients were emerged into two themes; (1) Psychological and emotional reactions, (2) Coping mechanisms. The sub themes were; anger, anxiety and depression which is triggered by a combination of issues of pressure from relatives, failure to save the dying patient, thoughts of wasted efforts to reverse the dying process, limited resources, limited technical and emotional support. The students cope by seeking help from peers, engagement in problem solving, distancing from patients, spirituality and engaging in personal stress reducing activities. Conclusion Insights from this study provide educators with a snapshot of student encounters, emotions, and coping strategies when facing dying patients and their families. Nursing students experience various negative emotional and psychological stressors triggered by a combination of issues that need to be addressed during care of dying patients. However, they devise different coping mechanisms to continue with provision of necessary end of life care as the clinical placement contributes to their learning, experience and builds confidence among student nurses.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141000928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fas Ligand enhances vessel maturation and inhibits vascular leakage associated with age-related macular degeneration","authors":"Adarsha Koirala, Ann Marshak-Rothstein, Bruce R. Ksander, M. Gregory-Ksander","doi":"10.21203/rs.3.rs-4331250/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4331250/v1","url":null,"abstract":"Abstract Neovascular age-related macular degeneration (AMD), results from choroidal neovascularization (CNV), retinal edema and loss of photoreceptors. Previous studies suggested that Fas Ligand (FasL) on retinal pigment epithelial cells inhibited CNV by inducing apoptosis of infiltrating Fas + vascular endothelial cells. However, induction of apoptosis depends on membrane-bound (mFasL) while the FasL cleavage product (sFasL) is neuroprotective. To better understand how FasL regulates the development of CNV, we used a mouse model of laser CNV to evaluate the development of CNV in mice with a FasL cleavage site mutation (ΔCS) and can only express the membrane-bound form of FasL. There was no significant difference in CNV size and area of vascular leakage in homozygous FasL ΔCS/ΔCS mice when compared to wild type mice. Unexpectedly, heterozygous FasL ΔCS/WT mice developed significantly less vascular leakage and showed accelerated neovessel maturation. However, CNV was not prevented in heterozygous FasL ΔCS/WT mice if the Fas receptor was deleted in myeloid cells (FasL ΔCS/+ Fas flox/flox Cre LysM ). Thus, FasL-mediated CNV inhibition depends on the extent of FasL cleavage, and on FasL engagement of Fas + myeloid cells. Moreover, accelerated neovessel maturation prevents vascular leakage in AMD.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141000494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Knowledge and perceptions of religious leaders toward HIV prevention among young people in a resource-limited setting: A qualitative study","authors":"Tom Murungi, Irene Kunihira, Pamela Oyella, M. Mugerwa, Peruth Gift, Mercy Jane Aceng, Lydia Abolo, Sean Steven Puleh","doi":"10.21203/rs.3.rs-3442966/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3442966/v1","url":null,"abstract":"Abstract Background: Currently, 410,000 new HIV infections among youth occur worldwide, which is a significant public health issue. Members of the clergy can be trustworthy allies in the reduction of HIV infections among the youth. However, little is known regarding their knowledge as well as the perceptions they hold towards HIV prevention among young people. Thus, we explored the knowledge and perceptions of religious leaders regarding HIV prevention among young people (15–24 years) in Lira district. Methods: This was a cross-sectional qualitative study conducted among 20 religious leaders in March 2021 in Lira district. Religious leaders were sampled purposively and recruited from modern religions (beliefs influenced by Christianity or Islam) in Lira district. Guides for key informant interviews were utilized to gather information. Each interview was audio recorded, transcribed, and entered into NVivo version 12 software, and the data was then ready for analysis. The main themes were determined using thematic analysis. Results: Although a few individuals had some misconceptions, the majority of participants had good knowledge about the transmission and prevention of HIV. Participants knew awareness creation, abstinence, and faithfulness in marriage as HIV prevention strategies and held positive perceptions. Perceived barriers to HIV prevention involvement were lack of knowledge and training, and inadequate resources whereas motivating factors were; being respected, and trusted, and having easy access to young people. Conclusion: In conclusion, religious leaders show limited HIV prevention knowledge due to religious beliefs, but understand the importance of measures like abstinence. Despite challenges, their involvement is crucial. Addressing knowledge gaps and providing support is vital. Future efforts should emphasize both behavioral measures and interventions like condom use, Post Exposure Prophylaxis, and Pre-Exposure Prophylaxis.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141000065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retinopathy of prematurity and neurodevelopmental outcome and quality of life at 10 years of age","authors":"Sudhir Sri, Elizabeth T. Jensen, Michael E. Msall, Joe Yi, Vasyl Zhabotynsky, Robert Joseph, Karl Kuban, Jean A. Frazier, Stephen Hooper, Hudson Santos, S. Gogcu, Jeffrey S Shenberger, Rebecca C Fry, T. O'Shea","doi":"10.21203/rs.3.rs-4324566/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4324566/v1","url":null,"abstract":"Abstract Objective In a cohort of 10-year-old children born extremely preterm, we evaluated the hypothesis that increasing severity of retinopathy of prematurity (ROP) is associated with increasing frequency of unfavorable neurodevelopmental and quality of life outcomes. Study Design Study participants were classified according to the severity of ROP. At 10 years of age, their neurocognitive abilities, academic achievement, and gross motor function were assessed, and they were evaluated for autism spectrum disorder, anxiety, depression, and quality of life. Results After adjustment for sample attrition and confounders, only the association with lower quality of life persisted. Increasing severity of visual impairment was associated with worse neurodevelopmental outcomes and lower quality of life. Conclusion Among extremely preterm children, severity of visual impairment, but not severity of ROP, was associated with adverse neurodevelopmental outcomes at 10 years of age. Both severe ROP and more severe visual impairment were associated with lower quality of life.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140999067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}