Research Square (Research Square)最新文献

{"title":"CXCL9 recombinant adeno-associated virus (AAV) virotherapy sensitizes glioblastoma (GBM) to anti-PD-1 immune checkpoint blockade","authors":"Christina von Roemeling, Oleg Yegorov, Changlin Yang, Kelena Klippel, Rylynn Russell, Vrunda Trivedi, Alisha Bhatia, Bently Doonan, Savannah Carpenter, Daniel Ryu, Adam Grippen, Hunter Futch, Yong Ran, Lan Hoang-Minh, Frances Weidert, Todd Golde, Duane Mitchell","doi":"10.21203/rs.3.rs-3463730/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3463730/v1","url":null,"abstract":"Abstract The promise of immunotherapy to induce long-term durable responses in conventionally treatment resistant tumors like glioblastoma (GBM) has given hope for patients with a dismal prognosis. Yet, few patients have demonstrated a significant survival benefit despite multiple clinical trials designed to invigorate immune recognition and tumor eradication. Insights gathered over the last two decades have revealed numerous mechanisms by which glioma cells resist conventional therapy and evade immunological detection, underscoring the need for strategic combinatorial treatments as necessary to achieve appreciable therapeutic effects. However, new combination therapies are inherently difficult to develop as a result of dose-limiting toxicities, the constraints of the blood-brain barrier, and the suppressive nature of the GBM tumor microenvironment (TME). GBM is notoriously devoid of lymphocytes driven in part by a paucity of lymphocyte trafficking factors necessary to prompt their recruitment, infiltration, and activation. We have developed a novel recombinant adeno-associated virus (AAV) gene therapy strategy that enables focal and stable reconstitution of the GBM TME with C-X-C motif ligand 9 (CXCL9), a powerful call-and-receive chemokine for cytotoxic T lymphocytes (CTLs). By precisely manipulating local chemokine directional guidance, AAV-CXCL9 increases tumor infiltration by CD8-postive cytotoxic lymphocytes, sensitizing GBM to anti-PD-1 immune checkpoint blockade (ICB). These effects are accompanied by immunologic signatures evocative of an inflamed and responsive TME. These findings support targeted AAV gene therapy as a promising adjuvant strategy for reconditioning GBM immunogenicity given its excellent safety profile, TME-tropism, modularity, and off-the-shelf capability, where focal delivery bypasses the constrains of the blood-brain barrier, further mitigating risks observed with high-dose systemic therapy.","PeriodicalId":500086,"journal":{"name":"Research Square (Research Square)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134901553","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":"Characterisation and mapping of a Globodera pallida resistance derived from the wild potato species Solanum spegazzinii","authors":"Ulrike Gartner, Miles R Armstrong, Sanjeev K Sharma, John T Jones, Vivian C Blok, Ingo Hein, Glenn J Bryan","doi":"10.21203/rs.3.rs-3583787/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3583787/v1","url":null,"abstract":"Abstract The potato cyst nematodes (PCN) Globodera pallida and Globodera rostochiensis are economically important potato pests in almost all regions where potato is grown. One important management strategy involves deployment through introgression breeding into modern cultivars of new sources of naturally occurring resistance from wild potato species. We describe a new source of resistance to G. pallida from wild potato germplasm . The diploid species Solanum spegazzinii Bitter accession CPC 7195 shows resistance to G. pallida pathotypes Pa1 and Pa2/3. A cross and first backcross of S. spegazzinii with Solanum tuberosum Group Phureja cultivar Mayan Gold was performed, and the level of resistance to G. pallida Pa2/3 was determined in progeny clones. Bulk-segregant analysis (BSA) using generic mapping enrichment sequencing (GenSeq) and genotyping-by-sequencing (GBS) was performed to identify single-nucleotide polymorphisms (SNPs) that are genetically linked to the resistance, using S. tuberosum Group Phureja clone DM1-3 516 R44 as a reference genome. These SNPs were converted into allele specific PCR assays, and the resistance was mapped to an interval of roughly 118 kb on chromosome VI. This newly identified resistance can be used in future efforts to produce modern cultivars with enhanced and broad-spectrum resistances to the major pests and pathogens of potato.","PeriodicalId":500086,"journal":{"name":"Research Square (Research Square)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134901567","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":"The psychology of Mona Lisa’s expression","authors":"Alessandro Soranzo","doi":"10.21203/rs.3.rs-3593306/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3593306/v1","url":null,"abstract":"Abstract The Mona Lisa's ambiguous expression has captivated viewers for centuries, prompting diverse explanations. This article proposes a novel interpretation grounded in the psychological theory of perceptual organisation. Central to the investigation is the “Ambiguity Smudge”, a dark region above the mouth, hypothesised to influence perceived expression due to perceptual organization. Through carefully crafted artwork and systematic manipulations of Mona Lisa reproductions, experiments reveal how alterations of the Ambiguity Smudge generate distinct expressions. Specifically, the manipulation of the perceptual relationships between the Ambiguity Smudge and the mouth yields significant shifts in perceived expression. These findings not only underscore the pivotal role of psychological principles in shaping ambiguous expressions in the Mona Lisa, but also extend to other Leonardo’s portraits, namely La Bella Principessa and Scapigliata. This study sheds light on the intersection of psychology and art, offering new perspectives on timeless masterpieces.","PeriodicalId":500086,"journal":{"name":"Research Square (Research Square)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134902830","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":"Remnant cholesterol and the risk of carotid plaque in hypertension: results from a community-based screening in Hangzhou, China","authors":"Zhecong Yu, Haifeng Yang, Biqi Shou, Zongxue Cheng, Caixia Jiang, Yang Ye, Jue Xu","doi":"10.21203/rs.3.rs-3582263/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3582263/v1","url":null,"abstract":"Abstract Background Elevated remnant cholesterol (RC) is considered a risk factor for atherosclerotic cardiovascular disease, but whether this association applies to the Chinese population with hypertension has not been found. We aimed to explore the association between RC levels and carotid plaque in patients with hypertension. Methods 8523 hypertensive patients aged ≥ 60 years with serum lipids and carotid ultrasonography data were included in this community-based screening. Fasting RC was calculated as total cholesterol minus high-density lipoprotein cholesterol minus low-density lipoprotein cholesterol (LDLC). The associations of RC levels with carotid plaque risk were evaluated using Logistic regression and restricted cubic spline models. Results Carotid plaque was screened in 4821 (56.6%) subjects. After multivariable-adjusted, RC was significantly related to carotid plaque [Odd ratio (OR)] = 1.043 per 0.1 mmol/L increase, 95% confidence interval (CI): 1.031–1.056]. The highest versus lowest quartile of RC was 1.928 (1.673–2.223) for carotid plaque. A nonlinear association was found between serum RC levels and the risk of carotid plaque (P for nonlinearity < 0.001). Moreover, an RC > 0.78 mmol/L differentiated patients at a higher risk of carotid plaque compared to those at lower concentrations, regardless of whether LDLC was on target at 2.59 mmol/L. Conclusion In Chinese patients with hypertension, elevated RC was positively associated with carotid plaque, independent of LDLC and other conventional risk factors.","PeriodicalId":500086,"journal":{"name":"Research Square (Research Square)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134991187","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":"In-silico classification and antigen library expression of Plasmodium falciparum STEVOR hypervariable infected erythrocyte surface-expressed multivariant protein family","authors":"Hristina Vasileva, Ernest Diez Benavente, Anna Last, Kevin KA Tetteh","doi":"10.21203/rs.3.rs-3591844/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3591844/v1","url":null,"abstract":"Abstract Background Malaria pathogenesis is dependent on complex interactions between host and parasite factors, where variant surface antigens such as the Pf EMP1 protein family play a critical role in disease severity through various mechanisms, including immune evasion, cytoadherence and sequestration. The under characterised infected erythrocytes variant surface-expressed antigens of the STEVOR protein family are also implicated in cytoadherence and rosette formation exhibiting high antigenic variability, potentially contributing to parasite immune evasion. This study describes a novel approach for the construction of a comprehensive library of STEVOR recombinant antigens. Methods This study used all available STEVOR protein sequence data from the PlasmoDB database to classify the variability between STEVOR members within isolates and between isolates. We have used bioinformatic and mathematical approaches to design an in-silico model to study the protein family variability with 100% reproducibility when performed on the same data set. Using information from the model, we have designed constructs and have expressed them with the CyDisCo co-expression plasmid to create the first STEVOR recombinant antigen library in a competent E. coli expression system. Finally, we have proven the recombinants antigenicity using the multiplex magnetic bead-based assay: Luminex. Results The large hypervariable domain of STEVOR protein family exhibited the highest variability with a mean diversity of 52.1%, as compared to the semi-conserved and the conserved STEVOR domains. The variability was captured in a library of 13 representative sequences, mostly derived from West African isolates. Those variants were expressed as recombinant proteins in BL21(DE3) E. coli competent cells together with the CyDisCo co-expression plasmid. The recombinants varied in expression levels, but not in antigenicity. Three semi-conserved recombinant antigens were also expressed as controls and those although with smaller size, demonstrated higher reactivity as compared to the variable domain recombinants. Conclusions This study presents an in-silico model that effectively elucidates the spatial relationship between amino acid sequences, applicable to sequence data from any organism. Moreover, it presents the first library of STEVOR hypervariable domain recombinant antigens. Expressed antigens have potential applications in serological studies as indicators of exposure to infection and to further dissect STEVOR variants associated with severe malarial disease outcome.","PeriodicalId":500086,"journal":{"name":"Research Square (Research Square)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134991343","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":"Analytical solution to the simultaneous Michaelis-Menten and second-order kinetics problem","authors":"Alejandro Perez Paz","doi":"10.21203/rs.3.rs-3590843/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3590843/v1","url":null,"abstract":"Abstract An analytic solution is presented for the simultaneous substrate elimination problem that combines Michaelis-Menten (MM) consumption with an irreversible second-order kinetics process.The implicit solution involves logarithm and inverse tangent functions and perfectly agrees with the numerical solution of the differential equation. A solution is also presented for the generalized dynamical problem that simultaneously combines MM kinetics with first and second-order processes.Useful exact expressions such as the half-life and the area under the curve are also derived for these problems.","PeriodicalId":500086,"journal":{"name":"Research Square (Research Square)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134991361","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":"Topological transformation from non-van der Waals solids to 2D transition metal chalcogenides in molten salts with solvated metals","authors":"Mian Li, Lin Gao, Kun Liang, Qing Huang","doi":"10.21203/rs.3.rs-3461588/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3461588/v1","url":null,"abstract":"Abstract Transition metal chalcogenides (TMCs) have attracted great attention due to their wide range of applications. The TMCs have been widely synthesized using techniques such as exfoliation and vapor-phase growth, while their structure and constituent tuning remains a challenge. Here, we show a general route to synthesize 2D TMCs by topological transformation of AMX 2 -type ternary metal chalcogenides in molten salts with solvated metals. In this process, the solvated metals in the molten salts play a role of etchant that can remove the A-layer atoms from the AMX 2 structure, resulting in the formation of laminated MX 2 layers. The laminated MX 2 layers provide natural template for cations intercalation or atom substitution to form 2D TMCs with various structures. In the present work, 2D TMCs with tunable stoichiometries (e.g. Cr 2 S 3 , Cr 3 S 4 , Cr 5 S 6 , and Cr 7 S 8 ), as well as 2D TMCs with heterostructures (e.g. Cr 2 S 3 -Ti 0.5 CrS 2 , Cr 2 S 3 -NbS 2 , and Cr 2 S 3 -HfS 2 ) were obtained. We further explored the potential of this route to tail the dielectric properties and improve the electromagnetic wave absorption ability of the chromium sulfides. This approach shows advantage in exploring 2D structures with unprecedented constituent and we believe it will open up opportunities for tuning the properties and broaden the functional applications of TMCs.","PeriodicalId":500086,"journal":{"name":"Research Square (Research Square)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134991578","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":"Direct and indirect impacts of urbanization on ecosystem health based on PLS-SEM in Xiangyang, China","authors":"ZHOU Yao","doi":"10.21203/rs.3.rs-3593308/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3593308/v1","url":null,"abstract":"Abstract This study proposes a framework for investigating the direct and indirect impacts of urbanization on ecosystem health by introducing partial least squares structural equation model (PLS-SEM), the method is then applied to Xiangyang, Hubei Province, China. The validity and reliability evaluation show that PLS-SEM model is reasonable. The results showed that the level of ecosystem health in Xiangyang decreased significantly in 2010–2020. Only spatial urbanization (SU) had a direct impact on ecosystem health (-0.251/-0.262), showing a negative correlation. Population urbanization (PU) had an impact on economic urbanization (EU) (0.687/0.662), and economic urbanization (EU) had an impact on spatial urbanization (SU) (0.634/0.702). Population urbanization (PU) and economic urbanization (EU) have indirect effects on ecosystem health index (EHI). This study provides a quantitative method to determine the causes of the decline in ecosystem health, which is essential for more effective measures to maintain ecosystem health. The two objectives of this study are: (1) To establish a framework for analyzing the impacts of urbanization on ecosystem health; (2) To quantify the direct and indirect impacts and interactions of urbanization on ecosystem health.","PeriodicalId":500086,"journal":{"name":"Research Square (Research Square)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134991627","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":"Effectiveness of a blended school-based mindfulness program for the prevention of co-rumination and internalizing problems in Dutch secondary school girls: a Cluster Randomized Controlled Trial","authors":"Patricia Vuijk, Kim Bul, Marieke Buil, M Rauws, Keshia Curie, Char Amesz, R Weerheijm, Heleen Riper","doi":"10.21203/rs.3.rs-3265929/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3265929/v1","url":null,"abstract":"Abstract Background: A growing body of literature indicates that adolescent girls who talk with close friends about interpersonal problems or worries in an excessive, speculative way and with an intense focus on distress (i.e., co-rumination ) are at heightened risk for developing internalizing symptoms and disorders as well as reduced friendship quality. However, to date, there are no prevention programs available that target high levels of co-rumination between adolescent girls. As such, we developed the blended school-based mindfulness prevention program Happy Friends, Positive Minds (HFPM) that targets co-rumination at the dyadic level, i.e., between two close female friends. The aim of this trial is to evaluate the effectiveness of HFPM to reduce co-rumination and internalizing problems and to enhance wellbeing and social-emotional behavior in Dutch adolescent girls. Methods : A cluster Randomized Controlled Trial (cRCT) will be conducted to evaluate HFPM effectiveness. We will recruit 160 female friendship dyads ( n = 320 girls) aged 13 to 15 years who will be characterized by high levels of self-reported co-rumination. The cRCT has two arms: (1) an intervention condition in which 160 girls (80 friendship dyads) will receive the 14-week HFPM program, and (2) a control condition in which 160 girls (80 dyads) will receive care-as-usual (CAU). Data will be collected at baseline (T0: October 2023), during the program (T1: December 2023; T2: February 2024; T3: April 2024), immediately after the program (T4: July 2024) and at one-year follow-up (T5: July 2025). Participant-level self-reported risk for (early onset) depression and anxiety, self-reported and observed co-rumination, self- and friend-reported friendship quality, self-reported positive and negative affect, self-reported interpersonal responses to positive affect and self-reported anhedonia symptoms will be the outcome variables. Discussion: This study will provide insights into the short-term and long-term effects of the HFPM program on girls’ internalizing problems, wellbeing and social-emotional behavior. Trials registration : International Standard Randomized Controlled Trials, identifier: ISRCTN54246670. Registered on 27 February 2023.","PeriodicalId":500086,"journal":{"name":"Research Square (Research Square)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134991916","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":"Isotopic evidence for nickel limitation of biological productivity in the ocean","authors":"Tzu-Hao Wang, Qiong Zhang, Tu-Te Hsieh, Gideon Henderson, Rosalind Rickaby","doi":"10.21203/rs.3.rs-2207343/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-2207343/v1","url":null,"abstract":"Abstract Nickel (Ni) is an essential element for many important enzyme systems 1,2 . Two puzzling aspects of Ni biogeochemical cycling in the modern ocean have emerged. First, unlike a number of bio-essential elements, Ni is never fully depleted in the surface ocean 3-13 . Second, a heavy Ni isotopic composition in the surface ocean, indicative of removal of light isotopes likely by productivity, is not observed globally 6-13 . Active debate persists regarding the isotopic fractionation of Ni associated with biological uptake and the bioavailability of Ni in the ocean 7,9,11-13 . Here we show that, in contrast to biological isotopic fractionation for most other elements, three cosmopolitan phytoplankton species preferentially take up isotopically heavy Ni from the culture media, with species-dependent magnitudes of fractionation, under varying Ni availability. This fractionation towards heavy Ni isotopes can be explained, in our experiments, by the characteristic strong Ni-binding of cellular metal acquisition systems, relative to weaker binding by ligands in the culture media, with a secondary influence of cellular relocation and/or efflux. In the open ocean, an inferred stronger binding of Ni to ligands present in seawater, relative to that of the phytoplankton, yields the inverse fractionation (towards light isotopes in the biomass) and limits the bioavailability of metals in the surface ocean. Reconciling seawater Ni concentration and isotope data, results from incubation experiments, and marine gene biogeography, we demonstrate that Ni is limited for marine phytoplankton in the mid-latitude surface ocean with low Ni concentration and heavy Ni isotope composition, with implications for the significance of Ni bioavailability on both ocean productivity and carbon cycling.","PeriodicalId":500086,"journal":{"name":"Research Square (Research Square)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134991969","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}