bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early steps of multi-receptor viral interactions dissected by high-density, multi-color single molecule mapping in living cells
Authors: Mateos Nicolas , Gutierrez-Martinez Enric , Angulo-Capel Jessica , Carlon-Andres Irene , Padilla-Parra Sergi , Garcia-Parajo Maria F. , Torreno-Pina Juan Andres 
Published: October 2023

AbstractDirect visualization of the early steps of multi-receptor viral interactions at the singlemolecule level has been largely impeded by the technical challenges associated to imaging individual multi-molecular systems at relevant spatial (nanometer) and temporal (millisecond) scales. Here, we present a four-color, high-density single-molecule spatiotemporal mapping methodology to capture real-time interactions between individual viruses and three different viral (co-)receptors on the membrane of living immune cells derived from donors. Together with quantitative tools, our approach revealed the existence of a coordinated spatiotemporal diffusion of the three different (co-)receptors prior to viral-engagement. By varying the temporal-windows of cumulated single-molecule localizations, we discovered that such a concerted diffusion impacts on the residence time of viruses on the host membrane and potential viral infectivity. Overall, our methodology opens a new door to the systematic analysis of the initial steps of viralhost interactions and paves the way to the investigation of other multi-molecular systems at the single-molecule level.
RAG1 and RAG2 Non-core Regions Are Implicated in Leukemogenesis and Off-target V(D)J Recombination in BCR-ABL1-driven B-cell Lineage Lym-phoblastic Leukemia
Authors: Yu Xiaozhuo , Zhou Wen , Chen Xiaodong , He Shunyu , Qin Mengting , Yuan Meng , Wang Yang , Odhiambo Woodvine otieno , Miao Yinsha , Ji Yanhong 
Published: October 2023

AbstractThe evolutionary conservation of non-core RAG regions suggests significant roles that might involve quantitative or qualitative alterations in RAG activity. Off-target V(D)J recombination contributes to lymphomagenesis and is exacerbated by RAG2’ C-terminus absence in Tp53-/-mice thymic lymphomas. However, the genomic stability effects of non-core regions from both cRAG1 and cRAG2 inBCR-ABL1+Blymphoblastic leukemia (BCR-ABL1+B-ALL), the characteristics, and mechanisms of non-core regions in suppressing off-target V(D)J recombination remains unclear. Here, we established three mouse models ofBCR-ABL1+B-ALL in mice expressing full-length RAG (fRAG), core RAG1 (cRAG1), and core RAG2 (cRAG2). The cRAG (cRAG1 and cRAG2) leukemia cells exhibited greater malignant tumor characteristics compared to fRAG cells. Additionally, cRAG cells showed higher frequency of off-target V(D)J recombination and oncogenic mutations than fRAG. We also revealed decreased RAG cleavage accuracy in cRAG cells and a smaller recombinant size in cRAG1 cells, which could potentially exacerbate off-target V(D)J recombination in cRAG cells. In conclusion, these findings indicate that the non-core RAG regions, particularly the non-core region of RAG1, play a significant role in preserving V(D)J recombination precision and genomic stability inBCR-ABL1+B-ALL.
A dicer-like3 protein affects paramutation at multiple loci inZea mays
Authors: Narain Ankur S. , Liao Irene T. , Talbot Joy-El R.B. , Deans Natalie C. , Hollick Jay B. 
Published: October 2023

ABSTRACTParamutation is a process by which meiotically-heritable gene regulation is altered bytrans-homolog interactions. InZea mays, genetic screens for functions maintaining paramutation-induced repressed states have identified loci encoding small RNA biogenesis components, thus implicating small RNAs in mediating thesetrans-homolog communications. Here we report that therequired to maintain repression5locus encodes the sole dicer-like3 protein responsible for non-anther-specific 24-nucleotide RNA production. We found dicer-like3 is essential for mediating paramutation at thebooster1locus and for the meiotic maintenance of transcriptionally repressed states at thepurple plant1locus. Despite an expected role in mediating RNA-directed DNA methylation, we found 5-methylcytosine levels largely unchanged at multiple repetitive sequences indicer-like3mutants, with minimal compensation from other small RNA sizes. The minor effects on plant heights and flowering time seen in the absence of dicer-like3 contrasts with other paramutation mutants and we highlight one specific allele repressed by RNA polymerase IV yet unaffected by dicer-like3 loss. These findings highlight diverse regulatory functions for individual components of 24-nucleotide biogenesis occurring in the grasses and support a working model in which this small RNA size class mediatestrans-homolog interactions that drive meiotically-heritable changes in gene regulation.
ARF6-dependent endocytic trafficking of the Interferon-γ receptor drives adaptive immune resistance in cancer
Authors: Wee Yinshen , Wang Junhua , Wilson Emily C. , Rich Coulson P. , Rogers Aaron , Tong Zongzhong , DeGroot Evelyn , Gopal Y.N. Vashisht , Davies Michael A. , Ekiz H. Atakan , Tay Joshua K.H. , Stubben Chris , Boucher Kenneth M. , Oviedo Juan M. , Fairfax Keke C. , Williams Matthew A. , Holmen Sheri L. , Wolff Roger K. , Grossmann Allie H. 
Published: October 2023

AbstractAdaptive immune resistance (AIR) is a protective process used by cancer to escape elimination by CD8+T cells. Inhibition of immune checkpoints PD-1 and CTLA-4 specifically target Interferon-gamma (IFNγ)-driven AIR. AIR begins at the plasma membrane where tumor cell-intrinsic cytokine signaling is initiated. Thus, plasma membrane remodeling by endomembrane trafficking could regulate AIR. Herein we report that the trafficking protein ADP-Ribosylation Factor 6 (ARF6) is critical for IFNγ-driven AIR. ARF6 prevents transport of the receptor to the lysosome, augmenting IFNγR expression, tumor intrinsic IFNγ signaling and downstream expression of immunosuppressive genes. In murine melanoma, loss of ARF6 causes resistance to immune checkpoint blockade (ICB). Likewise, low expression of ARF6 in patient tumors correlates with inferior outcomes with ICB. Our data provide new mechanistic insights into tumor immune escape, defined by ARF6-dependent AIR, and support that ARF6-dependent endomembrane trafficking of the IFNγ receptor influences outcomes of ICB.
Hydrogel-polyurethane fiber composites with enhanced microarchitectural control for heart valve replacement
Authors: Robinson Andrew , Nkansah Abbey , Bhat Sanchita , Karnik Shweta , Jones Sarah , Fairley Ashauntee , Leung Jonathan , Wancura Megan , Sacks Michael , Dasi Lakshmi , Cosgriff-Hernandez Elizabeth 
Published: October 2023

AbstractPolymeric heart valves offer the potential to overcome the limited durability of tissue based bioprosthetic valves and the need for anticoagulant therapy of mechanical valve replacement options. However, developing a single-phase material with requisite biological properties and target mechanical properties remains a challenge. In this study, a composite heart valve material was developed where an electrospun mesh provides tunable mechanical properties and a hydrogel coating confers an antifouling surface for thromboresistance. Key biological responses were evaluated in comparison to glutaraldehyde-fixed pericardium. Platelet and bacterial attachment were reduced by 38% and 98%, respectively, as compared to pericardium that demonstrated the antifouling nature of the hydrogel coating. There was also a notable reduction (59%) in the calcification of the composite material as compared to pericardium. A custom 3D printed hydrogel coating setup was developed to make valve composites for device-level hemodynamic testing. Regurgitation fraction (9.6 ± 1.8%) and effective orifice area (1.52 ± 0.34 cm2) met ISO 5840-2:2021 requirements. Additionally, the mean pressure gradient was comparable to current clinical bioprosthetic heart valves demonstrating preliminary efficacy. Although the hemodynamic properties are promising, it is anticipated that the random microarchitecture will result in suboptimal strain fields and peak stresses that may accelerate leaflet fatigue and degeneration. Previous computational work has demonstrated that bioinspired fiber microarchitectures can improve strain homogeneity of valve materials toward improving durability. To this end, we developed advanced electrospinning methodologies to achieve polyurethane fiber microarchitectures that mimic or exceed the physiological ranges of alignment, tortuosity, and curvilinearity present in the native valve. Control of fiber alignment from a random fiber orientation at a normalized orientation index (NOI) 14.2 ± 6.9% to highly aligned fibers at a NOI of 85.1 ± 1.4%. was achieved through increasing mandrel rotational velocity. Fiber tortuosity and curvilinearity in the range of native valve features were introduced through a post-spinning annealing process and fiber collection on a conical mandrel geometry, respectively. Overall, these studies demonstrate the potential of hydrogel-polyurethane fiber composite as a heart valve material. Future studies will utilize the developed advanced electrospinning methodologies in combination with model-directed fabrication toward optimizing durability as a function of fiber microarchitecture.
Repurposing of Glatiramer Acetate to Treat Heart Diseases
Authors: Aviel Gal , Elkahal Jacob , Umansky Kfir Baruch , Bueno-Levy Hanna , Miyara Shoval , Lendengolts Daria , Zhang Lingling , Petrover Zachary , Kain David , Shalit Tali , Aharoni Rina , Arnon Ruth , Mishaly David , Katz Uriel , Nachman Dean , Ammar Mahdi , Asleh Rabea , Amir Offer , Tzahor Eldad , Sarig Rachel 
Published: October 2023

AbstractMyocardial injury may ultimately lead to adverse ventricular remodeling and development of heart failure (HF), which is a major cause of morbidity and mortality worldwide. Given the slow pace and substantial costs of developing new therapeutics, drug repurposing is an attractive alternative. Studies of many organs, including the heart, highlight the importance of the immune system in modulating injury and repair outcomes. Glatiramer-acetate (GA) is an immunomodulatory drug prescribed for patients with multiple sclerosis. Here we report that short-term GA treatment improves cardiac function and reduces scar area in a mouse model of acute myocardial infarction, as well as in a rat model of ischemic HF. We provide bothin vivoandin vitromechanistic evidence indicating that in addition to its immunomodulatory functions, GA exerts beneficial pleiotropic effects, including cardiomyocyte protection and enhanced angiogenesis, mediated partially by extracellular vesicles carrying a pro-reparative cargo. Finally, as GA is a widely used drug with established efficacy and safety history, we conducted a small, prospective, randomized trial to determine its effect on patients admitted to the hospital with acute decompensated HF (ADHF). Strikingly, a short-term add-on administration of GA, resulted in marked reduction in the cytokine surge and NT-proBNP levels, both associated with acute HF exacerbations. Overall, these findings demonstrate the efficacy of GA in attenuating acute myocardial injury and modulating the inflammatory process in animal models and humans and highlight the potential of GA as a future therapy for a myriad of heart diseases.One Sentence SummaryGlatiramer acetate promotes reparative processes in rodent models of cardiac injury and reduces the inflammatory process in ADHF patients.
Methylomic, proteomic, and metabolomic correlates of traffic-related air pollution: A systematic review, pathway analysis, and network analysis relating traffic-related air pollution to subclinical and clinical cardiorespiratory outcomes
Authors: Casella Cameron , Kiles Frances , Urquhart Catherine , Michaud Dominique S. , Kirwa Kipruto , Corlin Laura 
Published: October 2023

AbstractA growing body of literature has attempted to characterize how traffic-related air pollution (TRAP) affects molecular and subclinical biological processes in ways that could lead to cardiorespiratory disease. To provide a streamlined synthesis of what is known about the multiple mechanisms through which TRAP could lead cardiorespiratory pathology, we conducted a systematic review of the epidemiological literature relating TRAP exposure to methylomic, proteomic, and metabolomic biomarkers in adult populations. Using the 139 papers that met our inclusion criteria, we identified the omic biomarkers significantly associated with short-or long-term TRAP and used these biomarkers to conduct pathway and network analyses. We considered the evidence for TRAP-related associations with biological pathways involving lipid metabolism, cellular energy production, amino acid metabolism, inflammation and immunity, coagulation, endothelial function, and oxidative stress. Our analysis suggests that an integrated multi-omics approach may provide critical new insights into the ways TRAP could lead to adverse clinical outcomes. We advocate for efforts to build a more unified approach for characterizing the dynamic and complex biological processes linking TRAP exposure and subclinical and clinical disease, and highlight contemporary challenges and opportunities associated with such efforts.
circulating tumor DNA in the immediate post-operative setting
Authors: Efthymiou Vasileios , Queenan Natalia , Haas Markus , Naegele Saskia , Goss Deborah , Faden Daniel L. 
Published: October 2023

AbstractBackgroundCirculating tumor DNA (ctDNA) has emerged as an accurate real-time biomarker of disease status across most solid tumor types. Most studies evaluating the utility of ctDNA have focused on time points weeks to months after surgery, which for many cancer types, is significantly later than decision-making time points for adjuvant treatment. In this systematic review, we summarize the state of the literature on the feasibility of using ctDNA as a biomarker in the immediate postoperative period.MethodsWe performed a systematic review evaluating the early kinetics, defined here as three days, of ctDNA in patients who underwent curative-intent surgery across several cancer types.ResultsAmong the 2057 studies identified, we evaluated eight cohort studies with ctDNA levels measured within the first three days after surgery. Across six different cancer types, all studies showed an increased risk of cancer recurrence in patients with a positive early postoperative ctDNA level.DiscussionWhile ctDNA clearance kinetics appear to vary based on tumor type, across all studies-detectable ctDNA after surgery was predictive of recurrence, suggesting early post-operative timepoints could be feasibly used for determining minimal residual disease. However, larger studies need to be performed to better understand the precise kinetics of ctDNA clearance across different cancer types as well as to determine optimal postoperative time points.SynopsisThis systematic review analyzed the use of ctDNA as a biomarker for minimal residual disease detection in the early postoperative setting and found that ctDNA detection within three days after surgery is associated with an increased risk of recurrence.
Reliable detection and quantification of plasmodesmal callose inNicotiana benthamianaleaves during defense responses
Authors: Sankoh Amie F. , Adjei Joseph , Roberts Daniel M. , Burch-Smith Tessa M. 
Published: October 2023

AbstractCallose, a beta-(1,3)-D-glucan polymer, is essential for regulating intercellular trafficking via plasmodesmata (PD). Pathogens manipulate PD-localized proteins to enable intercellular trafficking by removing callose at PD, or conversely by increasing callose accumulation at PD to limit intercellular trafficking during infection. Plant defense hormones like salicylic acid regulate PD-localized proteins to control PD and intercellular trafficking during innate immune defense responses such as systemic acquired resistance. Measuring callose deposition at PD in plants has therefore emerged as a popular parameter for assessing the intercellular trafficking activity during plant immunity. Despite the popularity of this metric there is no standard for how these measurements should be made. In this study, three commonly used methods for identifying and quantifying PD callose by aniline blue staining were evaluated to determine the most effective in theNicotiana benthamianaleaf model. The results reveal that the most reliable method used aniline blue staining and fluorescent microscopy to measure callose deposition in fixed tissue. Manual or semi-automated workflows for image analysis were also compared and found to produce similar results although the semi-automated workflow produced a wider distribution of data points.
Inhalable point-of-care urinary diagnostic platform
Authors: Zhong Qian , Tan Edward K.W. , Martin-Alonso Carmen , Parisi Tiziana , Hao Liangliang , Kirkpatrick Jesse D. , Fadel Tarek , Fleming Heather E. , Jacks Tyler , Bhatia Sangeeta N. 
Published: October 2023

AbstractThe late-stage detection of lung cancer leads to a high global mortality rate. Although low-dose computed tomography screening improves lung cancer survival in at-risk groups, this test still suffers from high rates of false positive results. In addition, inequality remains in the diagnosis of lung cancer as access to medical imaging infrastructure is limited. Here, we designed a needleless and imaging-free platform, termed PATROL (point-of-careaerosolizable nanosensors withtumor-responsiveoligonucleotide barcodes), to increase detection accuracy, to reduce resource disparities for early detection of lung cancer, and to enable timely interception. PATROL formulates a set of DNA-barcoded, activity-based nanosensors (ABNs) into inhalable formats that can be delivered using clinical nebulizers or inhalers. Lung cancer-associated proteases in the tumor microenvironment selectively cleave the ABNs, releasing synthetic DNA reporters that are eventually excreted via the urine. The barcoded nanosensor signatures present in urine samples are quantified within 20 minutes using a multiplexable paper-based lateral flow assay at room temperature. PATROL detects early-stage tumors in an autochthonous lung adenocarcinoma mouse model with high sensitivity and specificity. Tailoring the library of ABNs may enable the modular PATROL platform to not only lower the resource thresholds required for early detection of lung cancer, but also enable rapid detection of chronic pulmonary disorders and infections.
Geometry of navigation identifies genetic-risk and clinical Alzheimer’s disease
Authors: Lim Uzu , Cervantes Rodrigo Leal , Coughlan Gillian , Lambiotte Renaud , Spiers Hugo J. , Hornberger Michael , Harrington Heather A. 
Published: October 2023

ABSTRACTRecent research evidence demonstrates that the inability to orient oneself and navigate space is an early indicator of Alzheimer’s Disease. The video game Sea Hero Quest (SHQ) was designed to assess the players’ navigation ability, and several research works analysed the SHQ data using simple metrics such as length and time of navigation paths. Expanding these analyses, we propose new performance metrics that capture the geometry of paths, and analyse datasets of more than 60,000 navigators. The metrics identify players who failed the navigation task, the dementia patients, and carriers of the at-risk allele of the Apolipoprotein-E [APOE]. Furthermore the metrics detect weak navigation ability when only a fraction of navigation paths are used, with superior performance to baseline methods. Our findings demonstrate that the proposed performance metrics pave the way to a comprehensive pre-clinical screening toolbox for Alzheimer’s Disease.TEASERWe propose geometric methods to capture decline in navigation ability from dementia.
Neoadjuvant Immunotherapy and Chemoradiation Followed by Esophagectomy for Esophageal Cancer
Authors: Panda Nikhil , Fu Beverly , Potter Alexandra , Auchincloss Hugh G. , Klempner Samuel J. , Lanuti Michael , Yang Chi-Fu , Schumacher Lana 
Published: October 2023

ABSTRACTBackgroundTreatment of locally advanced esophageal cancer includes neoadjuvant chemoradiation (chemoRT) and esophagectomy. We evaluated perioperative and oncologic outcomes among patients who received neoadjuvant chemoRT and immunotherapy (I/O).MethodsAdults who underwent esophagectomy following neoadjuvant chemoRT or chemoRT+I/O for T1-4, N0-3, M0 esophageal cancer were identified from the National Cancer Database (2012-2020). Unadjusted, propensity score-matched, and Cox proportional hazards analyses compared perioperative outcomes and three-year overall survival (OS) between neoadjuvant chemoRT versus chemoRT+I/O cohorts.ResultsAmong 17,937 patients, 261 (1.5%) received neoadjuvant chemoRT+I/O. ChemoRT+I/O patients were younger (62 versus 64 years, p=0.002) and had a longer interval between chemotherapy and surgery (104.5 versus 97.0 days, p<0.001) compared with chemoRT patients. Among the chemoRT+I/O cohort, there were more undifferentiated tumors (46.4% versus 34.3%, p<0.001) with adenocarcinoma histology (93.9% versus 81.2%, p<0.001) compared with the chemoRT cohort. On unadjusted analysis, there were no significant differences regarding margin positivity, 30-day readmission, 30-day mortality, or 90-day mortality. ChemoRT+I/O patients had higher 3-year OS (61.4% 95%CI [54.2-67.7] versus 55.1% [54.3-55.9], p=0.02), more lymph nodes resected (median 17.0 IQR [11.0-25.0] versus 15.0 [10.0-22.0], p=0.007), and less pathologic nodal downstaging from N2 to N1/N0 (36.8% vs 48.4%, p<0.001) than chemoRT patients. Propensity score-matched analyses (n=217) revealed no differences in perioperative outcomes and 3-year OS (65.0% 95%CI [57.1-71.8] versus 56.0% [48.0-63.3], p=0.11) between the chemoRT+I/O and chemoRT cohort.ConclusionsThere were similar perioperative outcomes and 3-year OS between patients who received neoadjuvant chemoRT+I/O and chemoRT, supporting the feasibility of adding immunotherapy to neoadjuvant regimens.