bluuebunny/crossref_metadata_2025_split huggingface dataset:
Yield-Stress and Creep Control Depot Formation and Persistence of Injectable Hydrogels Following Subcutaneous Administration
Authors: Jons Carolyn K. , Grosskopf Abigail K. , Baillet Julie , Yan Jerry , Klich John H. , Appel Eric A. 
Published: May 2022

AbstractHydrogels that can be injected into the body using standard needles or catheters enable a minimally invasive strategy to prolong local delivery of therapeutic drug and cellular cargo. In particular, physically crosslinked hydrogels exhibit shear-thinning and self-healing behaviors enabling facile injectability and depot formation upon administration. While prior efforts to characterize these systems have focused on injectability and cargo release behaviors, prediction of cargo release in the body often assumes the materials form a depot rather than spreading out upon administration. Here, we evaluate how hydrogel rheology correlates with depot formation and persistence following subcutaneous administration in mice with two physicochemically-distinct, physically crosslinked hydrogel systems. We evaluate calcium-alginate and polymer-nanoparticle hydrogel systems exhibiting variable mechanical behaviors across several rheological properties (stiffness, viscoelasticity, yield stress, and creep). By relating measured rheological properties to depot formation and persistence time following subcutaneous administration, we identify that yield stress is predictive of initial depot formation while creep is predictive of depot persistence. Indeed, only materials with yield stresses greater than 25 Pa form robust depots and reduced creep correlates with longer depot persistence. These findings provide predictive insights into design considerations for hydrogel technologies capable of extended controlled release of therapeutic cargo.
In situ polyadenylation enables spatial mapping of the total transcriptome
Authors: McKellar David W. , Mantri Madhav , Hinchman Meleana , Parker John S.L. , Sethupathy Praveen , Cosgrove Benjamin D. , De Vlaminck Iwijn 
Published: May 2022

AbstractSpatial transcriptomics reveals the spatial context of gene expression, but current methods are limited to assaying polyadenylated (A-tailed) RNA transcripts. Here we demonstrate that enzymatic in situ polyadenylation of RNA enables detection of the full spectrum of RNAs, expanding the scope of sequencing-based spatial transcriptomics to the total transcriptome. We apply this Spatial Total RNA-Sequencing (STRS) approach to study skeletal muscle regeneration and viral-induced myocarditis. Our analyses reveal the spatial patterns of noncoding RNA expression with near-cellular resolution, identify spatially defined expression of noncoding transcripts in skeletal muscle regeneration, and highlight host transcriptional responses associated with local viral RNA abundance. In situ polyadenylation requires the addition of only a single step to a widely used protocol for spatial RNA-sequencing, and thus could be broadly and quickly adopted. Spatial RNA-sequencing of the total transcriptome will enable new insights into spatial gene regulation and biology.
Lung spatial profiling reveals a T cell signature in COPD patients with fatal SARS-CoV-2 infection
Authors: Yang Chen Xi , Tomchaney Michael , Landecho Manuel F. , Zamacona Borja R. , Oto Marta Marin , Zulueta Javier , Malo Joshua , Knoper Steve , Contoli Marco , Papi Alberto , Vasilescu Dragoş M. , Sauler Maor , Straub Christof , Tan Cheryl , Martinez Fernando D. , Bhattacharya Deepta , Rosas Ivan O. , Kheradmand Farrah , Hackett Tillie-Louise , Polverino Francesca 
Published: May 2022

AbstractRationalePeople with pre-existing lung diseases like chronic obstructive pulmonary disease (COPD) are more likely to get very sick from SARS-CoV-2 disease 2019 (COVID-19), but an interrogation of the immune response to COVID-19 infection, spatial throughout the lung structure is lacking in patients with COPD.ObjectivesTo profile the immune microenvironment of lung parenchyma, airways, and vessels of never- and ever-smokers with or without COPD, whom all died of COVID-19, using spatial transcriptomic and proteomic profiling.FindingsThe parenchyma, airways, and vessels of COPD patients, compared to control lungs had: 1) significant enrichment for lung resident CD45RO+ memory T cells; 2) downregulation of genes associated with T cell antigen-priming and memory T cell differentiation; 3) higher expression of proteins associated with SARS-CoV-2 entry and major receptor ubiquitously across the ROIs and in particular the lung parenchyma, despite similar SARS-CoV-2 structural gene expression levels.ConclusionsThe lung parenchyma, airways, and vessels of COPD patients have increased T-lymphocytes with a blunted memory T cell response and a more invasive SARS-CoV-2 infection pattern, and may underlie the higher death toll observed with COVID-19.
Artificial intelligence-based gas chromatography-olfactometry for sensory evaluation of key compounds in food ingredients
Authors: Shang Liang , Liu Chuanjun , Tang Fengzhen , Chen Bin , Liu Lianqing , Hayashi Kenshi 
Published: May 2022

ABSTRACTThe use of an artificial intelligence (AI)-based prediction model of the structure-odor relationship (SOR) has shown great potential in the replacement of human panelists in gas chromatography-olfactometry (GCO). However, the Al-based GCO encounters issues such as poor accuracy, generalization, and practicality, owning to the insufficient feature extraction of odorant molecular structure. The purpose of this study is to the prediction of odor perception categories based on the odorant structure feature extraction by diverse deep neural networks, including molecular graphic convolution neural network (MG-CNN), molecular graph transformer neural network, and atom interaction neural networks. The results of the performance comparison of different feature extractors demonstrate that the MG-CNN model produces the highest accuracy and thus may be most suitable for the SOR prediction. It is hoped that the proposed method can be applied in practice as an auxiliary tool of GCO for the sensory evaluation of key compounds in food ingredients.HighlightsDifferent deep neural networks were used to predict categorized odor descriptors.End-to-end-based representation learning was performed for molecular feature extraction.Molecular graphs with pre-training of convolution neural networks was most accurate.Graphical Abstract
p38 MAPK Signaling Enhances Reovirus Replication by Facilitating Efficient Virus Entry, Virus Capsid Uncoating and Post-Uncoating Steps
Authors: Mohamed Adil , Shmulevitz Maya 
Published: May 2022

AbstractMammalian orthoreovirus serotype 3 Dearing an orphan human virus currently being pursued as an oncolytic virus in multiple phase I/II clinical trials. Previous clinical trials have emphasized the importance of patient pre-screening for prognostic markers to improve therapeutic success. However, currently, only generic cancer markers such as EGFR, Hras, Kras, Nras, Braf and/or p53 are utilized and have exhibited limited benefit in predicting therapeutic efficacy. Utilization of more specific markers that influence specific steps during reovirus replication could prove beneficial as prognostic markers. This study delineated the role of p38 MAPK signaling during reovirus infection and illustrated a connection between specific p38 MAPK isoforms and reovirus infection. Using a panel of specific p38 MAPK inhibitors and an inactive inhibitor analogue, we demonstrated that p38 MAPK signaling is essential for establishment of reovirus infection by enhancing reovirus endocytosis, facilitating efficient reovirus uncoating at the endo-lysosomal stage, and augmenting post uncoating replication steps. Using a broad panel of human breast cancer cell lines, we observed susceptibility of reovirus infection corresponded with virus binding and uncoating efficiency, which was strongly correlated with status of the p38β isoform. Together, our study proposes p38β as a potential prognostic marker for early stages of reovirus infection that are crucial to establishment of successful reovirus infection.
Strengthening vaccination delivery system resilience in the context of protracted humanitarian crisis: a realist-informed systematic review
Authors: Ismail Sharif A. , Lam Sze Tung , Bell Sadie , Fouad Fouad M. , Blanchet Karl , Borghi Josephine 
Published: May 2022

ABSTRACTBackgroundChildhood vaccination is among the most effective public health interventions available for the prevention of communicable disease, but coverage in many humanitarian settings is sub-optimal. This systematic review critically evaluated peer-review and grey literature evidence on the effectiveness of system-level interventions for improving vaccination coverage in protracted crises, focusing on how they work, and for whom, to better inform preparedness and response for future crises.MethodsRealist-informed systematic review of peer-reviewed and grey literature. Keyword-structured searches were performed in MEDLINE, EMBASE and Global Health, CINAHL, the Cochrane Collaboration and WHOLIS, and grey literature searches performed through the websites of UNICEF, the Global Polio Eradication Initiative (GPEI) and Technical Network for Strengthening Immunization Services. Results were independently double-screened for inclusion on title and abstract, and full text. Data were extracted using a pre-developed template, capturing information on the operating contexts in which interventions were implemented, intervention mechanisms, and vaccination-related outcomes. Study quality was assessed using the MMAT tool. Findings were narratively synthesised.Results50 studies were included, most describing interventions applied in conflict or near-post conflict settings in sub-Saharan Africa, and complex humanitarian emergencies. Vaccination campaigns were the most commonly addressed adaptive mechanism (n=17). Almost all campaigns operated using multi-modal approaches combining service delivery through multiple pathways (fixed and roving), health worker recruitment and training and community engagement to address both vaccination supply and demand. Creation of collaterals through service integration showed generally positive evidence of impact on routine vaccination uptake by bringing services closer to target populations and leveraging trust that had already been built with communities. Robust community engagement emerged as a key unifying mechanism for outcome improvement across almost all of the intervention classes, in building awareness and trust among crisis-affected populations. Some potentially transformative mechanisms for strengthening resilience in vaccination delivery were identified, but evidence for these remains limited.ConclusionA number of interventions to support adaptations to routine immunisation delivery in the face of protracted crisis are identifiable, as are key unifying mechanisms (multi-level community engagement) apparently irrespective of context, but evidence remains piecemeal. Adapting these approaches for local system resilience-building remains a key challenge.
Can process mapping and a multi-site Delphi of perioperative professionals inform our understanding of system-wide factors that may impact operative risk?
Authors: Stubbs DJ , Bashford T , Gilder FJ , Nourallah B , Ercole A , Levy N , Clarkson PJ 
Published: May 2022

ABSTRACTObjectivesTo examine whether the use of process mapping and a multidisciplinary Delphi can identify potential contributors to perioperative risk. We hypothesised that this approach may identify factors not represented in common perioperative risk tools and give insights of use to future research in this area.DesignMultidisciplinary modified Delphi studySettingTwo centres (one tertiary, one secondary) in the United Kingdom during 2020 amidst coronavirus pressures.Participants91 stakeholders from 23 professional groups involved in the perioperative care of older patients. Key stakeholder groups were identified through the use of process mapping of local perioperative care pathways.ResultsResponse rate ranged from 51% in round one to 19% in round three. After round one, free text suggestions from the panel were combined with variables identified from perioperative risk scores. This yielded a total of 410 variables that were voted on in subsequent rounds. Including new suggestions from round two, 468/519 (90%) of the statements presented to the panel reached a consensus decision by the end of round three. Identified risk factors included patient level factors (such as ethnicity and socio-economic status); and organisational or process factors related to the individual hospital (such as policies, staffing, and organisational culture). 66/160 (41%) of the new suggestions did not feature in systematic reviews of perioperative risk scores or key process indicators. No factor categorised as ‘organisational’ is currently present in any perioperative risk score.ConclusionsThrough process mapping and a modified Delphi we gained insights into additional factors that may contribute to perioperative risk. Many were absent from currently used risk stratification scores. These results enable an appreciation of the contextual limitations of currently used risk tools and could support future research into the generation of more holistic datasets for the development of perioperative risk assessment tools.Strengths and Weaknesses-Novel use of process mapping to identify key perioperative stakeholders-Multidisciplinary Delphi panel to gain breadth of perspective-Performed across two sites-Comprehensive results may be of use to other researchers designing perioperative research databases-Results may be limited by low response rate in final round (although majority of consensus decisions made in round two)
COVID-19 patients share common, corticosteroid-independent features of impaired host immunity to pathogenic molds
Authors: Tappe Beeke , Lauruschkat Chris D. , Strobel Lea , Pantaleón García Jezreel , Kurzai Oliver , Rebhan Silke , Kraus Sabrina , Pfeuffer-Jovic Elena , Bussemer Lydia , Possler Lotte , Held Matthias , Hünniger Kerstin , Kniemeyer Olaf , Schäuble Sascha , Brakhage Axel A. , Panagiotou Gianni , White P. Lewis , Einsele Hermann , Löffler Jürgen , Wurster Sebastian 
Published: May 2022

AbstractPatients suffering from coronavirus disease-2019 (COVID-19) are at high risk for deadly secondary fungal infections such as COVID-19-associated pulmonary aspergillosis (CAPA) and COVID-19-associated mucormycosis (CAM). Despite this clinical observation, direct experimental evidence for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)-driven alterations of antifungal immunity is scarce. Using anex-vivowhole blood (WB) stimulation assay, we challenged blood from twelve COVID-19 patients withAspergillus fumigatusandRhizopus arrhizusantigens and studied the expression of activation, maturation, and exhaustion markers, as well as cytokine secretion. Compared to healthy controls, T-helper cells from COVID-19 patients displayed increased expression levels of the exhaustion marker PD-1 and weakenedA. fumigatus- andR. arrhizus-induced activation. While baseline secretion of proinflammatory cytokines was massively elevated, WB from COVID-19 patients elicited diminished release of T-cellular (e.g., IFN-γ, IL-2) and innate immune cell-derived (e.g., CXCL9, CXCL10) cytokines in response toA. fumigatusandR. arrhizusantigens. Additionally, samples from COVID-19 patients showed deficient granulocyte activation by mold antigens and reduced fungal killing capacity of neutrophils. These features of weakened anti-mold immune responses were largely decoupled from COVID-19 severity, the time elapsed since diagnosis of COVID-19, and recent corticosteroid uptake, suggesting that impaired anti-mold defense is a common denominator of the underlying SARS-CoV-2 infection. Taken together, these results expand our understanding of the immune predisposition to post-viral mold infections and could inform future studies of immunotherapeutic strategies to prevent and treat fungal superinfections in COVID-19 patients.
Vaccination as personal public-good provision
Authors: Reddinger J. Lucas , Charness Gary , Levine David 
Published: May 2022

AbstractVaccination against infectious diseases has both private and public benefits. We study whether social preferences—concerns for the well-being of other people—are associated with one’s decision regarding vaccination. We measure these social preferences for 549 online subjects with a public-good game and an altruism game. To the extent that one gets vaccinated out of concern for the health of others, contribution in the public-good game is analogous to an individual’s decision to obtain vaccination, while our altruism game provides a different measure of altruism, equity, and efficiency concerns. We proxy vaccine demand with how quickly a representative individual voluntarily took the initial vaccination for COVID-19 (after the vaccine was widely available). We collect COVID-19 vaccination history separately from the games to avoid experimenter-demand effects. We find a strong result: Contribution in the public-good game is associated with greater demand to voluntarily receive a first dose, and thus also to vaccinate earlier. Compared to a subject who contributes nothing, one who contributes the maximum ($4) is 58% more likely to obtain a first dose voluntarily in the four-month period that we study (April through August 2021). In short, people who are more pro-social are more likely to take a voluntary COVID-19 vaccination. Behavior in our altruism game does not predict vaccination. We recommend further research on the use of pro-social preferences to help motivate individuals to vaccinate for other transmissible diseases, such as the flu and HPV.
An anaphase switch in astral microtubule dynamics specifically requires the APC/CCdc20-dependent degradation of the mitotic cyclin Clb4
Authors: Zucca Federico , Li Jiaming , Visintin Clara , Gygi Steven P. , Visintin Rosella 
Published: May 2022

AbstractKey for accurate chromosome partitioning to the offspring is the ability of mitotic spindle microtubules to respond to different molecular signals and remodel their dynamics accordingly. Spindle microtubules are conventionally divided into three classes: kinetochore, interpolar and astral microtubules (kMTs, iMTs and aMTs, respectively), among all aMT regulation remains elusive. Here, we show that aMT dynamics are tightly regulated. aMTs remain unstable up to metaphase and are stabilized at anaphase onset. This switch in aMT dynamics, crucial for proper spindle orientation, specifically requires the degradation of the mitotic cyclin Clb4 by the Anaphase Promoting Complex bound to its activator subunit Cdc20 (APC/CCdc20). These data highlight a unique role for mitotic cyclin Clb4, provide a framework to understand aMT regulation in vertebrates and uncover mechanistic principles of how the APC/CCdc20 choreographs the timing of late mitotic events by sequentially impacting on the three classes of spindle microtubules.
Prefusion-Stabilized Lassa Virus Trimer Identifies Neutralizing Nanobodies and Reveals an Apex-Situated Site of Vulnerability
Authors: Gorman Jason , Cheung Crystal Sao-Fong , Duan Zhijian , Sun Yaping , Wang Pengfei , Boyington Jeffrey C. , Biju Andrea , Bylund Tatsiana , Cheng Cheng , Ou Li , Stephens Tyler , Tsybovsky Yaroslav , Verardi Raffaello , Wang Shuishu , Yang Yongping , Zhang Baoshan , Zheng ChengYan , Zhou Tongqing , Mascola John R. , Ho David D. , Ho Mitchell , Kwong Peter D. 
Published: May 2022

ABSTRACTLassa virus (LASV) is responsible for 100,000-300,000 zoonotic infections annually and poses a threat to public health. Development of antibody-based therapeutics or vaccines has been challenging because neutralizing antibodies – even among Lassa hemorrhagic fever survivors – are generally of low titer, and the target of neutralizing antibodies, the trimeric glycoprotein complex (GPC), a type 1-fusion machine with GP1 and GP2 subunits, has been difficult to produce. Here, we use structure-based design to obtain a soluble LASV GPC by engineering an inter-protomer disulfide (R207GCGP1-L326CGP2) and appending the T4-fibritin trimerization domain. We verified the antigenicity of this prefusion-stabilized LASV GPC against a panel of human antibodies and used electron microscopy (EM) to confirm its trimeric association. We panned the prefusion-stabilized LASV GPC against single domain ‘nanobody’ libraries and identified one of camel origin, which we named D5, which bound GPC with 27 nM affinity and neutralized the Josiah strain of LASV with an IC50 of 12 µg/ml when formatted into a bivalent IgG2a context. The cryo-EM structure of a ternary complex of the D5 nanobody, the antigen-binding fragment of human antibody 8.11G, and LASV GPC revealed D5 to recognize a site-of-vulnerability at the trimer apex. The recognized site appeared to be specific to GPC lacking cleavage of between GP1 and GP2 subunits. Collectively, our findings suggest that GPC-cleavage intermediates may be targets for LASV neutralization and define an apex-situated site of vulnerability for vaccine development.SignificanceLassa virus (LASV) infection is expanding outside its traditionally endemic areas in West Africa, posing a biothreat to the world. LASV-neutralizing antibodies, moreover, have proven difficult to elicit. To gain insight into requirements for antibody-mediated neutralization of LASV, we developed a prefusion-stabilized LASV glycoprotein trimer (GPC), panned it against phage libraries comprised single-domain antibodies or nanobodies from shark and camel, and identified one, D5, which – when placed into bivalent IgG2a context – could neutralize LASV. Cryo-EM analysis revealed D5 to recognize a cleavage-dependent site-of-vulnerability at the trimer apex. We propose this apex-situated site to be an attractive target for LASV vaccine and therapeutic development.