bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endothelial cells are a key target of IFN-g during response to combined PD-1/CTLA-4 ICB treatment in a mouse model of bladder cancer
Authors: Freshour Sharon L. , Chen Timothy H.P. , Fisk Bryan , Shen Haolin , Mosior Matthew , Skidmore Zachary L. , Fronick Catrina , Bolzenius Jennifer K. , Griffith Obi L. , Arora Vivek K. , Griffith Malachi 
Published: March 2023

SummaryTo explore mechanisms of response to combined PD-1/CTLA-4 immune checkpoint blockade (ICB) treatment in individual cell types, we generated scRNA-seq using a mouse model of invasive urothelial carcinoma with three conditions: untreated tumor, treated tumor, and tumor treated after CD4+ T cell depletion. After classifying tumor cells based on detection of somatic variants and assigning non-tumor cell types using SingleR, we performed differential expression analysis, overrepresentation analysis, and gene set enrichment analysis (GSEA) within each cell type. GSEA revealed that endothelial cells were enriched for upregulated IFN-g response genes when comparing treated cells to both untreated cells and cells treated after CD4+ T cell depletion. Functional analysis showed that knocking outIFNgR1in endothelial cells inhibited treatment response. Together, these results indicated that IFN-g signaling in endothelial cells is a key mediator of ICB induced anti-tumor activity.
Ultrasound neuromodulation of an anti-inflammatory pathway at the spleen produces sustained improvement of experimental pulmonary hypertension
Authors: Zafeiropoulos Stefanos , Ahmed Umair , Bekiaridou Alexandra , Mughrabi Ibrahim T , Jayaprakash Naveen , Saleknezhad Nafiseh , Chadwick Chrystal , Daytz Anna , Sato Izumi , Atish-Fregoso Yemil , Carroll Kaitlin , Al-Abed Yousef , Fudim Marat , Puleo Christopher , Giannakoulas George , Nicolls Mark , Diamond Betty , Zanos Stavros 
Published: March 2023

AbstractBackgroundInflammation is pathogenically implicated in pulmonary arterial hypertension (PAH); however, it has not been adequately targeted therapeutically. We investigated whether neuromodulation of an anti-inflammatory neuroimmune pathway involving the splenic nerve using noninvasive, focused ultrasound stimulation of the spleen (sFUS) can improve experimental pulmonary hypertension (PH).MethodsPH was induced in rats either by SU5416 (20 mg/kg SQ) injection, followed by 21 (or 35) days of hypoxia (SuHx model), or by monocrotaline (60 mg/kg IP) injection (MCT model). Animals were randomized to receive either daily, 12-min-long sessions of sFUS or sham stimulation, for 14 days. Catheterizations, echocardiography, indices of autonomic function, lung and heart histology and immunohistochemistry, spleen flow cytometry and lung single-cell-RNA sequencing were performed after treatment to assess the effects of sFUS.ResultsSplenic denervation right before induction of PH results in a more severe phenotype. In both SuHx and MCT models of PH, sFUS treatment reduces right ventricular (RV) systolic pressure by 25-30% compared to sham therapy, without affecting systemic pressure, and improves RV function and autonomic indices. sFUS reduces wall thickness, apoptosis, and proliferation in small pulmonary arterioles, suppresses CD3+ and CD68+ cell infiltration in lungs and RV fibrosis and hypertrophy and lowers brain natriuretic peptide. Beneficial effects persist for weeks after sFUS discontinuation and are more robust with early and longer treatment. Splenic denervation abolishes sFUS therapeutic benefits. sFUS partially normalizes CD68+ and CD8+ T-cells cell counts in the spleen and downregulates several inflammatory genes and pathways in nonclassical and classical monocytes, and macrophages in the lung. Differentially expressed genes in those cell types are significantly enriched for human PAH-associated genes.ConclusionssFUS causes dose-dependent, sustained improvement of hemodynamic, autonomic, laboratory and pathological manifestations in two models of experimental PH. Mechanistically, sFUS normalizes immune cell populations in the spleen and downregulates inflammatory genes and pathways in the lung, many of which are relevant in human disease.
Learning to learn: Single session acquisition of new rules by freely-moving mice
Authors: Levi Amir , Aviv Noam , Stark Eran 
Published: March 2023

AbstractLearning from examples and adapting to new rules are fundamental attributes of human cognition. However, it is unclear what conditions allow for fast and successful learning, especially in non-human subjects. To determine how rapidly freely-moving mice can learn a new rule, we designed a two-alternative forced-choice visual discrimination paradigm in which the rules governing the task can change between sessions. We find that experienced animals can learn a new rule after being exposed to only five training and three testing trials. The propensity for single session learning improves over time and is accurately predicted based on animal experience and rule difficulty. After establishing procedural learning of a paradigm, mice continuously improve their performance on new rules. Thus, mice learn to learn.
A meta-analysis of liver microbiome in beef and dairy cattle using metatranscriptome sequencing reads
Authors: Park Tansol , Li Wenli , Zanton Geoffrey 
Published: March 2023

AbstractThe gut-liver axis is at the forefront of host-microbial interactions given the proximity of liver to the gut and connection via portal circulation. In recent years, many studies in human and mouse models have demonstrated the existence of a significant microbial community embedded in diverse tissue types, including blood and liver. Yet, in cattle, the rumen microbiome has been the primary focus. The liver microbiome and its metabolic role in host health and performance remain largely unexplored. While there has been considerable work focusing on the liver of diseased cattle, the objective of this study was to evaluate, through meta-analysis, the commensal liver microbiome in various cattle breeds. To our knowledge, this is the first study in which a core liver microbiome has been described in cattle without overt liver disease. We discovered abundant microbial taxa in the liver, varying by host age, species, and developmental stage. Eight bacterial phyla (Actinobacteria, Bacteroidetes, Cyanobacteria, Deinococcus-Thermus, Firmicutes, Fusobacteria, Proteobacteria, and Tenericutes) were found to be the core microbial taxa, representing almost half of the total liver bacterial population. Additionally, we identified several KEGG pathways with significant association with cattle age. This study provides a baseline knowledge of the liver microbiome as identified by metatranscriptome sequencing in cattle. Besides finding the microbial taxa previously reported by studies using DNA-based, 16S rRNA amplicon sequencing methods, this study identified several core phyla that have not been reported in cattle liver, highlighting the improved sensitivity or ability in detecting microbes by RNA-over DNA-based methods.
Transcriptional Biomarker Discovery Towards Building A Load Stress Reporting System for EngineeredEscherichia coliStrains
Authors: Huang Yiming , Wipat Anil , Bacardit Jaume 
Published: March 2023

AbstractForeign proteins are produced by inserting synthetic constructs into host bacteria in biotechnology applications. This process can cause resource competition between synthetic circuits and host cells, placing a metabolic burden on the host cells which may result load stress and detrimental physiological changes. Consequently, the host bacteria can experience slow growth, while the synthetic system may suffer from suboptimal function and reduced productivity. To address this issue, we developed machine learning strategies to select a minimal number of genes that could serve as biomarkers for the design of load stress reporters. We identified pairs of biomarkers that showed discriminative capacity to detect the load stress states induced in 41 engineeredE. colistrains. These biomarker genes are mainly involved in Envelope stress response, Ion transport, Energy production and conversion.
SQ3370, the first clinical click chemistry-activated cancer therapeutic, shows safety in humans and translatability across species
Authors: Srinivasan Sangeetha , Yee Nathan A. , Zakharian Michael , Alečković Maša , Mahmoodi Amir , Nguyen Tri-Hung , Mejía Oneto José M. 
Published: March 2023

AbstractBackgroundSQ3370 is the first demonstration of the Click Activated Protodrugs Against Cancer (CAPAC™) platform that uses click chemistry to activate drugs directly at tumor sites, maximizing therapeutic exposure. SQ3370 consists of a tumor-localizing biopolymer (SQL70) and a chemically-attenuated doxorubicin (Dox) protodrug SQP33; the protodrug is activated upon clicking with the biopolymer at tumor sites. Here, we present data from preclinical studies and a Phase 1 dose-escalation clinical trial in adult patients with advanced solid tumors (NCT04106492) demonstrating SQ3370’s activation at tumor sites, safety, systemic pharmacokinetics (PK), and immunological activity.MethodsTreatment cycles consisting of an intratumoral or subcutaneous injection of SQL70 biopolymer followed by 5 daily intravenous doses of SQP33 protodrug were evaluated in tumor-bearing mice, healthy dogs, and adult patients with solid tumors.ResultsSQL70 effectively activated SQP33 at tumor sites, resulting in high Dox concentrations that were well tolerated and unachievable by conventional treatment. SQ3370 was safely administered at 8.9x the veterinary Dox dose in dogs and 12x the conventional Dox dose in patients, with no dose-limiting toxicity reported to date. SQ3370’s safety, toxicology, and PK profiles were highly translatable across species. SQ3370 increased cytotoxic CD3+and CD8+T-cells in patient tumors indicating T-cell-dependent immune activation in the tumor microenvironment.ConclusionsSQ3370, the initial demonstration of click chemistry in humans, enhances the safety of Dox at unprecedented doses and has the potential to increase therapeutic index. Consistent safety, toxicology, PK, and immune activation results observed with SQ3370 across species highlight the translatability of the click chemistry approach in drug development.Trial registrationNCT04106492; 7 September 2019
Paradoxical activation of a type VI secretion system (T6SS) phospholipase effector by its cognate immunity protein
Authors: Jensen Steven J. , Ruhe Zachary C. , Williams August F. , Nhan Dinh Q. , Garza-Sánchez Fernando , Low David A. , Hayes Christopher S. 
Published: March 2023

AbstractType VI secretion systems (T6SS) deliver cytotoxic effector proteins into target bacteria and eukaryotic host cells. Antibacterial effectors are invariably encoded with cognate immunity proteins that protect the producing cell from self-intoxication. Here, we identify transposon insertions that disrupt thetliimmunity gene ofEnterobacter cloacaeand induce auto-permeabilization through unopposed activity of the Tle phospholipase effector. This hyper-permeability phenotype is T6SS-dependent, indicating that the mutants are intoxicated by Tle delivered from neighboring sibling cells rather than by internally produced phospholipase. Unexpectedly, an in-frame deletion oftlidoes not induce hyper-permeability because Δtlinull mutants fail to deploy active Tle. Instead, the most striking phenotypes are associated with disruption of thetlilipoprotein signal sequence, which prevents immunity protein localization to the periplasm. Immunoblotting reveals that most hyper-permeable mutants still produce Tli, presumably from alternative translation initiation codons downstream of the signal sequence. These observations suggest that cytosolic Tli is required for the activation and/or export of Tle. We show that Tle growth inhibition activity remains Tli-dependent when phospholipase delivery into target bacteria is ensured through fusion to the VgrG β-spike protein. Together, these findings indicate that Tli has distinct functions depending on its subcellular localization. Periplasmic Tli acts as a canonical immunity factor to neutralize incoming effector proteins, while a cytosolic pool of Tli is required to activate the phospholipase domain of Tle prior to T6SS-dependent export.
The special thing of clubs in the German football Bundesliga – about the legal forms of the clubs and the resulting consequences
Authors: Ingerfurth Stefan 
Published: March 2023

PurposeAlso due to the “50+1 rule”, which exists in the German football Bundesliga and was introduced to regulate competition, clubs with a wide variety of legal forms participate. The aim of this article is to explain the consequences of the rule, the dominance of nonprofit organisations in German football and to contribute to the discussion on whether other football leagues should follow this model.Design/methodology/approachThe study looks at the German Bundesliga with its special 50+1 rule. With reference to stakeholder theory, the management challenges of participants in the Bundesliga are elaborated.FindingsThere are still clubs that participate as purely nonprofit associations, even though from an organisational point of view there are some arguments against this legal form. Due to the 50+1 rule, a nonprofit association has the majority of decision-making powers in each participating organisation. The goals desired by the 50+1 rule, such as “maintaining football as a common good” and at the same time “competitive balance”, do not seem to be achieved.Originality/valueThe article shows that regulation in the leagues appears to make sense and, in the case of the German Bundesliga, has led to participants with different legal forms. However, it also shows that the 50+1 rule is also associated with opposing goals that cannot be achieved in equal measure.
Blockchain applications in supply chain management: a systematic review of reviews
Authors: Khan Mohd Ziyauddin , Kumar Ashwani , Sahu Aditya Kumar 
Published: March 2023

Purpose
A fragmented research field exists on the applications of disruptive technologies like blockchain in supply chain management. Thus, the purpose of this study is to present a systematic review of literature reviews, summarising the applications of blockchain in various kinds and facets of the supply chain to date.

Design/methodology/approach
The literature search was conducted using Scopus and Web Of Science databases, and reporting was performed using PRISMA guidelines. In total, 43 review papers were identified, and 15 reviews applicable to the study were synthesised.

Findings
Blockchain technology is still in its infancy; however, it is gaining high utility in supply chain management. The technology is constantly expanding its application base, and it has enormous potential to cut out intermediaries and improve the efficiency of supply chains. Taking a look at the past and the present, the current study explores unexplored research avenues for the future.

Research limitations/implications
This study provides key insights to academia interested in exploring and advancing the topic.

Practical implications
This study will benefit practitioners and business managers exercising the potential of such a technology in various industrial contexts.

Social implications
The outcome of this study has the potential to bring many benefits to society at large. These benefits, if fully realised, could positively impact the society.

Originality/value
To the best of the authors’ knowledge, this is the first broad systematic review of reviews analysing the information about blockchain applications and implementation in the supply chain. Based on its constructive overview of the review studies published to date, this study contributes to the supply chain management literature by providing a table of reference for future researchers.
The effects of ethnic conflict and foreign fighters on conflict duration: a statistical analysis
Authors: Pehlivan Oğuzhan , Gokmen Yunus 
Published: March 2023

PurposeForeign fighters (FFs) appeared in at least approximately one-fourth of conflicts over the past 200 years. This study aims to reveal the impact of FFs in conflicts, whether they resolve the conflict faster or they drag out the conflict, and investigate the single and simultaneous impacts of ethnic conflict (EC) and FFs on conflict duration (CD).Design/methodology/approachThe data set consisting of 352 conflicts from 1818 to 2022 was collected from different sources. Logarithmic Linear Regression with Dummy Variables and the Cox Regression models were used to check the hypotheses.FindingsOne of the key findings of this analysis is that the use of FFs extends the duration of conflicts. Similarly, conflicts involving EC increase CD. Additionally, the simultaneous effect of FFs and EC together increases the CD much more, and it is noted CD significantly varies regionally.Research limitations/implicationsAs this study focused on the factors that affect the duration of the conflict in the hypotheses, the findings only can contribute to explaining the duration rather than factors such as the number of casualties and economic losses. The authors believe that policy and key decision-makers can benefit from the results and think twice before deciding to use FFs in conflicts.Originality/valueThis study offers a separate and simultaneous effect of EC and FFs on CD, which provides some empirical contributions to conflict management by filling the gap in this area.
Sustainable design concepts and their definitions: an inductive content-analysis-based literature review
Authors: Horani Lara F. 
Published: March 2023

PurposeThis research aims to explore various definitions of sustainability and sustainable design and determine the researcher's understanding of sustainable design concepts. In the past decades under the three elements of sustainability, between 1975 and 2021. This study is to conceptually construct sustainable design. It enhances and widens previous research to comprehend sustainable design. To this aim, a systematic review of the relevant collection of literature on sustainability and sustainable design will be conducted, guided by two questions: What is sustainable design? Do the sustainable design definitions involve economic, social and environmental elements? Since the concept of sustainability is to balance environmental, economic and social elements in product and service design.Design/methodology/approachThe author conducts an inductive content analysis of concepts and definitions mentioned or discussed in several journals, a total of 573 articles were published, with a clear definition of sustainable design included in the review process. In the analysis, 56 definitions have been used.FindingsIn the analysis, 56 definitions for environments, environmental design, environmental innovations, social design, eco-efficiency, eco-design, ecological product, environmentally friendly product and the concept of sustainable design have been used. The most often used definition, according to the research analysis, is sustainable design. This research found sustainable design definitions might be unclear and the concepts could be misunderstood. Thus, the goal of this research was to provide an effective system for sustainable design definitions, with adequate flexibility to create obvious differences to encourage further research in this field to develop comprehensive definitions for essential concepts, the different definitions of sustainable design show a lack of understanding of the real meaning of the concepts. As a result, these inconsistencies are likely to restrict future research and the adaptation of sustainable design concepts in the industry.Originality/valueThe development of sustainable design concepts and definitions, as used by many authors and organizations, is aided by the availability of numerous information sources. As a result, lots of new terms have emerged in the sustainability field, or old ones have been developed, but definitions and conceptual meanings haven't received sufficient analysis. Because the meanings of certain phrases are poor, identical or just differ slightly, the variety of definitions generates significant misunderstanding regarding their usage.
DeFi Common Sense: Crypto‐backed Lending in Janesh s/o Rajkumar v Unknown Person (‘CHEFPIERRE’)
Authors: Chan Timothy , Low Kelvin F.K. 
Published: March 2023

One of the selling points of cryptoassets has been the ability to subject them to so‐called ‘smart contracts’ embedded upon blockchains; yet, despite numerous common law decisions accepting cryptoassets as property, until Janesh s/o Rajkumar v Unknown Person (‘CHEFPIERRE’) no courts have had the occasion to consider how such property (in this case, an NFT) interact with these ‘smart contracts’. The case considers ‘smart contracts’ in the context of decentralised finance (DeFi), thus also raising questions concerning the legal effectiveness and prudence of using cryptoassets as objects of security. Although the non‐participation of the defendant meant that the court was deprived of full arguments, the judgment remains worthy of consideration, both for what the court does consider – specifically, criticisms of the Ainsworth test of property – and what it does not.
Multilevel longitudinal relations among impulsive traits, positive expectancies, and binge drinking from late adolescence to adulthood: A developmental test of acquired preparedness
Authors: Waddell Jack T. , Chassin Laurie 
Published: March 2023

AbstractBackgroundThe Acquired Preparedness Model (APM) posits that highly impulsive individuals develop stronger positive alcohol expectancies, which in turn predicts heavier drinking. However, most acquired preparedness studies have focused solely on between‐person relations, despite the theory suggesting that there are potential developmental‐specific within‐person relations. Thus, the current study tested the APM from late adolescence into adulthood, while disaggregating within‐ from between‐person relations.MethodsData come from a multigenerational study of familial alcohol use disorder (N=653) spanning three waves 5 years apart. Participants reported their lack of conscientiousness, sensation seeking, positive alcohol expectancies, and binge drinking at each wave. First, missing data techniques were used to create a “ghost timepoint,” allowing the specification of four developmental‐specific timepoints representing late adolescence (age 18 to 20), emerging adulthood (age 21 to 25), young adulthood (age 26 to 29), and adulthood (age 30 to 39). Second, a Random‐Intercept Cross‐Lagged Panel Model tested between‐person and within‐person relations among variables.ResultsAt the between‐person level, lower conscientiousness and sensation seeking were correlated with higher positive expectancies, and positive expectancies were correlated with more binge drinking. There were no within‐person prospective relations among conscientiousness, sensation seeking, and positive expectancies. However, within‐person increases in lack of conscientiousness during late adolescence predicted within‐person increases in emerging adult binge drinking, and within‐person increases in late adolescent and emerging adult binge drinking predicted within‐person increases in lack of conscientiousness during emerging and young adulthood, respectively. Similarly, within‐person increases in late adolescent and young adult sensation seeking predicted within‐person increases in binge drinking during emerging adulthood and adulthood, respectively. Binge drinking did not reciprocally predict sensation seeking.ConclusionsFindings suggest that acquired preparedness effects may be between persons rather than within persons. However, several within‐person developmental‐specific relations among conscientiousness, sensation seeking, and binge drinking were observed, outside of expectancies. Findings are discussed in terms of theory and prevention.