bluuebunny/crossref_metadata_2025 huggingface dataset:
New Media and the Rise of the Popular Woman Writer, 1832-1860
Authors: Easley Alexis
Published: September 2021

The idea of ‘new media’ is nothing new. Long before Twitter and Facebook, the rise of new periodical genres and formats provided opportunities for Victorian women writers and readers to participate in popular print culture as never before. This study illuminates the relationship between the rise of the popular woman writer the expansion and diversification of newspaper and periodical print media during a period of revolutionary change. It includes discussion of canonical women writers such as Felicia Hemans, Charlotte Brontë, and George Eliot, as well as lesser-known figures such as Eliza Cook, Frances Brown, Eliza Meteyard, and Rose Ellen Hendriks. In addition, it explores the networks of women writers connected with cheap family magazines such as Chambers’s Edinburgh Journal during the 1830s and ’40s. It also examines the ways women readers actively responded to a robust popular print culture by creating scrapbooks and engaging in forms of celebrity worship. The book closes with discussion of the ways Victorian women’s participation in popular print culture anticipates our own engagement with new media in the twenty-first century.
Elizabeth Bowen's Psychoanalytic Fiction
Authors: Coulson Victoria
Published: September 2021

Despite the exceptional literary quality, remarkable conceptual sophistication and compelling socio-historical interest of Elizabeth Bowen’s writing, her fiction has received relatively little critical attention in comparison to the work of such acknowledged giants of the modern canon as, for example, Woolf and Joyce. The past decade has seen a lively burgeoning of interest in Bowen’s work, recent scholarship focusing with a new intensity on the question of the relationship between Bowen’s writing and the socio-political matrix from which it emerges. Situating itself within this new wave of scholarship and engaging closely with its socio-historical and literary-critical concerns, this book sets out to offer a provocative and substantial new account of Bowen’s fiction that highlights in particular the force and originality of Bowen’s virtually psychoanalytic thinking about development, sexuality and gender.
Jewish Medical Practitioners in the Medieval Muslim World
Authors: Lev Efraim
Published: September 2021

This book aims to bring together all available biographical data on Jewish medical practitioners (physicians and pharmacists) across all the socio-economic strata, living in urban as well as in rural locations in the Muslim world during the 9th-16th centuries. The biographies are based mainly on information gathered from the wealth of primary sources found in the Cairo Genizah (letters, commercial documents, court orders, lists of donors) and Muslim Arabic sources (biographical dictionaries, historical and geographical literature). Each one of the biographies presented in the book is a small case study! The biographies enable a unique insight into all aspect of life of Jewish physicians/pharmacists in the medieval Muslim world. The analysis of the more than 600 biographies that are presented in the book exposes readers to various issues such as: professional, personal and daily lives; their successes and failures; families and dynasties of practitioners, clarifying their communal and even financial affairs as well as their inter-religious relationships. Both the biographies and the discussion elucidate various views and aspects of the medicine practiced at that period by Muslim, Jews and Christians. Therefore, the book demonstrates an important and different angle on medieval Arabic medicine.
The Potential of CR-SE for K-12 Computer Science Education: Perspectives from Two Leaders
Authors: Mirakhur Zitsi , Fancsali Cheri , Hill Kathryn
Published: September 2021

This interview examines the close connection between equity and computer science (CS), and Culturally Responsive-Sustaining Education (CR-SE). The conversation speaks with emergent leaders in CS and provides insights into how they are bringing CS education to New York City's 1.1 million students, and how they understand and enact CR-SE practices in their work.
#NormalNeverWorked: The Fight for Black Liberation in the context of Education and COVID 19
Authors: Forbes Jacqueline , Mitchell Nicholas , Baxley Gwendolyn , Davis Ja'Dell , Rosario-Wallace Gloria , Kochon Christian
Published: September 2021

The impact of the Novel Coronavirus (COVID-19) highlights familiar inequities across U.S. institutions that are integral to social well-being. While longing for a return to "normal" is expected in a time of unprecedented loss of human life and the relinquishing of routines and comforts, equity-minded individuals understand that "normal" has been and continues to be oppressive at its core. Interested in the ways that COVID-19 has disrupted the normalcy of oppression and inequity, and the possibilities for Black liberation in this new context, we sat with educators and asked them to consider the urgency and possibility of now in the context of ongoing racial uprisings, persistent anti-Blackness, and the global impact of COVID-19. This article focuses on the themes that emerged, commenting on the opportunities and challenges of Black liberatory practices, whiteness, self care, metacognition about practices, and culturally responsive-sustaining education. While the disproportionate impacts of everyday educational violence on Black students, educators, families, and communities continue to be overlooked, these educators offer hope and a way forward, one rooted in the humanizing love that CR-SE and Black liberatory practices offer.
Fair and Square Redistricting
Authors: Fox James
Published: September 2021

Fair maps are the foundation of a representative democracy. Gerrymanderers wish to create an unrepresentative legislature. The counter to gerrymandering is a fair map where the party sharre of districts matches the party share of the statewide votes. This redistricting criterion was recently codified in the Ohio State Constitution. https://www.legislature.ohio.gov/laws/ohio-constitution/section?const=11.06 A Guide to a new approach for drawing fair maps has been written for citizens, advocates and members of redistricting commissions, as well as legislators and judges. This Guide includes a test for gerrymandering. A research article details, justifies and applies the approach. As more people become aware of approaches such as this, more are likely to ask, “Why aren’t we using procedures like this to build maps where the districts are compact and the maps are fair?”
Prudent Adventure: how does political status affect local government innovations?
Authors: Wang Yuhao
Published: September 2021

What are the concerns and motivations behind policy innovations? Theories claim that local policymakers carry out policy innovations mainly because of economic reasons or other internal concerns but seldomly notice the political structure they face. This study constructs a unique dataset of Chinese local government innovations during 2001-2016 and categorizes them with Natural Language Processing (NLP) techniques. We then examine how economic factors affect policy innovations and how political status brings better explanations. In a centralized authoritarian state like China, local politicians concern political resources and risks more than economic development. We argue that local officials can take the adventure to make institutional rearrangements when enabled but ultimately have to be prudent when closely bonded with the center.
Synthesis of L-asparagine Catalyzed by a Novel Asparagine Synthase Coupled With an ATP Regeneration System
Authors: Luo Wei , Xu Jinglong , Chen Huiying , Zhang Huili , Yang Peilong , Yu Xiaobin
Published: September 2021

Compared with low-yield extraction from plants and environmentally unfriendly chemical synthesis, biocatalysis by asparagine synthetase (AS) for preparation of L-asparagine (L-Asn) has become a potential synthetic method. However, low enzyme activity of AS and high cost of ATP in this reaction restricts the large-scale preparation of L-Asn by biocatalysis. In this study, gene mining strategy was used to search for novel AS with high enzyme activity by expressing them in Escherichia coli BL21 (DE3) or Bacillus subtilis WB600. The obtained LsaAS-A was determined for its enzymatic properties and used for subsequent preparation of L-Asn. In order to reduce the use of ATP, a class III polyphosphate kinase 2 from Deinococcus ficus (DfiPPK2-Ⅲ) was cloned and expressed in E. coli BL21 (DE3), Rosetta (DE3) or RosettagamiB (DE3) for ATP regeneration. A coupling reaction system including whole cells expressing LsaAS-A and DfiPPK2-Ⅲ was constructed to prepare L-Asn from L-aspartic acid (L-Asp). Batch catalytic experiments showed that sodium hexametaphosphate (>60 mmol L−1) and L-Asp (>100 mmol L−1) could inhibit the synthesis of L-Asn. Under fed-batch mode, L-Asn yield reached 90.15% with twice feeding of sodium hexametaphosphate. A final concentration of 218.26 mmol L−1 L-Asn with a yield of 64.19% was obtained when L-Asp and sodium hexametaphosphate were fed simultaneously.
Differential Expression of the TLR4 Gene in Pan-Cancer and Its Related Mechanism
Authors: Hu Jialing , Xu Jiasheng , Feng Xiaojin , Li Yiran , Hua Fuzhou , Xu Guohai
Published: September 2021

Previous studies have revealed the relationship between toll-like receptor 4 (TLR4) polymorphisms and cancer susceptibility. However, the relationship between TLR4 and prognosis and immune cell infiltration in pan-cancer patients is still unclear. Through the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases, the distinct expression of the TLR4 gene in 24 tumors and normal tissues was analyzed. Univariate Cox proportional hazards regression analysis was used to identify the cancer types whose TLR4 gene expression was related to prognosis. The relationship between TLR4 and tumor cell immune invasion was studied. Spearman’s rank correlation coefficient was used to analyze the relationship among TLR4 and immune neoantigens, tumor mutation burden (TMB), microsatellite instability (MSI), DNA repair genes, and DNA methylation. Gene Set Enrichment Analysis (GSEA) was used to identify the tumor-related pathways that the TLR4 gene was highly expressed in; the expression of the TLR4 gene was verified with the Human Protein Atlas (HPA) database. Low expression of TLR4 was associated with an inferior prognosis in kidney renal clear cell carcinoma (KIRC), skin cutaneous melanoma (SKCM), and uterine corpus endometrial carcinoma (UCEC), while high expression was related to a poor prognosis in head and neck squamous cell carcinoma (HNSC), prostate adenocarcinoma (PRAD), stomach adenocarcinoma (STAD), and testicular germ cell tumor (TGCT). The expression of TLR4 was negatively correlated with the expression of B cells in STAD. The expression of TLR4 was positively correlated with the infiltration of B cells, CD4 and CD8 T cells, neutrophils, macrophages, and dendritic cells in STAD, KIRC, UCEC, TGCT, and SKCM. The expression of the TLR4 gene in KIRC, SKCM, STAD, TGCT, and UCEC was highly correlated with inducible T-cell costimulator (ICOS), cytotoxic T lymphocyte-associated molecule 4 (CTLA4), and CD28 immune checkpoints. Spearman’s rank correlation coefficient showed that the expression of TLR4 gene was significantly correlated with TMB in STAD and UCEC and was prominently correlated with MSI in TGCT, STAD, and SKCM. The expression of the TLR4 gene was highly correlated with MLH1, MSH2, and MSH6 in KIRC, SKCM, and STAD. The expression of the TLR4 gene was remarkably correlated with the methyltransferases DNA methyltransferase 2 (DNMT2) and DNA methyltransferase 3-beta (DNMT3B) in SKCM and STAD. Enrichment analysis showed that TLR4 was highly expressed in the chemokine signaling pathway and the cell adhesion molecule and cytokine receptor interaction pathway. In summary, the expression of TLR4 is linked to the prognosis of KIRC, SKCM, STAD, TGCT, and UCEC patients and the level of immune infiltration of CD4, CD8 T cells, macrophages, neutrophils, and dendritic cells.
Association of the Cervical Microbiota With Pregnancy Outcome in a Subfertile Population Undergoing In Vitro Fertilization: A Case-Control Study
Authors: Hao Xinyao , Li Pingping , Wu Shanshan , Tan Jichun
Published: September 2021

The microorganisms of the reproductive tract have been implicated to affect in vitro fertilization (IVF) outcomes. However, studies on the reproductive tract microbiota of infertile women are limited and the correlation between cervical microbiota and IVF outcome remains elusive. This study aimed to characterize the cervical microbiota of IVF patients undergoing embryo transfer (ET) and assess associations between the cervical microbiota and pregnancy outcomes while exploring the underlying contributing factors. We launched a nested case-control study of 100 patients with two fresh or frozen-thawed cleavage embryos transferred per IVF cycle. Cervical swabs were collected on the day of ET and divided into four groups according to clinical pregnancy outcomes. Variable regions 3 and 4 (V3-V4) of the 16S rRNA gene were amplified and sequenced on the Illumina MiSeq platform. In fresh IVF-ET cycles, the clinical pregnancy group (FP, n = 25) demonstrated higher α diversity (P = 0.0078) than the non-pregnancy group (FN, n = 26). Analysis of similarity (ANOSIM) revealed a significant difference in β diversity between the two groups (R = 0.242, P = 0.001). In frozen-thawed ET cycles, though not significant, similar higher α diversity was found in the clinical pregnancy group (TP, n = 27) compared to the non-pregnancy group (TN, n = 22) and ANOSIM analysis showed a significant difference between the two groups (R = 0.062, P = 0.045). For patients in fresh IVF-ET groups, Lactobacillus, Akkermansia, Desulfovibrio, Atopobium, and Gardnerella showed differentially abundance between pregnant and non-pregnant women and they accounted for the largest share of all taxa investigated. Among them, Lactobacillus was negatively correlated with the other genera and positively correlated with serum estradiol levels. Logistic regression analysis suggested that the composition of the cervical microbiota on the day of ET was associated with the clinical pregnancy in fresh IVF-ET cycles (P = 0.030). Our results indicate that cervical microbiota composition has an impact on the outcome of assisted reproductive therapy.
Comparison of Procedure and Fluoroscopy Time Between Left Bundle Branch Area Pacing and Right Ventricular Pacing for Bradycardia: The Learning Curve for the Novel Pacing Strategy
Authors: Wang Zhao , Zhu Haojie , Li Xiaofei , Yao Yan , Liu Zhimin , Fan Xiaohan
Published: September 2021

Background: Left bundle branch area pacing (LBBAP) is a novel physiological pacing approach.

Objective: To assess learning curve for LBBAP and compare the procedure and fluoroscopy time between LBBAP and right ventricular pacing (RVP).

Methods: Consecutive bradycardia patients who underwent LBBAP or RVP were prospectively recruited from June 2018 to June 2020. The procedure and fluoroscopy time for ventricular lead placement, pacing parameters, and periprocedural complications were recorded. Restricted cubic splines were used to fit learning curves for LBBAP.

Results: Left bundle branch area pacing was successful in 376 of 406 (92.6%) patients while 313 patients received RVP. Learning curve for LBBAP illustrated initial (1–50 cases), improved (51–150 cases), and stable stages (151–406 cases) with gradually increased success rates (88.0 vs. 90.0 vs. 94.5%, P = 0.106), steeply decreased median procedure (26.5 vs. 14.0 vs. 9.0min, P < 0.001) and fluoroscopy time (16.0 vs. 6.0 vs. 4.0min, P < 0.001), and shortened stimulus to left ventricular activation time (Sti-LVAT; 78.7 vs. 78.1 vs. 71.2 ms, P < 0.001). LBBAP at the stable stage showed longer but close median procedure (9.0 vs. 6.9min, P < 0.001) and fluoroscopy time (4.0 vs. 2.8min, P < 0.001) compared with RVP.

Conclusion: The procedure and fluoroscopy time of LBBAP could be reduced significantly with increasing procedure volume and close to that of RVP for an experienced operator.
Epicardial Contribution to the Developing and Injured Heart: Exploring the Cellular Composition of the Epicardium
Authors: Streef Thomas J. , Smits Anke M.
Published: September 2021

The epicardium is an essential cell population during cardiac development. It contributes different cell types to the developing heart through epithelial-to-mesenchymal transition (EMT) and it secretes paracrine factors that support cardiac tissue formation. In the adult heart the epicardium is a quiescent layer of cells which can be reactivated upon ischemic injury, initiating an embryonic-like response in the epicardium that contributes to post-injury repair processes. Therefore, the epicardial layer is considered an interesting target population to stimulate endogenous repair mechanisms. To date it is still not clear whether there are distinct cell populations in the epicardium that contribute to specific lineages or aid in cardiac repair, or that the epicardium functions as a whole. To address this putative heterogeneity, novel techniques such as single cell RNA sequencing (scRNA seq) are being applied. In this review, we summarize the role of the epicardium during development and after injury and provide an overview of the most recent insights into the cellular composition and diversity of the epicardium.
Understanding the Last Mile Transportation Concept Impacting Underserved Global Communities to Save Lives During COVID-19 Pandemic
Authors: Jones Erick C. , Azeem Gohar , Jones Erick C. , Jefferson Felicia , Henry Marcia , Abolmaali Shannon , Sparks Janice
Published: September 2021

The underserved population could be at risk during the times of crisis, unless there is strong involvement from government agencies such as local and state Health departments and federal Center for Disease Control (CDC). The COVID-19 pandemic was a crisis of different proportion, creating a different type of burden on government agencies. Vulnerable communities including the elderly populations and communities of color have been especially hard hit by this pandemic. This forced these agencies to change their strategies and supply chains to support all populations receiving therapeutics. The National Science Foundation [National Science Foundation (NSF) Award Abstract # 2028612] funded RAID Labs to help federal agencies with strategies. This paper is based on a NSF funded grant to work on investigating supply chain strategies that would minimize the impact on underserved populations during pandemic. This NSF funded study identified the phenomena of last mile importance. The last mile transportation concept was critical in saving lives during the pandemic for underserved populations. The supply chain model then maximizes social goods by sending drugs or vaccines to the communities that need it the most regardless of ability to pay. The outcome of this study helped us prioritize the communities that need the vaccines the most. This informs our supply chain model to shift resources to these areas showing the value in real time prioritization of the COVID-19 supply chain. This paper provides information can be used in our healthcare supply chain model to ensure timely delivery of vaccines and supplies to COVID-19 patients that are the most vulnerable and hence the overall impact of COVID-19 can be minimized. The use of electrical vehicles for last mile transportation can help in significantly fighting the climate change.
Analysis of Immune–Stromal Score-Based Gene Signature and Molecular Subtypes in Osteosarcoma: Implications for Prognosis and Tumor Immune Microenvironment
Authors: Zheng Dingzhao , Yang Kaichun , Chen Xinjiang , Li Yongwu , Chen Yongchun
Published: September 2021

Objective: Infiltrating immune and stromal cells are essential for osteosarcoma progression. This study set out to analyze immune–stromal score-based gene signature and molecular subtypes in osteosarcoma.

Methods: The immune and stromal scores of osteosarcoma specimens from the TARGET cohort were determined by the ESTIMATE algorithm. Then, immune-stromal score-based differentially expressed genes (DEGs) were screened, followed by univariate Cox regression analysis. A LASSO regression analysis was applied for establishing a prognostic model. The predictive efficacy was verified in the GSE21257 dataset. Associations between the risk scores and chemotherapy drug sensitivity, immune/stromal scores, PD-1/PD-L1 expression, immune cell infiltrations were assessed in the TARGET cohort. NMF clustering analysis was employed for characterizing distinct molecular subtypes based on immune-stromal score-based DEGs.

Results: High immune/stromal scores exhibited the prolonged survival duration of osteosarcoma patients. Based on 85 prognosis-related stromal–immune score-based DEGs, a nine-gene signature was established. High-risk scores indicated undesirable prognosis of osteosarcoma patients. The AUCs of overall survival were 0.881 and 0.849 in the TARGET cohort and GSE21257 dataset, confirming the well predictive performance of this signature. High-risk patients were more sensitive to doxorubicin and low-risk patients exhibited higher immune/stromal scores, PD-L1 expression, and immune cell infiltrations. Three molecular subtypes were characterized, with distinct clinical outcomes and tumor immune microenvironment.

Conclusion: This study developed a robust prognostic gene signature as a risk stratification tool and characterized three distinct molecular subtypes for osteosarcoma patients based on immune–stromal score-based DEGs, which may assist decision-making concerning individualized therapy and follow-up project.
Glycerol Monolaurate Ameliorated Intestinal Barrier and Immunity in Broilers by Regulating Intestinal Inflammation, Antioxidant Balance, and Intestinal Microbiota
Authors: Kong Linglian , Wang Zhenhua , Xiao Chuanpi , Zhu Qidong , Song Zhigang
Published: September 2021

This study was conducted to investigate the impact of glycerol monolaurate (GML) on performance, immunity, intestinal barrier, and cecal microbiota in broiler chicks. A total of 360 one-day-old broilers (Arbor Acres) with an average weight of 45.7 g were randomly allocated to five dietary groups as follows: basal diet and basal diets complemented with 300, 600, 900, or 1200 mg/kg GML. Samples were collected at 7 and 14 days of age. Results revealed that feed intake increased (P < 0.05) after 900 and 1200 mg/kg GML were administered during the entire 14-day experiment period. Dietary GML decreased (P < 0.05) crypt depth and increased the villus height-to-crypt depth ratio of the jejunum. In the serum and jejunum, supplementation with more than 600 mg/kg GML reduced (P < 0.05) interleukin-1β, tumor necrosis factor-α, and malondialdehyde levels and increased (P < 0.05) the levels of immunoglobulin G, jejunal mucin 2, total antioxidant capacity, and total superoxide dismutase. GML down-regulate (P < 0.05) jejunal interleukin-1β and interferon-γ expression and increased (P < 0.05) the mRNA level of zonula occludens 1 and occludin. A reduced (P < 0.05) expression of toll-like receptor 4 and nuclear factor kappa-B was shown in GML-treated groups. In addition, GML modulated the composition of the cecal microbiota of the broilers, improved (P < 0.05) microbial diversity, and increased (P < 0.05) the abundance of butyrate-producing bacteria. Spearman’s correlation analysis revealed that the genera Barnesiella, Coprobacter, Lachnospiraceae, Faecalibacterium, Bacteroides, Odoriacter, and Parabacteroides were related to inflammation and intestinal integrity. In conclusion, GML ameliorated intestinal morphology and barrier function in broiler chicks probably by regulating intestinal immune and antioxidant balance, as well as intestinal microbiota.
L2pB1 Cells Contribute to Tumor Growth Inhibition
Authors: Shibad Varuna , Bootwala Ali , Mao Changchuin , Bader Hanna , Vo Hung , Landesman-Bollag Esther , Guo Conrad , Rubio Angel , Near Richard , Gao Wenda , Challa Sreekar , Chukka Vennela , Gao Jeffrey , Kelly Avery , Landesman Tamar , VanHelene Tyler , Zhong Xuemei
Published: September 2021

Natural IgM (nIgM) antibodies play critical roles in cancer immunosurveillance. However, the role of B-1 B cells, the lymphocytes that produce nIgM, remains to be elucidated. L2pB1 cells, a subpopulation of B-1 B cells, have a unique poly-self-reactive nIgM repertoire and are capable of phagocytosis, potent antigen presentation, and immunomodulation. Using an inducible knock-in and knockout mouse model, we investigated the effect of the loss of L2pB1 cells in a B16F10 melanoma model. Our results show active tumor infiltration of L2pB1 cells in wild type mice, and conversely, depletion of L2pB1 cells results in larger tumor mass and increased angiogenesis. In vitro analysis revealed that L2pB1 cells contribute to the growth inhibition of melanoma cells in both 2D cell culture and 3D tumor spheroids. Similar effects were observed in an MC38 murine colon cancer model. Moreover, our data suggest that one of the ways that L2pB1 cells can induce tumor cell death is via lipoptosis. Lastly, we tested whether L2pB1 cell-derived monoclonal nIgM antibodies can specifically recognize tumor spheroids. Nine of the 28 nIgM-secreting L2pB1 clones demonstrated specific binding to tumor spheroids but did not bind control murine embryonic fibroblasts. Our study provides evidence that L2pB1 cells contribute to cancer immunity through their unique nIgM repertoire, tumor recognition, and lipoptosis. Taken together, because of their ability to recognize common features of tumors that are independent of genetic mutations, L2pB1 cells and their nIgM could be potential candidates for cancer treatment that can overcome tumor heterogeneity-associated drug resistance.
The SARM1 TIR NADase: Mechanistic Similarities to Bacterial Phage Defense and Toxin-Antitoxin Systems
Authors: DiAntonio Aaron , Milbrandt Jeffrey , Figley Matthew D.
Published: September 2021

The Toll/interleukin-1 receptor (TIR) domain is the signature signalling motif of innate immunity, with essential roles in innate immune signalling in bacteria, plants, and animals. TIR domains canonically function as scaffolds, with stimulus-dependent multimerization generating binding sites for signalling molecules such as kinases and ligases that activate downstream immune mechanisms. Recent studies have dramatically expanded our understanding of the TIR domain, demonstrating that the primordial function of the TIR domain is to metabolize NAD+. Mammalian SARM1, the central executioner of pathological axon degeneration, is the founding member of the TIR-domain class of NAD+ hydrolases. This unexpected NADase activity of TIR domains is evolutionarily conserved, with archaeal, bacterial, and plant TIR domains all sharing this catalytic function. Moreover, this enzymatic activity is essential for the innate immune function of these proteins. These evolutionary relationships suggest a link between SARM1 and ancient self-defense mechanisms that has only been strengthened by the recent discovery of the SARM1 activation mechanism which, we will argue, is strikingly similar to bacterial toxin-antitoxin systems. In this brief review we will describe the regulation and function of SARM1 in programmed axon self-destruction, and highlight the parallels between the SARM1 axon degeneration pathway and bacterial innate immune mechanisms.
Exceptional 20th Century Shifts in Deep-Sea Ecosystems Are Spatially Heterogeneous and Associated With Local Surface Ocean Variability
Authors: O’Brien Charlotte L. , Spooner Peter T. , Wharton Jack H. , Papachristopoulou Eirini , Dutton Nicolas , Fairman David , Garratt Rebecca , Li Tianying , Pallottino Francesco , Stringer Fiona , Thornalley David J. R.
Published: September 2021

Traditionally, deep-sea ecosystems have been considered to be insulated from the effects of modern climate change, but with the recognition of the importance of food supply from the surface ocean and deep-sea currents to sustaining these systems, the potential for rapid response of benthic systems to climate change is gaining increasing attention. However, very few ecological time-series exist for the deep ocean covering the twentieth century. Benthic responses to past climate change have been well-documented using marine sediment cores on glacial-interglacial timescales, and ocean sediments have also begun to reveal that planktic species assemblages are already being influenced by global warming. Here, we use benthic foraminifera found in mid-latitude and subpolar North Atlantic sediment cores to show that, in locations beneath areas of major surface water change, benthic ecosystems have also changed significantly over the last ∼150 years. The maximum benthic response occurs in areas which have seen large changes in surface circulation, temperature, and/or productivity. We infer that the observed surface-deep ocean coupling is due to changes in the supply of organic matter exported from the surface ocean and delivered to the seafloor. The local-to-regional scale nature of these changes highlights that accurate projections of changes in deep-sea ecosystems will require (1) increased spatial coverage of deep-sea proxy records, and (2) models capable of adequately resolving these relatively small-scale oceanographic features.
Pulmonary Emphysema Regional Distribution and Extent Assessed by Chest Computed Tomography Is Associated With Pulmonary Function Impairment in Patients With COPD
Authors: Gomes Plácido , Bastos Hélder Novais e , Carvalho André , Lobo André , Guimarães Alan , Rodrigues Rosana Souza , Zin Walter Araujo , Carvalho Alysson Roncally S.
Published: September 2021

Objective: This study aimed to evaluate how emphysema extent and its regional distribution quantified by chest CT are associated with clinical and functional severity in patients with chronic obstructive pulmonary disease (COPD).

Methods/Design: Patients with a post-bronchodilator forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) < 0.70, without any other obstructive airway disease, who presented radiological evidence of emphysema on visual CT inspection were retrospectively enrolled. A Quantitative Lung Imaging (QUALI) system automatically quantified the volume of pulmonary emphysema and adjusted this volume to the measured (EmphCTLV) or predicted total lung volume (TLV) (EmphPLV) and assessed its regional distribution based on an artificial neural network (ANN) trained for this purpose. Additionally, the percentage of lung volume occupied by low-attenuation areas (LAA) was computed by dividing the total volume of regions with attenuation lower or equal to −950 Hounsfield units (HU) by the predicted [LAA (%PLV)] or measured CT lung volume [LAA (%CTLV)]. The LAA was then compared with the QUALI emphysema estimations. The association between emphysema extension and its regional distribution with pulmonary function impairment was then assessed.

Results: In this study, 86 patients fulfilled the inclusion criteria. Both EmphCTLV and EmphPLV were significantly lower than the LAA indices independently of emphysema severity. CT-derived TLV significantly increased with emphysema severity (from 6,143 ± 1,295 up to 7,659 ± 1,264 ml from mild to very severe emphysema, p < 0.005) and thus, both EmphCTLV and LAA significantly underestimated emphysema extent when compared with those values adjusted to the predicted lung volume. All CT-derived emphysema indices presented moderate to strong correlations with residual volume (RV) (with correlations ranging from 0.61 to 0.66), total lung capacity (TLC) (from 0.51 to 0.59), and FEV1 (~0.6) and diffusing capacity for carbon monoxide DLCO (~0.6). The values of FEV1 and DLCO were significantly lower, and RV (p < 0.001) and TLC (p < 0.001) were significantly higher with the increasing emphysema extent and when emphysematous areas homogeneously affected the lungs.

Conclusions: Emphysema volume must be referred to the predicted and not to the measured lung volume when assessing the CT-derived emphysema extension. Pulmonary function impairment was greater in patients with higher emphysema volumes and with a more homogeneous emphysema distribution. Further studies are still necessary to assess the significance of CTpLV in the clinical and research fields.
Systematic Review on the Correlation of Quantitative PCR Cycle Threshold Values of Gastrointestinal Pathogens With Patient Clinical Presentation and Outcomes
Authors: Bonacorsi Stéphane , Visseaux Benoit , Bouzid Donia , Pareja Josep , Rao Sonia N. , Manissero Davide , Hansen Glen , Vila Jordi
Published: September 2021

Background: Quantitative (q) polymerase chain reaction (PCR) cycle threshold (Ct) values represent the number of amplification cycles required for a positive PCR result and are a proxy of pathogen quantity in the tested sample. The clinical utility of Ct values remains unclear for gastrointestinal infections.

Objectives: This systematic review assesses the global medical literature for associations between Ct values of gastrointestinal pathogens and patient presentation and clinical outcomes.

Data Sources: MEDLINE, EMBASE, Cochrane library databases: searched January 14–17, 2020.

Study Eligibility Criteria: Studies reporting on the presence or absence of an association between Ct values and clinical outcomes in adult and pediatric populations were included. Animal studies, reviews, meta-analyses, and non-English language studies were excluded.

Participants: Humans infected with gastrointestinal pathogens, detected with qPCR.

Interventions: Diagnostics assessing Ct values. Extracted data were reported narratively.

Results: Thirty-three eligible studies were identified; the most commonly studied pathogens were Clostridioides difficile (n = 15), norovirus (n = 10), and rotavirus (n = 9). Statistically significant associations between low C. difficile Ct values and increased symptom severity or poor outcome were reported in 4/8 (50%) studies, and increased risk of death in 1/2 (50%) studies; no significant associations were found between Ct value and duration of symptoms or length of hospital stay. Among studies of norovirus, 5/7 (71%), mainly genogroup II, reported symptomatic cases with significantly lower median Ct values than controls. Significantly lower rotavirus Ct values were also observed in symptomatic cases vs. controls in 3/7 (43%) studies, and associated with more severe symptoms in 2/2 studies. Contradictory associations were identified for non-C. difficile bacterial and parasitic pathogens.

Conclusions: In conclusion, some studies reported clinically useful associations between Ct values and patient or healthcare outcomes; additional, well-designed, large-scale trials are warranted based on these findings.

Systematic Review Registration: [PROSPERO], identifier [CRD42020167239].
Immunosuppressive Potential of Activated Human Amniotic Cells in an Experimental Murine Model of Skin Allo- and Xenotransplantation
Authors: Kolanko Emanuel , Grajoszek Aniela , Czekaj Piotr
Published: September 2021

Isolated human amniotic cells (hAC) could be used as a source of immunomodulatory factors in regenerative medicine and transplantation. However, in previous experimental studies, native hAC administered to skin graft recipients did not induce graft immunotolerance. To strengthen the immunomodulatory properties of hAC prior to administration to the recipient, we activated them ex vivo using pro-inflammatory cytokines. In this study, we compared the transplantation efficiency of skin allografts (mouse to mouse) and xnografts (rat to mouse) in recipient mice divided into three main groups receiving: 1. Placebo (control group); 2. Cyclosporine A (CsA) [10 or 50 mg/kg body weight (bw)]; 3. suspension of hAC activated ex vivo by IL-1β and INFγ, administered into a tail vein or subcutaneously. During 15 days of observation, hAC administered intravenously or subcutaneously after allotransplantation appeared to be as safe and efficient as CsA at the dose of 10 mg/kg bw in preventing rejection of skin allo- and xenografts. After xenotransplantation, however, only hAC administered intravenously prevented rejection to an extent comparable to CsA. Both CsA (10 mg/kg bw) and activated hAC reduced inflammatory infiltration in the skin (after intravenous injection) and did not increase the concentration of the inflammation marker SAP in serum or percentage of leukocytes in blood. Finally, we concluded that administration of activated hAC is safe and efficient in the presented animal model of skin allo- and xenotransplantation in a route-dependent manner. Activated hAC injected intravenously exhibit an immunosuppressive effect comparable to CsA administered at the dose of 10 mg/kg bw in both allo- and xenotransplantation.
Amnion-Derived Mesenchymal Stromal/Stem Cell Paracrine Signals Potentiate Human Liver Organoid Differentiation: Translational Implications for Liver Regeneration
Authors: Lo Nigro Antonio , Gallo Alessia , Bulati Matteo , Vitale Giampiero , Paini Diego Sebastian , Pampalone Mariangela , Galvagno Daniele , Conaldi Pier Giulio , Miceli Vitale
Published: September 2021

The prevalence of end-stage liver diseases has reached very high levels globally. The election treatment for affected patients is orthotopic liver transplantation, which is a very complex procedure, and due to the limited number of suitable organ donors, considerable research is being done on alternative therapeutic options. For instance, the use of cell therapy, such as the transplantation of hepatocytes to promote liver repair/regeneration, has been explored, but standardized protocols to produce suitable human hepatocytes are still limited. On the other hand, liver progenitor and multipotent stem cells offer potential cell sources that could be used clinically. Different studies have reported regarding the therapeutic effects of transplanted mesenchymal stromal/stem cells (MSCs) on end-stage liver diseases. Moreover, it has been shown that delivery of MSC-derived conditioned medium (MSC-CM) can reduce cell death and enhance liver proliferation in fulminant hepatic failure. Therefore, it is believed that MSC-CM contains many factors that probably support liver regeneration. In our work, we used an in vitro model of human liver organoids to study if the paracrine components secreted by human amnion-derived MSCs (hAMSCs) affected liver stem/progenitor cell differentiation. In particular, we differentiated liver organoids derived from bipotent EpCAM+ human liver cells and tested the effects of hAMSC secretome, derived from both two-dimensional (2D) and three-dimensional (3D) hAMSC cultures, on that model. Our analysis showed that conditioned medium (CM) produced by 3D hAMSCs was able to induce an over-expression of mature hepatocyte markers, such as ALB, NTCP, and CYP3A4, compared with both 2D hAMSC cultures and the conventional differentiation medium (DM). These data were confirmed by the over-production of ALB protein and over-activity of CYP3A4 observed in organoids grown in 3D hAMSC-CM. Liver repair dysfunction plays a role in the development of liver diseases, and effective repair likely requires the normal functioning of liver stem/progenitor cells. Herein, we showed that hAMSC-CM produced mainly by 3D cultures had the potential to increase hepatic stem/progenitor cell differentiation, demonstrating that soluble factors secreted by those cells are potentially responsible for the reaction. This work shows a potential approach to improve liver repair/regeneration also in a transplantation setting.
Identification and Antibiotic Profiling of Wohlfahrtiimonas chitiniclastica, an Underestimated Human Pathogen
Authors: Kopf Anna , Bunk Boyke , Coldewey Sina M. , Gunzer Florian , Riedel Thomas , Schröttner Percy
Published: September 2021

In the past 12 years, several case reports have clearly demonstrated that Wohlfahrtiimonas chitiniclastica is capable of causing sepsis and bacteremia in humans. However, since most clinicians are not familiar with this species, little is known about its pathogenicity and treatment options while it is as rare but underestimated human pathogen. Therefore, a larger strain collection is required so that methods can be identified that are most suitable to obtain rapid and reliable identification. Moreover, the antimicrobial resistance profile needs to be elucidated in order to explore possible treatment options. Over a period of 6 years, we therefore have collected a total of 14 W. chitiniclastica isolates in routine diagnostics, which now served as the basis for a comprehensive characterization with respect to identification and antibiotic profiling. We compared the accuracy and convenience of several identification techniques in which MALDI-TOF MS and sequencing of the 16S rRNA gene have proven to be suitable for identification of W. chitiniclastica. In addition, whole genome sequencing (WGS)-based digital DNA-DNA hybridization (dDDH) was used as a reference method for strain identification, and surprised with the detection of a novel W. chitiniclastica subspecies. A combination of in silico and in vitro analyses revealed a first insight into the antimicrobial resistance profile and the molecular basis of antimicrobial resistance. Based on our findings, trimethoprim/sulfamethoxazole, levofloxacin, and cephalosporins (e.g., ceftazidime) may be the best antibiotics to use in order to treat infections caused by W. chitiniclastica, while resistance to fosfomycin, amikacin and tobramycin is observed.
The Role of the Moraxella catarrhalis CopB Protein in Facilitating Iron Acquisition From Human Transferrin and Lactoferrin
Authors: Chan Clement , Ng Dixon , Schryvers Anthony B.
Published: September 2021

Moraxella catarrhalis is a Gram-negative bacterium that is responsible for a substantial proportion of upper respiratory infections in children and lower respiratory infections in the elderly. Moraxella catarrhalis resides exclusively on the mucosal surfaces of the upper respiratory tract of humans and is capable of directly acquiring iron for growth from the host glycoproteins human transferrin (hTf) and human lactoferrin (hLf). The iron-bound form of these glycoproteins is initially captured by the surface lipoproteins Tf or Lf binding protein B (TbpB or LbpB) and delivered to the integral outer membrane TonB-dependent transport (TBDT) proteins, Tf binding protein A (TbpA) or Lf binding protein A (LbpA). The extraction of iron involves conformational changes in Lf and Tf to facilitate iron removal followed by its transport across the outer membrane by a well characterized process for TBDTs. Surprisingly the disruption of the gene encoding another TBDT, CopB, results in a reduction in the ability to grow on human Tf or Lf. The possibility that this could have been due to an artifact of mutant construction that resulted in the inhibition of TonB-mediated process was eliminated by a complete deletion of the CopB gene. A systematic evaluation of the impact on growth under various conditions by deletions of the genes encoding TbpA, LbpA, and CopB as well as mutations of the iron liganding residues and TonB box region of CopB was implemented. The results indicate that although CopB is capable of effectively acquiring iron from the growth medium, it does not directly acquire iron from Tf or Lf. We propose that the indirect effect on iron transport from Tf and Lf by CopB could possibly be explained by the association of TBDTs at gaps in the peptidoglycan layer that may enhance the efficiency of the process. This concept is supported by previous studies demonstrating an indirect effect on growth of Tf and Lf by deletion of the peptidoglycan binding outer membrane lipoprotein RmpM in Neisseria that also reduced the formation of larger complexes of TBDTs.
Trophic Enrichment Factors of Carbon and Nitrogen Isotopic Ratios (Δ13C and Δ15N) in Four Marine Ciliates
Authors: Park Jun Young , Jung Jae-Ho , Kwak Jung Hyun , Park Heum Gi , Kang Chang-Keun , Park Hyun Je
Published: September 2021

Understanding the magnitude and causes of isotopic fractionation between organisms and their dietary resources is crucial for gaining knowledge on stable isotope ecology. However, little is known regarding the diet-tissue fractionation values of marine ciliates, which play a critical role in the reconstruction of microbial food webs. In the present study, we conducted experiments on two benthic (Pseudokeronopsis pararubra and Protocruzia labiata) and two pelagic (Strombidium sulcatum and Uronemella filificum) marine ciliates, where they were fed with isotopically constant foods (Chaetoceros calcitrans and Isochrysis galbana) under laboratory culture conditions to determine their carbon and nitrogen isotopic fractionation values (Δ13C and Δ15N). The stable isotope values (δ13C and δ15N) of ciliates for all experiments rapidly increased after the initial feeding, with half-lives ranging from 6.1 to 23.0h for δ13C and from 3.1 to 24.9h for δ15N. The Δ13C and Δ15N for all ciliates represented significantly positive enrichments, with overall mean fractionations of 0.6±0.2 and 1.2±0.4, respectively. Irrespective of the dietary type, both Δ13C and Δ15N were very similar for the same ciliate species. These results suggest that Δ13C and Δ15N for marine ciliates are similar to those found in common marine organisms with very little food-dependent variation. Overall, quantifying the specific isotopic fractionation of marine ciliates is expected to provide fundamental information on the trophic transfer of carbon, nitrogen, and energy flow through the microbial pathway in marine ecosystems.
The bZIP Transcription Factor LtAP1 Modulates Oxidative Stress Tolerance and Virulence in the Peach Gummosis Fungus Lasiodiplodia theobromae
Authors: Zhang He , Shen Wanqi , Zhang Dongmei , Shen Xingyi , Wang Fan , Hsiang Tom , Liu Junwei , Li Guohuai
Published: September 2021

Lasiodiplodia theobromae is one of the primary causal agents in peach gummosis disease, leading to enormous losses in peach production. In our previous study, a redox-related gene, LtAP1, from the fungus was significantly upregulated in peach shoots throughout infection. Here, we characterized LtAP1, a basic leucine zipper transcription factor, during peach gummosis progression using the CRISPR-Cas9 system and homologous recombination. The results showed that LtAP1-deletion mutant had slower vegetative growth and increased sensitivity to several oxidative and nitrosative stress agents. LtAP1 was highly induced by exogenous oxidants treatment in the L. theobromae wild-type strain. In a pathogenicity test, the deletion mutant showed decreased virulence (reduced size of necrotic lesions, less gum release, and decreased pathogen biomass) on infected peach shoots compared to the wild-type strain. The mutant showed severely reduced transcription levels of genes related to glutaredoxin and thioredoxin in L. theobroame under oxidative stress or during infection, indicating an attenuated capacity for reactive oxygen species (ROS) detoxification. When shoots were treated with an NADPH oxidase inhibitor, the pathogenicity of the mutant was partially restored. Moreover, ROS production and plant defense response were strongly activated in peach shoots infected by the mutant. These results highlight the crucial role of LtAP1 in the oxidative stress response, and further that it acts as an important virulence factor through modulating the fungal ROS-detoxification system and the plant defense response.