bluuebunny/crossref_metadata_2025 huggingface dataset:
Salmonella Biofilm Formation, Chronic Infection, and Immunity Within the Intestine and Hepatobiliary Tract
Authors: Harrell Jaikin E. , Hahn Mark M. , D’Souza Shaina J. , Vasicek Erin M. , Sandala Jenna L. , Gunn John S. , McLachlan James B.
Published: February 2021

Within the species of Salmonella enterica, there is significant diversity represented among the numerous subspecies and serovars. Collectively, these account for microbes with variable host ranges, from common plant and animal colonizers to extremely pathogenic and human-specific serovars. Despite these differences, many Salmonella species find commonality in the ability to form biofilms and the ability to cause acute, latent, or chronic disease. The exact outcome of infection depends on many factors such as the growth state of Salmonella, the environmental conditions encountered at the time of infection, as well as the infected host and immune response elicited. Here, we review the numerous biofilm lifestyles of Salmonella (on biotic and abiotic surfaces) and how the production of extracellular polymeric substances not only enhances long-term persistence outside the host but also is an essential function in chronic human infections. Furthermore, careful consideration is made for the events during initial infection that allow for gut transcytosis which, in conjunction with host immune functions, often determine the progression of disease. Both typhoidal and non-typhoidal salmonellae can cause chronic and/or secondary infections, thus the adaptive immune responses to both types of bacteria are discussed with particular attention to the differences between Salmonella Typhi, Salmonella Typhimurium, and invasive non-typhoidal Salmonella that can result in differential immune responses. Finally, while strides have been made in our understanding of immunity to Salmonella in the lymphoid organs, fewer definitive studies exist for intestinal and hepatobiliary immunity. By examining our current knowledge and what remains to be determined, we provide insight into new directions in the field of Salmonella immunity, particularly as it relates to chronic infection.
Percutaneous Treatment of Venous Erectile Dysfunction
Authors: Hoppe Hanno , Diehm Nicholas
Published: February 2021

Erectile dysfunction is a defined as recurring inability to achieve and maintain satisfactory erection for sexual intercourse associated with relevant life impairment. The underlying etiologies may be manifold and complex. Currently, vascular etiologies are highly prevalent especially amongst elderly men. Of special interest, especially venogenic causes are of increasing relevance. Therapeutic options comprise risk factor modification, pharmacotherapy, surgical treatment, and endovascular treatment. Especially endovascular treatment options have recently increased in popularity including transcatheter embolization procedures for veno-occlusive dysfunction.
Electrocardiographic Risk Stratification in COVID-19 Patients
Authors: Chorin Ehud , Dai Matthew , Kogan Edward , Wadhwani Lalit , Shulman Eric , Nadeau-Routhier Charles , Knotts Robert , Bar-Cohen Roi , Barbhaiya Chirag , Aizer Anthony , Holmes Douglas , Bernstein Scott , Spinelli Michael , Park David , Chinitz Larry , Jankelson Lior
Published: February 2021

Background: The COVID-19 pandemic has resulted in worldwide morbidity at unprecedented scale. Troponin elevation is a frequent laboratory finding in hospitalized patients with the disease, and may reflect direct vascular injury or non-specific supply-demand imbalance. In this work, we assessed the correlation between different ranges of Troponin elevation, Electrocardiographic (ECG) abnormalities, and mortality.

Methods: We retrospectively studied 204 consecutive patients hospitalized at NYU Langone Health with COVID-19. Serial ECG tracings were evaluated in conjunction with laboratory data including Troponin. Mortality was analyzed in respect to the degree of Troponin elevation and the presence of ECG changes including ST elevation, ST depression or T wave inversion.

Results: Mortality increased in parallel with increase in Troponin elevation groups and reached 60% when Troponin was >1 ng/ml. In patients with mild Troponin rise (0.05–1.00 ng/ml) the presence of ECG abnormality and particularly T wave inversions resulted in significantly greater mortality.

Conclusion: ECG repolarization abnormalities may represent a marker of clinical severity in patients with mild elevation in Troponin values. This finding can be used to enhance risk stratification in patients hospitalized with COVID-19.
Calcium Dobesilate (CaD) Attenuates High Glucose and High Lipid-Induced Impairment of Sarcoplasmic Reticulum Calcium Handling in Cardiomyocytes
Authors: Deng Jianxin , Cai Xiangsheng , Hao Mingyu , Liu Xueting , Chen Zelong , Li Haiyan , Liu Junying , Liao Yunxiu , Fu Hao , Chen Huiyan , Qin Gangjian , Yan Dewen
Published: February 2021

Calcium dobesilate (CaD) is used effectively in patients with diabetic microvascular disorder, retinopathy, and nephropathy. Here we sought to determine whether it has an effect on cardiomyocytes calcium mishandling that is characteristic of diabetic cardiomyopathy. Cardiomyocytes were sterile isolated and cultured from 1 to 3 days neonatal rats and treated with vehicle (Control), 25 mM glucose+300 μM Palmitic acid (HG+PA), 100 μM CaD (CaD), or HG+PA+CaD to test the effects on calcium signaling (Ca2+ sparks, transients, and SR loads) and reactive oxygen species (ROS) production by confocal imaging. Compared to Control, HG+PA treatment significantly reduced field stimulation-induced calcium transient amplitudes (2.22 ± 0.19 vs. 3.56 ± 0.21, p < 0.01) and the levels of caffeine-induced calcium transients (3.19 ± 0.14 vs. 3.72 ± 0.15, p < 0.01), however significantly increased spontaneous Ca2+ sparks firing levels in single cardiomyocytes (spontaneous frequency 2.65 ± 0.23 vs. 1.72 ± 0.12, p < 0.01) and ROS production (67.12 ± 4.4 vs. 47.65 ± 2.12, p < 0.05), which suggest that HG+PA treatment increases the Spontaneity Ca2+ spark frequency, and then induced partial reduction of SR Ca2+ content and subsequently weaken systolic Ca2+ transient in cardiomyocyte. Remarkably, these impairments in calcium signaling and ROS production were largely prevented by pre-treatment of the cells with CaD. Therefore, CaD may contribute to a good protective effect on patients with calcium mishandling and contractile dysfunction in cardiomyocytes associated with diabetic cardiomyopathy.
STEM for Everyone: A Mixed Methods Approach to the Conception and Implementation of an Evaluation Process for STEM Education Programs for Students With Disabilities
Authors: Griffiths Amy Jane , Brady John , Riley Nicholas , Alsip James , Trine Vanessa , Gomez Lauren
Published: February 2021

Some students with autism spectrum disorder and other learning differences may have superior visual acuity, increased attentional focus, and logical thinking abilities, lending to an affinity for science, technology, engineering, and mathematics (STEM) fields. At the same time, economists report that, the United States will experience a 28.2% increase in STEM-related jobs between 2014 and 2024. Although students with disabilities (SWD) can help to fill those positions, 85% of SWD graduates are either underemployed or unemployed as they enter young adulthood. Thus, there is a need to develop, evaluate, and report outcomes of STEM preparation programs specifically tailored to SWD. This mixed-methods study was designed to develop an evaluation procedure to measure a STEM school’s program for SWD and to analyze the first two years of data to help shape the evaluation process. A comprehensive evaluation model of STEM education for children with learning differences was developed and tested. Implications for practice and future research are discussed.
Population Density and Temperature Influence the Return on Maternal Investment in Wild House Mice
Authors: Gerber Nina , Auclair Yannick , König Barbara , Lindholm Anna K.
Published: February 2021

In mammals, reproduction is influenced by sexual competition, temperature and food availability and these factors might be crucial already during early life. Favorable early life environment and high maternal investment are expected to improve survival and reproduction. For example, in mammals, maternal investment via lactation predicts offspring growth. As body mass is often associated with fitness consequences, females have the potential to influence offspring fitness through their level of investment, which might interact with effects of population density and temperature. Here, we investigate the relationship between house mouse (Mus musculus domesticus) pup body mass at day 13 (used as approximation for weaning mass) and individual reproductive parameters, as well as longevity, under natural variation in population density and temperature (as approximation for season). Further, we assessed the extent to which mothers influence the body mass of their offspring until weaning. To do so, we analyzed life data of 384 house mice from a free-living wild commensal population that was not food limited. The mother’s contribution accounted for 49% of the variance in pup body mass. Further, we found a complex effect of population density, temperature and maternal investment on life-history traits related to fitness: shorter longevity with increasing pup body mass at day 13, delayed first reproduction of heavier pups when raised at warmer temperatures, and increased lifetime reproductive success for heavier pups at high densities. Our study shows that the effects of maternal investment are not independent of the effects of the environment. It thus highlights the importance of considering ecological conditions in combination with maternal effects to unravel the complexity of pup body mass on fitness measures.
Impacts of Postfire Management Are Unjustified in Spotted Owl Habitat
Authors: Hanson Chad T. , Chi Tonja Y.
Published: February 2021

In mixed-conifer forests inhabited by California spotted owls, land managers hypothesize that without human intervention natural conifer regeneration will take many decades or longer to begin within interior areas of large high-severity fire patches, due to long distances from live tree seed sources. As a result, widespread post-fire logging, followed by sprayed application of herbicides and planting of conifer seedlings, are used to create tree plantations. These are activities routinely conducted in spotted owl territories following fires, despite current data that indicate this approach has adverse impacts on spotted owl occupancy. Land managers acknowledge such impacts, but continue these forest management practices, assuming they are a necessary harm, one that is warranted to ensure the later return of mature conifer forests used by spotted owls for nesting and roosting. However, few data have been gathered to test this hypothesis. At 5 years post-fire, we surveyed field plots on a grid within large high-severity fire patches in spotted owl habitat within the Rim fire of 2013 in the Sierra Nevada, California. In our analysis the percentage of plots lacking conifer regeneration decreased significantly with larger plot sizes, a finding contrary to previous studies which assumed vast “deforested” areas in wildland fires, a bias created by small plot size. We found higher conifer regeneration closer to live-tree edges, but we consistently found natural post-fire conifer regeneration at all distances into interior spaces of large high-severity fire patches, including >300 m from the nearest live trees. Distance from live-tree edges did not affect pine dominance in post-fire regeneration. The post-fire natural conifer regeneration reported in our results suggests that the adverse effects of current post-fire management in spotted owl habitat are not necessary practices that can be justified.
Opportunities for Transdisciplinary Science to Mitigate Biosecurity Risks From the Intersectionality of Illegal Wildlife Trade With Emerging Zoonotic Pathogens
Authors: Aguirre A. Alonso , Gore Meredith L. , Kammer-Kerwick Matt , Curtin Kevin M. , Heyns Andries , Preiser Wolfgang , Shelley Louise I.
Published: February 2021

Existing collaborations among public health practitioners, veterinarians, and ecologists do not sufficiently consider illegal wildlife trade in their surveillance, biosafety, and security (SB&S) efforts even though the risks to health and biodiversity from these threats are significant. We highlight multiple cases to illustrate the risks posed by existing gaps in understanding the intersectionality of the illegal wildlife trade and zoonotic disease transmission. We argue for more integrative science in support of decision-making using the One Health approach. Opportunities abound to apply transdisciplinary science to sustainable wildlife trade policy and programming, such as combining on-the-ground monitoring of health, environmental, and social conditions with an understanding of the operational and spatial dynamics of illicit wildlife trade. We advocate for (1) a surveillance sample management system for enhanced diagnostic efficiency in collaboration with diverse and local partners that can help establish new or link existing surveillance networks, outbreak analysis, and risk mitigation strategies; (2) novel analytical tools and decision support models that can enhance self-directed local livelihoods by addressing monitoring, detection, prevention, interdiction, and remediation; (3) enhanced capacity to promote joint SB&S efforts that can encourage improved human and animal health, timely reporting, emerging disease detection, and outbreak response; and, (4) enhanced monitoring of illicit wildlife trade and supply chains across the heterogeneous context within which they occur. By integrating more diverse scientific disciplines, and their respective scientists with indigenous people and local community insight and risk assessment data, we can help promote a more sustainable and equitable wildlife trade.
The Function of the Metals in Regulating Epigenetics During Parkinson’s Disease
Authors: Wei Xiangzhen , Cai Menghua , Jin Lifang
Published: February 2021

Parkinson’s means Parkinson’s disease, a chronic degenerative disease of central nervous system. The main area which is affected by this disease is motor system. Since it firstly founded by James Parkinson in his 1817 publication, nowadays, people still have lots of questions about this disease. This review mainly summarizes the epigenetics of Parkinson’s. DNA methylation is one of the epigenetic mechanisms of Parkinson’s. During the development of disease, global hypomethylation, and hypermethylation happen in different areas of patients. Another epigenetic mechanism is histone modification. People believe that some metals can induce Parkinson’s disease by modulating epigenetic mechanisms. This review summarizes the relationships between different metals and Parkinson’s disease. However, the specific roles of most metals in epigenetics are still unknown, which need further research.
Prevalence of the Brazilian TP53 Founder c.1010G>A (p.Arg337His) in Lung Adenocarcinoma: Is Genotyping Warranted in All Brazilian Patients?
Authors: Vieira Igor Araujo , Andreis Tiago Finger , Fernandes Bruna Vieira , Achatz Maria Isabel , Macedo Gabriel S. , Schramek Daniel , Ashton-Prolla Patricia
Published: February 2021

In Southern and Southeastern Brazil, there is a germline pathogenic variant with incomplete penetrance located in the oligomerization domain of TP53, c.1010G>A (p.Arg337His). Due to a founder effect, the variant is present in 0.3% of the general population of the region. Recently, this variant was identified in 4.4 and 8.9% of two apparently unselected, single center case series of Brazilian lung adenocarcinoma (LUAD) patients from the Southeastern and Central regions of the country, respectively. In the present study, our aim was to examine TP53 c.1010G>A allele and genotype frequencies in LUAD samples obtained from patients diagnosed in Southern Brazil. A total of 586 LUAD samples (tumor DNA) recruited from multiple centers in the region were tested, and the mutant allele was identified using TaqMan® assays in seven cases (7/586, 1.2%) which were submitted to next generation sequencing analyses for confirmation. Somatic EGFR mutations were more frequent in TP53 c.1010G>A carriers than in non-carriers (57.1 vs. 17.6%, respectively). Further studies are needed to confirm if TP53 c.1010G>A is a driver in LUAD carcinogenesis and to verify if there is a combined effect of EGFR and germline TP53 c.1010G>A. Although variant frequency was higher than observed in the general population, it is less than previously reported in LUAD patients from other Brazilian regions. Additional data, producing regional allele frequency information in larger series of patients and including cost-effectiveness analyses, are necessary to determine if TP53 c.1010G>A screening in all Brazilian LUAD patients is justified.
P2RX1-Involved Glycolytic Metabolism Supports Neutrophil Activation in Acute Pancreatitis
Authors: Wang Xu , Liu Dadong , Qin Weiting , Liu Yishu , Yuan Xiao , Zhang Xiaoxin , Dai Chunhua , Zhang Danyi
Published: February 2021

Acute pancreatitis (AP) is characterized by disordered inflammation of the pancreas, and the underlying mechanisms remain unclear. Purinergic signaling plays crucial roles in initiating and amplifying inflammatory signals. Recent evidence reveals that targeting dysregulated purinergic signaling is promising for treating inflammation-associated diseases. To explore the potential involvement of purinergic signaling in AP, we investigated the expression profiles of purinergic signaling molecules in human and mouse pancreas tissues. Results showed that purinergic receptor P2RX1 was among the most highly expressed genes in both human and mouse pancreas tissues. Genetic ablation or specific antagonism of P2RX1 markedly alleviated inflammatory responses in caerulein-induced AP mice. Bone marrow chimeras and adoptive transfer studies revealed that neutrophil-derived P2RX1 contributed to the inflammatory responses in AP. Further studies demonstrated that P2RX1 promoted neutrophil activation by facilitating glycolytic metabolism. Therefore, our study indicates that purinergic receptor P2RX1 may be a potential therapeutic target to treat disordered inflammation in AP.
cGAMP/Saponin Adjuvant Combination Improves Protective Response to Influenza Vaccination by Microneedle Patch in an Aged Mouse Model
Authors: Vassilieva Elena V. , Li Song , Korniychuk Heorhiy , Taylor Dahnide M. , Wang Shelly , Prausnitz Mark R. , Compans Richard W.
Published: February 2021

Current strategies for improving protective response to influenza vaccines during immunosenescence do not adequately protect individuals over 65 years of age. Here, we used an aged mouse model to investigate the potential of co-delivery of influenza vaccine with the recently identified combination of a saponin adjuvant Quil-A and an activator of the STING pathway, 2’3 cyclic guanosine monophosphate–adenosine monophosphate (cGAMP)viadissolving microneedle patches (MNPs) applied to skin. We demonstrate that synergy between the two adjuvant components is observed after their incorporation with H1N1 vaccine into MNPs as revealed by analysis of the immune responses in adult mice. Aged 21-month-old mice were found to be completely protected against live influenza challenge after vaccination with the MNPs adjuvanted with the Quil-A/cGAMP combination (5 µg each) and demonstrated significantly reduced morbidity compared to the observed responses in these mice vaccinated with unadjuvanted MNPs. Analysis of the lung lysates of the surviving aged mice post challenge revealed the lowest level of residual inflammation in the adjuvanted groups. We conclude that combining influenza vaccine with a STING pathway activator and saponin-based adjuvant in MNPs is a novel option for skin vaccination of the immunosenescent population, which is at high risk for influenza.
Addition of Rituximab in Reduced Intensity Conditioning Regimens for B-Cell Malignancies Does Not Influence Transplant Outcomes: EBMT Registry Analyses Following Allogeneic Stem Cell Transplantation for B-Cell Malignancies
Authors: Tomaszewska Agnieszka , Jagasia Madan , Beohou Eric , van der Werf Steffie , Blaise Didier , Kanfer Edward , Milpied Noel , Reményi Péter , Ciceri Fabio , Bourhis Jean H. , Chevallier Patrice , Solano Carlos , Socié Gerard , Bruno Benedetto , Rambaldi Alessandro , Castagna Luca , Kröger Nicolaus , Corradini Paolo , Afanasyev Boris , Ladetto Marco , Niederwieser Dietger , Scheid Christof , Sengeloev Henrik , Kroschinsky Frank , Yakoub-Agha Ibrahim , Schoemans Helene , Koenecke Christian , Penack Olaf , Perić Zinaida , Greinix Hildegard , Duarte Rafael F. , Basak Grzegorz W.
Published: February 2021

Rituximab (R) is increasingly incorporated in reduced intensity conditioning (RIC) regimens for allogeneic hematopoietic cell transplantation (alloHCT) in patients with B-cell malignancies, not only to improve disease control, but also to prevent graft-versus-host disease (GVHD). There are no randomized prospective data to validate this practice, although single center data and the CIBMTR analysis have shown promising results. We aimed at validation of these findings in a large registry study. We conducted a retrospective analysis using the EBMT registry of 3,803 adult patients with B-cell malignancies undergoing alloHCT (2001–2013) with either rituximab (R-RIC-9%) or non-rituximab (RIC-91%) reduced intensity regimens respectively. Median age and median follow up were 55 years (range 19.1–77.3) and 43.2 months (range 0.3–179.8), respectively. There was no difference in transplant outcomes (R-RIC vs RIC), including 1-year overall survival (69.9% vs 70.7%), 1-year disease-free survival (64.4% vs 62.2%), 1-year non-relapse mortality (21% vs 22%), and day-100 incidence of acute GVHD 2-4° (12% vs 12%). In summary, we found that addition of rituximab in RIC regimens for B-cell malignancies had no significant impact on major transplant outcome variables. Of note, data on chronic GVHD was not available, limiting the conclusions that can be drawn from the present study.
Regulation of the NLRP3 Inflammasome by Post-Translational Modifications and Small Molecules
Authors: Seok Jin Kyung , Kang Han Chang , Cho Yong-Yeon , Lee Hye Suk , Lee Joo Young
Published: February 2021

Inflammation is a host protection mechanism that eliminates invasive pathogens from the body. However, chronic inflammation, which occurs repeatedly and continuously over a long period, can directly damage tissues and cause various inflammatory and autoimmune diseases. Pattern recognition receptors (PRRs) respond to exogenous infectious agents called pathogen-associated molecular patterns and endogenous danger signals called danger-associated molecular patterns. Among PRRs, recent advancements in studies of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome have established its significant contribution to the pathology of various inflammatory diseases, including metabolic disorders, immune diseases, cardiovascular diseases, and cancer. The regulation of NLRP3 activation is now considered to be important for the development of potential therapeutic strategies. To this end, there is a need to elucidate the regulatory mechanism of NLRP3 inflammasome activation by multiple signaling pathways, post-translational modifications, and cellular organelles. In this review, we discuss the intracellular signaling events, post-translational modifications, small molecules, and phytochemicals participating in the regulation of NLRP3 inflammasome activation. Understanding how intracellular events and small molecule inhibitors regulate NLRP3 inflammasome activation will provide crucial information for elucidating the associated host defense mechanism and the development of efficient therapeutic strategies for chronic diseases.
Correlations in Somatic Hypermutation Between Sites in IGHV Genes Can Be Explained by Interactions Between AID and/or Polη Hotspots
Authors: Krantsevich Artem , Tang Catherine , MacCarthy Thomas
Published: February 2021

The somatic hypermutation (SHM) of Immunoglobulin (Ig) genes is a key process during antibody affinity maturation in B cells. The mutagenic enzyme activation induced deaminase (AID) is required for SHM and has a preference for WRChotspots in DNA. Error-prone repair mechanisms acting downstream of AID introduce further mutations, including DNA polymerase eta (Polη), part of the non-canonical mismatch repair pathway (ncMMR), which preferentially generates mutations at WAhotspots. Previously proposed mechanistic models lead to a variety of predictions concerning interactions between hotspots, for example, how mutations in one hotspot will affect another hotspot. Using a large, high-quality, Ig repertoire sequencing dataset, we evaluated pairwise correlations between mutations site-by-site using an unbiased measure similar to mutual information which we termed “mutational association” (MA). Interactions are dominated by relatively strong correlations between nearby sites (short-range MAs), which can be almost entirely explained by interactions between overlapping hotspots for AID and/or Polη. We also found relatively weak dependencies between almost all sites throughout each gene (longer-range MAs), although these arise mostly as a statistical consequence of high pairwise mutation frequencies. The dominant short-range interactions are also highest within the most highly mutating IGHV sub-regions, such as the complementarity determining regions (CDRs), where there is a high hotspot density. Our results suggest that the hotspot preferences for AID and Polη have themselves evolved to allow for greater interactions between AID and/or Polη induced mutations.
IL-1 Inhibitors in the Treatment of Monogenic Periodic Fever Syndromes: From the Past to the Future Perspectives
Authors: Malcova Hana , Strizova Zuzana , Milota Tomas , Striz Ilja , Sediva Anna , Cebecauerova Dita , Horvath Rudolf
Published: February 2021

Autoinflammatory diseases (AIDs) represent a rare and heterogeneous group of disorders characterized by recurrent episodes of inflammation and a broad range of clinical manifestations. The most common symptoms involve recurrent fevers, musculoskeletal symptoms, and serositis; however, AIDs can also lead to life-threatening complications, such as macrophage activation syndrome (MAS) and systemic AA amyloidosis. Typical monogenic periodic fever syndromes include cryopyrin-associated periodic fever syndrome (CAPS), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency/hyper IgD syndrome (MKD/HIDS), and familial Mediterranean fever (FMF). However, a number of other clinical entities, such as systemic juvenile idiopathic arthritis (sJIA), adult-onset Still’s disease (AOSD), Kawasaki disease (KD) and idiopathic recurrent pericarditis (IRP), display similar phenotypical and immunological features to AIDs. All these diseases are pathophysiologicaly characterized by dysregulation of the innate immune system and the central pathogenic role is attributed to the IL-1 cytokine family (IL-1α, IL-1β, IL-1Ra, IL-18, IL-36Ra, IL-36α, IL-37, IL-36β, IL-36g, IL-38, and IL-33). Therefore, reasonable therapeutic approaches aim to inhibit these cytokines and their pathways. To date, several anti-IL-1 therapies have evolved. Each drug differs in structure, mechanism of action, efficacy for the treatment of selected diseases, and side effects. Most of the available data regarding the efficacy and safety of IL-1 inhibitors are related to anakinra, canakinumab, and rilonacept. Other promising therapeutics, such as gevokizumab, tadekinig alfa, and tranilast are currently undergoing clinical trials. In this review, we provide sophisticated and up-to-date insight into the therapeutic uses of different IL-1 inhibitors in monogenic periodic fever syndromes.
Warburg Effect Is a Cancer Immune Evasion Mechanism Against Macrophage Immunosurveillance
Authors: Chen Jing , Cao Xu , Li Bolei , Zhao Zhangchen , Chen Siqi , Lai Seigmund W. T. , Muend Sabina A. , Nossa Gianna K. , Wang Lei , Guo Weihua , Ye Jian , Lee Peter P. , Feng Mingye
Published: February 2021

Evasion of immunosurveillance is critical for cancer initiation and development. The expression of “don’t eat me” signals protects cancer cells from being phagocytosed by macrophages, and the blockade of such signals demonstrates therapeutic potential by restoring the susceptibility of cancer cells to macrophage-mediated phagocytosis. However, whether additional self-protective mechanisms play a role against macrophage surveillance remains unexplored. Here, we derived a macrophage-resistant cancer model from cells deficient in the expression of CD47, a major “don’t eat me” signal, via a macrophage selection assay. Comparative studies performed between the parental and resistant cells identified self-protective traits independent of CD47, which were examined with both pharmacological or genetic approaches in in vitro phagocytosis assays and in vivo tumor models for their roles in protecting against macrophage surveillance. Here we demonstrated that extracellular acidification resulting from glycolysis in cancer cells protected them against macrophage-mediated phagocytosis. The acidic tumor microenvironment resulted in direct inhibition of macrophage phagocytic ability and recruitment of weakly phagocytic macrophages. Targeting V-ATPase which transports excessive protons in cancer cells to acidify extracellular medium elicited a pro-phagocytic microenvironment with an increased ratio of M1-/M2-like macrophage populations, therefore inhibiting tumor development and metastasis. In addition, blockade of extracellular acidification enhanced cell surface exposure of CD71, targeting which by antibodies promoted cancer cell phagocytosis. Our results reveal that extracellular acidification due to the Warburg effect confers immune evasion ability on cancer cells. This previously unrecognized role highlights the components mediating the Warburg effect as potential targets for new immunotherapy harnessing the tumoricidal capabilities of macrophages.
T-Bet Controls Cellularity of Intestinal Group 3 Innate Lymphoid Cells
Authors: Schroeder Jan-Hendrik , Meissl Katrin , Hromadová Dominika , Lo Jonathan W. , Neves Joana F. , Howard Jane K. , Helmby Helena , Powell Nick , Strobl Birgit , Lord Graham M.
Published: February 2021

Innate lymphoid cells (ILC) play a significant immunological role at mucosal surfaces such as the intestine. T-bet-expressing group 1 innate lymphoid cells (ILC1) are believed to play a substantial role in inflammatory bowel disease (IBD). However, a role of T-bet-negative ILC3 in driving colitis has also been suggested in mouse models questioning T-bet as a critical factor for IBD. We report here that T-bet deficient mice had a greater cellularity of NKp46-negative ILC3 correlating with enhanced expression of RORγt and IL-7R, but independent of signaling through STAT1 or STAT4. We observed enhanced neutrophilia in the colonic lamina propria (cLP) of these animals, however, we did not detect a greater risk of T-bet-deficient mice to develop spontaneous colitis. Furthermore, by utilizing an in vivo fate-mapping approach, we identified a population of T-bet-positive precursors in NKp46-negative ILC3s. These data suggest that T-bet controls ILC3 cellularity, but does do not drive a pathogenic role of ILC3 in mice with a conventional specific pathogen-free microbiota.
Transcriptomic Analysis of Long-Term Protective Immunity Induced by Vaccination With Mycoplasma gallisepticum Strain ts-304
Authors: Kulappu Arachchige Sathya N. , Young Neil D. , Kanci Condello Anna , Omotainse Oluwadamilola S. , Noormohammadi Amir H. , Wawegama Nadeeka K. , Browning Glenn F.
Published: February 2021

Live attenuated vaccines are commonly used to control Mycoplasma gallisepticum infections in chickens. M. gallisepticum ts-304 is a novel live attenuated vaccine strain that has been shown to be safe and effective. In this study, the transcriptional profiles of genes in the tracheal mucosa in chickens challenged with the M. gallisepticum wild-type strain Ap3AS at 57 weeks after vaccination with ts-304 were explored and compared with the profiles of unvaccinated chickens that had been challenged with strain Ap3AS, unvaccinated and unchallenged chickens, and vaccinated but unchallenged chickens. At two weeks after challenge, pair-wise comparisons of transcription in vaccinated-only, vaccinated-and-challenged and unvaccinated and unchallenged birds detected no differences. However, the challenged-only birds had significant up-regulation in the transcription of genes and enrichment of gene ontologies, pathways and protein classes involved in infiltration and proliferation of inflammatory cells and immune responses mediated through enhanced cytokine and chemokine production and signaling, while those predicted to be involved in formation and motor movement of cilia and formation of the cellular cytoskeleton were significantly down-regulated. The transcriptional changes associated with the inflammatory response were less severe in these mature birds than in the relatively young birds examined in a previous study. The findings of this study demonstrated that vaccination with the attenuated M. gallisepticum strain ts-304 protects against the transcriptional changes associated with the inflammatory response and pathological changes in the tracheal mucosa caused by infection with M. gallisepticum in chickens for at least 57 weeks after vaccination.
Physicochemical Effects of Niobic Acid Addition Into Dental Adhesives
Authors: Garcia Isadora Martini , Leitune Vicente Castelo Branco , Balbinot Gabrielade Souza , Balhaddad AbdulRahman A. , Melo Mary Anne S. , Samuel Susana Maria Werner , Collares Fabrício Mezzomo
Published: February 2021

The incorporation of metallic oxides in dental adhesives has been a strategy to confer improved radiopacity and physicochemical properties for polymers. Tailoring the structure of these fillers could contribute to their application in therapeutic strategies for dental restorations. The aim of this study was to evaluate the incorporation of niobic acid into experimental dental adhesives, and compare these adhesives to niobium pentoxide containing adhesives. A control group without Nb2O5·n H2O or Nb2O5 was also used for comparison. Niobium-based particles have been used as a feasible approach, mainly because of their bioactivity. In this study, hydrated niobium pentoxide, also called niobic acid (Nb2O5·n H2O), was incorporated into an experimental dental adhesive as a potential catalyst for monomer conversion. A base resin for dental adhesive was formulated with methacrylate monomers and photoinitiators. Two types of oxides were tested as filler for this adhesive: Nb2O5·n H2O or niobium pentoxide (Nb2O5). Both fillers were added separately into the experimental adhesive at 0, 2.5, 5, and 10 wt.%. One group without Nb2O5·n H2O or Nb2O5 (0 wt.% of filler addition) was used as a control group. The formulated materials were analyzed for radiopacity according to the ISO 4049 and used FTIR analysis to assess the degree of conversion (DC) and the maximum polymerization rate (RPmax). Mechanical properties were analyzed by ultimate tensile strength (UTS) in a testing machine. Softening in solvent was conducted by measuring Knoop microhardness before and after immersion of samples in ethanol. Normality of data was assessed with Shapiro-Wilk, and comparisons between factors were conducted with two-way ANOVA and Tukey at 5% of significance. Both fillers, Nb2O5 or Nb2O5·n H2O, increased the radiopacity of dental adhesives in comparison to the unfilled adhesive (p < 0.05). There were no differences among groups for the ultimate tensile strength (p > 0.05), and all groups containing Nb2O5 or Nb2O5·n H2O improved the resistance against softening in solvent (p < 0.05). The groups with 5 and 10 wt% addition of Nb2O5 showed decreased DC compared to the control group (p < 0.05), while the addition of Nb2O5·nH2O up to 10 wt% did not alter the DC (p > 0.05). The polymerization rate did not change among groups (p > 0.05). In conclusion, Nb2O5·n H2O is a promising filler to be incorporated into dental adhesives providing proper mechanical properties, improved resistance against solvents, and increased radiopacity, without changing the DC.
Study on Quantitative Characterization of Morphological Characteristics and High Temperature Performance Evaluation of Coarse Aggregate Based on Computer Vision
Authors: Liu Zhanliang , Zhang Chen , Shao Linlong , Wang Jiangfeng
Published: February 2021

The morphological characteristics of aggregate include outline shape, angularity, and surface texture, which determine the mutual extrusion and friction between aggregates, and significantly affect the performance of asphalt pavement. At present, the research on the morphological characteristics of coarse aggregate is mainly focused on indoor visual identification technology (AIMS, XCT, etc.), in which the applicability of the proposed aggregate shape characterization index is weak, and these instruments could not serve the practical engineering well. In this article, the Coarse Aggregate Morphological Identification System (CAMIS) is developed based on computer vision technology, and the system can recognize the shape features of aggregates above 2.36 mm particle size and carry out uninterrupted feeding and removal based on the mechanical arm system, which can realize large sample detection. Based on CAMIS aggregate identification system and laboratory tests (rutting test, dynamic modulus test, and penetration shear test), the shape identification and performance test of aggregate samples from construction site are carried out, and an aggregate performance evaluation index, CEI, suitable for high-temperature areas is proposed in combination with the improved response surface method. The processing parameters of vertical shaft impact aggregate crusher are optimized based on the CEI index, and the recommended processing parameters are verified by laboratory tests. The results show that the morphological characteristics of coarse aggregate affect the high temperature performance in order angularity, needle flake, axial coefficient, and convexity. The combination of processing parameters of vertical axis impact crusher is recommended to be of 45 m/s rotational speed, 3 t/h feed quantity, and 30% air intake. Verified by laboratory tests, the aggregate identification system CAMIS developed in this article and the proposed aggregate performance evaluation index, CEI, are highly reliable.
Paediatric Medicines in Europe: The Paediatric Regulation—Is It Time for Reform?
Authors: Toma Maddalena , Felisi Mariagrazia , Bonifazi Donato , Bonifazi Fedele , Giannuzzi Viviana , Reggiardo Giorgio , de Wildt Saskia , Ceci Adriana ,   TEDDY European Network of Excellence for Paediatric Research
Published: February 2021

Objectives: In this paper, we investigated the effects of the European Paediatric Regulation (EC) N° 1901/2006 with respect to satisfying the paediatric therapeutic needs, assessed in terms of the increased number of paediatric medicinal products, new therapeutic indications in specific high-need conditions (neonates, oncology, rare disease, etc.) and increased number of paediatric clinical studies supporting the marketing authorisation.

Methods: We analysed the paediatric medicinal products approved by the European Medicines Agency in the period January 2007-December 2019, by collecting the following data: year of approval, active substance, legal basis for the marketing authorisation, type of medicinal product (i.e., chemical, biological, or ATMP), orphan drug status, paediatric indication, Anatomical Therapeutic Chemical code (first-level), number and type of paediatric studies. Data were compared with similar data collected in the period 1996–2006.

Results: In the period January 1996–December 2019, in a total of 1,190 medicinal products and 843 active substances, 34 and 38%, respectively, were paediatric. In the two periods, before and after the Paediatric Regulation implementation, the paediatric/total medicinal products ratio was constant while the paediatric/total active substances ratio decreased. Moreover, excluding generics and biosimilars, a total of 106 and 175 paediatric medicines were granted a new paediatric indication, dosage or age group in the two periods; out of 175, 128 paediatric medicines had an approved Paediatric Investigational Plan. The remaining 47 were approved without an approved Paediatric Investigational Plan, following the provisions of Directive 2001/83/EC and repurposing an off-patent drug. The analysis of the clinical studies revealed that drugs with a Paediatric Investigational Plan were supported by 3.5 studies/drug while drugs without a Paediatric Investigational Plan were supported by only 1.6 studies/drug.

Discussion: This report confirms that the expectations of the European Paediatric Regulation (EC) N° 1901/2006 have been mainly satisfied. However, the reasons for the limited development of paediatric medicines in Europe, should be further discussed, taking advantage of recent initiatives in the regulatory field, such as the Action Plan on Paediatrics, and the open consultation on EU Pharmaceutical Strategy.
Subchondral Trabecular Microstructure and Articular Cartilage Damage Variations Between Osteoarthritis and Osteoporotic Osteoarthritis: A Cross-sectional Cohort Study
Authors: Zhou Feng , Chu Linyang , Liu Xuqiang , He Zihao , Han Xuequan , Yan Mengning , Qu Xinhua , Li Xiaofeng , Yu Zhifeng
Published: February 2021

Osteoporotic osteoarthritis (OP-OA) is a specific type of OA. In this study, we aimed to assess the subchondral plate and rod microstructural differences between OA and OP-OA patients by using an individual trabeculae segmentation (ITS) system and to analyze the relationships between subchondral microstructures and cartilage damage in OA and OP-OA patients. Overall, 31 femoral heads were included in this study, which included 11 samples with OA and 13 samples with OP-OA; the normal control (NC) group contained 7 healthy femoral heads. ITS was performed to segment the subchondral trabecular bone into plate and rod trabeculae based on microcomputed tomography (micro-CT) images. We compared the plate and rod trabeculae of the subchondral trabecular bone between OA and OP-OA patients. The Osteoarthritis Research Society International (OARSI) score was employed to evaluate cartilage damage based on histological observations. Pearson's correlation coefficient and linear regression analysis were applied to analyze the relationships between subchondral microstructures and articular cartilage damage. Results showed that several microstructural parameters, including bone volume fraction (BV/TV), plate bone volume fraction (pBV/TV), rod bone volume fraction (rBV/TV), plate trabecular number (pTb.N), rod trabecular number (rTb.N), junction density between rod and plate (R-P Junc.D), and junction density between plate and plate (P-P Junc.D), were significantly decreased in patients with OP-OA compared with those in patients with OA (p< 0.05). Histological observations indicated that cartilage damage was more serious in patients with OP-OA than that in patients with OA (p< 0.05). Moreover, BV/TV, pBV/TV, pTb.N, and pTb.Th were significantly related to the OARSI score in both OA and OP-OA patients. These results indicated that there were differences in the subchondral rod and plate trabeculae between OA and OP-OA patients. Subchondral decreased plate trabeculae (pBV/TV, pTb.N, and pTb.Th) might account for cartilage damage in the progression of OP-OA. This study provided new insights to research OA when it is combined with OP.
The Polymycovirus-Mediated Growth Enhancement of the Entomopathogenic Fungus Beauveria bassiana Is Dependent on Carbon and Nitrogen Metabolism
Authors: Filippou Charalampos , Diss Rebecca M. , Daudu John O. , Coutts Robert H. A. , Kotta-Loizou Ioly
Published: February 2021

Polymycoviridae is a growing family of mycoviruses whose members typically have non-conventional capsids and multi-segmented, double-stranded (ds) RNA genomes. Beauveria bassiana polymycovirus (BbPmV) 1 is known to enhance the growth and virulence of its fungal host, the entomopathogenic ascomycete and popular biological control agent B. bassiana. Here we report the complete sequence of BbPmV-3, which has six genomic dsRNA segments. Phylogenetic analysis of RNA-dependent RNA polymerase (RdRp) protein sequences revealed that BbPmV-3 is closely related to the partially sequenced BbPmV-2 but not BbPmV-1. Nevertheless, both BbPmV-3 and BbPmV-1 have similar effects on their respective host isolates ATHUM 4946 and EABb 92/11-Dm, affecting pigmentation, sporulation, and radial growth. Production of conidia and radial growth are significantly enhanced in virus-infected isolates as compared to virus-free isogenic lines on Czapek-Dox complete and minimal media that contain sucrose and sodium nitrate. However, this polymycovirus-mediated effect on growth is dependent on the carbon and nitrogen sources available to the host fungus. Both BbPmV-3 and BbPmV-1 increase growth of ATHUM 4946 and EABb 92/11-Dm when sucrose is replaced by lactose, trehalose, glucose, or glycerol, while the effect is reversed on maltose and fructose. Similarly, both BbPmV-3 and BbPmV-1 decrease growth of ATHUM 4946 and EABb 92/11-Dm when sodium nitrate is replaced by sodium nitrite, potassium nitrate, or ammonium nitrate. In conclusion, the effects of polymycoviruses on B. bassiana are at least partially mediated via its metabolic pathways.
Targeting Salmonella Typhimurium Invasion and Intracellular Survival Using Pyrogallol
Authors: Birhanu Biruk Tesfaye , Lee Eon-Bee , Lee Seung-Jin , Park Seung-Chun
Published: February 2021

Salmonella enterica serovar Typhimurium, an intracellular pathogen, evades the host immune response mechanisms to cause gastroenteritis in animals and humans. After invading the host cells, the bacteria proliferate in Salmonella-containing vacuole (SCV) and escapes from antimicrobial therapy. Moreover, Salmonella Typhimurium develops resistance to various antimicrobials including, fluoroquinolones. Treating intracellular bacteria and combating drug resistance is essential to limit the infection rate. One way of overcoming these challenges is through combination therapy. In this study, Pyrogallol (PG), a polyphenol, is combined with marbofloxacin (MAR) to investigate its effect on Salmonella Typhimurium invasion and intracellular survival inhibition. The Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of PG against Salmonella Typhimurium were 128 and 256 μg/mL, respectively. The lowest fractional inhibitory concentration (FIC) index for a combination of PG and MAR was 0.5. The gentamycin protection assay revealed that PG (30 μg/mL) alone and in combination with sub-MIC of MAR inhibited 72.75 and 76.18% of the invading bacteria in Caco-2 cells, respectively. Besides, the intracellular survival of Salmonella Typhimurium was reduced by 7.69 and 74.36% in treatment with PG alone and combined with sub-MIC of MAR, respectively, which was visualized by the confocal microscopy. PG has also shown to increase the intracellular accumulation of fluoroquinolone by 15.2 and 34.9% at 30 and 100 μg/mL concentration, respectively. Quantitative real-time PCR demonstrated PG suppressed the genetic expression of hilA, invF, sipB, and acrA by 14.6, 15.4, 13.6, and 36%, respectively. However, the downregulation of hilA, invF, sipB, and acrA increased to 80, 74.6, 78, and 70.1%, in combination with sub-MIC of MAR, respectively. Similarly, PG combined with MAR inhibited the expression of sdiA, srgE, and rck genes by 78.6, 62.8, and 61.8%, respectively. In conclusion, PG has shown antimicrobial activity against Salmonella Typhimurium alone and in combination with MAR. It also inhibited invasion and intracellular survival of the bacteria through downregulation of quorum sensing, invading virulence, and efflux pump genes. Hence, PG could be a potential antimicrobial candidate which could limit the intracellular survival and replication of Salmonella Typhimurium.