bluuebunny/crossref_metadata_2025 huggingface dataset:
An Extracellular Redox Signal Triggers Calcium Release and Impacts the Asexual Development of Toxoplasma gondii
Authors: Alves Eduardo , Benns Henry J. , Magnus Lilian , Dominicus Caia , Dobai Tamás , Blight Joshua , Wincott Ceire J. , Child Matthew A.
Published: August 2021

The ability of an organism to sense and respond to environmental redox fluctuations relies on a signaling network that is incompletely understood in apicomplexan parasites such as Toxoplasma gondii. The impact of changes in redox upon the development of this intracellular parasite is not known. Here, we provide a revised collection of 58 genes containing domains related to canonical antioxidant function, with their encoded proteins widely dispersed throughout different cellular compartments. We demonstrate that addition of exogenous H2O2 to human fibroblasts infected with T. gondii triggers a Ca2+ flux in the cytosol of intracellular parasites that can induce egress. In line with existing models, egress triggered by exogenous H2O2 is reliant upon both Calcium-Dependent Protein Kinase 3 and diacylglycerol kinases. Finally, we show that the overexpression a glutaredoxin-roGFP2 redox sensor fusion protein in the parasitophorous vacuole severely impacts parasite replication. These data highlight the rich redox network that exists in T. gondii, evidencing a link between extracellular redox and intracellular Ca2+ signaling that can culminate in parasite egress. Our findings also indicate that the redox potential of the intracellular environment contributes to normal parasite growth. Combined, our findings highlight the important role of redox as an unexplored regulator of parasite biology.
Mixed Mating in a Multi-Origin Population Suggests High Potential for Genetic Rescue in North Island Brown Kiwi, Apteryx mantelli
Authors: Undin Malin , Lockhart Peter J. , Hills Simon F. K. , Armstrong Doug P. , Castro Isabel
Published: August 2021

Reinforcement translocations are increasingly utilised in conservation with the goal of achieving genetic rescue. However, concerns regarding undesirable results, such as genetic homogenisation or replacement, are widespread. One factor influencing translocation outcomes is the rate at which the resident and the introduced individuals interbreed. Consequently, post-release mate choice is a key behaviour to consider in conservation planning. Here we studied mating, and its consequences for genomic admixture, in the North Island brown kiwi Apteryx mantelli population on Ponui Island which was founded by two translocation events over 50 years ago. The two source populations used are now recognised as belonging to two separate management units between which birds differ in size and are genetically differentiated. We examined the correlation between male and female morphometrics for 17 known pairs and quantified the relatedness of 20 pairs from this admixed population. In addition, we compared the genetic similarity and makeup of 106 Ponui Island birds, including 23 known pairs, to birds representing the source populations for the original translocations. We found no evidence for size-assortative mating. On the contrary, genomic SNP data suggested that kiwi of one feather did not flock together, meaning that mate choice resulted in pairing between individuals that were less related than expected by random chance. Furthermore, the birds in the current Ponui Island population were found to fall along a gradient of genomic composition consistent with non-clustered representation of the two parental genomes. These findings indicate potential for successful genetic rescue in future Apteryx reinforcement translocations, a potential that is currently under utilised due to restrictive translocation policies. In light of our findings, we suggest that reconsideration of these policies could render great benefits for the future diversity of this iconic genus in New Zealand.
The Predictive Value of Carotid Ultrasonography With Cardiovascular Risk Factors—A “SPIDER” Promoting Atherosclerosis
Authors: Li Hongwei , Xu Xiaolin , Luo Baoming , Zhang Yuling
Published: August 2021

Insufficient recommendations do not support the clinical use of carotid ultrasonography for further risk stratification in moderate-to-high risk patients with cardiovascular disease (CVD). A literature review was performed to assess six aspects of the research progress and limitations of carotid ultrasonography and carotid atherosclerosis-related risk factors: (1) structures of the carotid intima and media; (2) plaques; (3) inflammation; (4) dynamics of carotid blood flow; (5) early detection and intervention; and (6) risk factors for CVD. Although carotid intima-media thickness and carotid plaques are well-acknowledged independent predictors of CVD risk, normative and cut-off values are difficult to define due to the heterogeneous measurements reported in previous studies. Plaque properties, including location, number, density, and size, become more important risk predictors for cardiovascular disease, but a better approach for clinical use needs to be further established. Three-dimensional ultrasound and contrast-enhanced ultrasound are promising for promoting risk stratification with more details on plaque morphology. Moreover, inflammatory diseases and biomarkers should be evaluated for a full assessment of the inflammatory burden for atherosclerosis. Carotid flow velocity is not only an indicator for stenosis but also a potential risk predictor. Carotid atherosclerosis should be detected and treated early, and additional clinical trials are needed to determine the efficacy of these measures in reducing CVD risk. Cardiovascular risk factors tend to affect carotid plaques, and early treat-to-target therapy might yield clinical benefits. Based on the aforementioned six aspects, we consider that these six important factors act like a “SPIDER” spinning the web of atherosclerosis; a timely comprehensive assessment and intervention may halt the progression to CVD. Carotid ultrasound results should be combined with other atherosclerotic factors, and a comprehensive risk assessment may help to guide cardiovascular prevention decisions.
Bmal1 Downregulation Worsens Critical Limb Ischemia by Promoting Inflammation and Impairing Angiogenesis
Authors: Xu Lirong , Liu Yutong , Cheng Qianyun , Shen Yang , Yuan Ye , Jiang Xiaolang , Li Xu , Guo Daqiao , Jiang Junhao , Lin Changpo
Published: August 2021

Critical limb ischemia (CLI) is the most advanced clinical stage of peripheral vascular disease with high mobility and mortality. CLI patients suffer from lower extremity rest pain, ulceration, and gangrene caused by insufficient blood and oxygen supply. Seeking for effective biomarkers and therapeutic targets is of great significance for improving the life quality of CLI patients. The circadian clock has been reported to be involved in the progression of kinds of cardiovascular diseases. Whether and how circadian genes play a role in CLI remains unknown. In this study, by collecting femoral artery and muscle specimens of CLI patients who underwent amputation, we confirmed that the circadian gene Bmal1 is downregulated in the CLI femoral artery and ischemic distal lower limb muscle. Furthermore, we verified that Bmal1 affects CLI by regulating lipid metabolism, inflammation, and angiogenesis. A hindlimb ischemia model performed in wild-type and Bmal1−/− mice confirmed that Bmal1 disruption would lead to impaired angiogenesis. In vitro experiments indicated that the decreased expression of Bmal1 would increase ox-LDL uptake and impair endothelial cell functions, including proliferation, migration, and tube formation. As for mechanisms, Bmal1 represses inflammation by inhibiting lipid uptake and by activating IL-10 transcription and promotes angiogenesis by transcriptionally regulating VEGF expression. In conclusion, we provide evidence that the circadian gene Bmal1 plays an important role in CLI by inhibiting inflammation and promoting angiogenesis. Thus, Bmal1 may be an effective biomarker and a potential therapeutic target in CLI.
Immune Protection of Stem Cell-Derived Islet Cell Therapy for Treating Diabetes
Authors: Tahbaz Meghan , Yoshihara Eiji
Published: August 2021

Insulin injection is currently the main therapy for type 1 diabetes (T1D) or late stage of severe type 2 diabetes (T2D). Human pancreatic islet transplantation confers a significant improvement in glycemic control and prevents life-threatening severe hypoglycemia in T1D patients. However, the shortage of cadaveric human islets limits their therapeutic potential. In addition, chronic immunosuppression, which is required to avoid rejection of transplanted islets, is associated with severe complications, such as an increased risk of malignancies and infections. Thus, there is a significant need for novel approaches to the large-scale generation of functional human islets protected from autoimmune rejection in order to ensure durable graft acceptance without immunosuppression. An important step in addressing this need is to strengthen our understanding of transplant immune tolerance mechanisms for both graft rejection and autoimmune rejection. Engineering of functional human pancreatic islets that can avoid attacks from host immune cells would provide an alternative safe resource for transplantation therapy. Human pluripotent stem cells (hPSCs) offer a potentially limitless supply of cells because of their self-renewal ability and pluripotency. Therefore, studying immune tolerance induction in hPSC-derived human pancreatic islets will directly contribute toward the goal of generating a functional cure for insulin-dependent diabetes. In this review, we will discuss the current progress in the immune protection of stem cell-derived islet cell therapy for treating diabetes.
Interactions Between Figs and Gall-Inducing Fig Wasps: Adaptations, Constraints, and Unanswered Questions
Authors: Borges Renee M.
Published: August 2021

The ancient interaction between figs (Ficus, Moraceae) and their pollinating fig wasps is an unusual example of a mutualism between plants and gall-inducing insects. This review intends to offer fresh perspectives into the relationship between figs and the diversity of gall-inducing sycophiles which inhabit their enclosed globular inflorescences that function as microcosms. Besides gall-inducing pollinators, fig inflorescences are also inhabited by other gall-inducing wasps. This review evaluates the state of current knowledge on gall-induction by fig wasps and exposes the many lacunae in this area. This review makes connections between fig and gall-inducing wasp traits, and suggests relatively unexplored research avenues. This manuscript calls for an integrated approach that incorporates such diverse fields as life-history theory, plant mate choice, wasp sexual selection and local mate competition, plant embryology as well as seed and fruit dispersal. It calls for collaboration between researchers such as plant developmental biologists, insect physiologists, chemical ecologists and sensory biologists to jointly solve the many valuable questions that can be addressed in community ecology, co-evolution and species interaction biology using the fig inflorescence microcosm, that is inhabited by gall-inducing mutualistic and parasitic wasps, as a model system.
COL12A1 rs970547 Polymorphism Does Not Alter Susceptibility to Anterior Cruciate Ligament Rupture: A Meta-Analysis
Authors: Lv Zheng-tao , Wang Wei , Zhao Dong-ming , Huang Jun-ming
Published: August 2021

Objective: Currently available evidence regarding the association between collagen type XII α1 (COL12A1) polymorphism and risk of anterior cruciate ligament rupture (ACLR) remains elusive. The aim of our present study was to assess the association between COL12A1 rs970547 polymorphism and ACLR risk.

Methods: Five online databases, namely, PubMed, EMBASE, ISI Web of Science, CENTRAL, and CNKI, were searched from their inception data up to December 2020 to identify relative observational studies. The methodological quality of each individual study was evaluated using the Newcastle-Ottawa Scale (NOS). The “model-free approach” was employed to estimate the magnitude of effect of COL12A1 rs970547 polymorphism on ACLR, and the association was expressed using odds ratio (OR) and its associated 95% confidence interval (95% CI). Subgroup analysis was performed by ethnicity and sex of included subjects.

Results: Eight studies involving 1,477 subjects with ACLR and 100,439 healthy controls were finally included in our study. The methodological quality of included studies was deemed moderate to high based on NOS scores. The “model-free” approach suggested no genotype differences between ACLR and healthy control for the rs970547 polymorphism, but we still used the allele model to present the combined data. Under the random-effect model, there was no significant difference in the frequency of effecting allele between ACLR and control (OR: 0.91, 95% CI 0.77, 1.08; p = 0.28). Stratified analysis by sex and ethnicity also showed no difference in allele frequency.

Conclusion: The findings of this current meta-analysis suggested that rs970547 was not associated with ACLR risk in male, female, and the overall population among Asians or Caucasians.
Case Report: A Novel Mutation in NFKB1 Associated With Pyoderma Gangrenosum
Authors: Fang Ran , Wang Jun , Jiang Xiao-yun , Wang Shi-hao , Cheng Hao , Zhou Qing
Published: August 2021

Pyoderma gangrenosum (PG) is a rare, destructive inflammatory skin disease of which a painful nodule or pustule breaks down to form a progressively enlarging ulcer. Ulcerations associated with PG may occur after trauma or injury to the skin. The etiology has not been clearly elucidated. Our report described a PG patient with a heterozygous splice-donor-site mutation in NFKB1 (c.730+5G>A) causing the absence of exon 8 and the formation of truncated p105 (p.Asp191_Lys244delinsGlu; p105delEx8), which led to distinct symptoms of high fever and excessive inflammation in wound area after routine surgical procedures. The functional analysis showed that the variant caused reduced phosphorylation of p105 and resulted in the decreased processing of p105 to p50. We conclude that the patient's symptoms were caused by dysregulation of the NF-κB signaling pathway.
Gender-Related Impact of Sclerostin Antibody on Bone in the Osteogenesis Imperfecta Mouse
Authors: Cardinal Mickaël , Chretien Antoine , Roels Thomas , Lafont Sébastien , Ominsky Michael S. , Devogelaer Jean-Pierre , Manicourt Daniel H. , Behets Catherine
Published: August 2021

Osteogenesis imperfecta (OI), which is most often due to a collagen type 1 gene mutation, is characterized by low bone density and bone fragility. In OI patients, gender-related differences were reported, but data in the literature are not convergent. We previously observed that sclerostin antibody (Scl-Ab), which stimulates osteoblast Wnt pathway via sclerostin inactivation, improved spine and long-bone parameters and biomechanical strength in female oim/oim mice, a validated model of human type 3 OI. Here, we wanted to highlight the effect of Scl-Ab on male oim/oim bones in order to identify a possible distinct therapeutic effect from that observed in females. According to the same protocol as our previous study with female mice, male wild-type (Wt) and oim/oim mice received vehicle or Scl-Ab from 5 to 14 weeks of age. Clinimetric and quantitative bone parameters were studied using X-rays, peripheral quantitative computed tomography, microradiography, and dynamic histomorphometry and compared to those of females. Contrary to Wt mice, male oim/oim had significantly lower weight, snout–sacrum length, and bone mineral content than females at 5 weeks. No significant difference in these clinimetric parameters was observed at 14 weeks, whereas male oim showed significantly more long-bone fractures than females. Scl-Ab improved bone mineral density and bone volume/total volume ratio (BV/TV) of vertebral body in Wt and oim/oim, without significant difference between male and female at 14 weeks. Male vehicle oim/oim had a significantly lower cortical thickness (Ct.Th) and BV/TV of tibial diaphysis than female and showed a higher number of fractures at 14 weeks. Scl-Ab increased midshaft periosteal apposition rate in such a way that tibial Ct.Th of male oim/oim was not significantly different from the female one at 14 weeks. The number of fractures was lower in male than female oim/oim after 14 weeks of Scl-Ab treatment, but this difference was not significant. Nevertheless, Scl-Ab–treated oim/oim male and female mice remained smaller than the Wt ones. In conclusion, our results highlighted differences between male and female oim/oim at 4 and 14 weeks of age, as well as some male-specific response of cortical bone to Scl-Ab. These gender-related particularities of oim/oim should be considered when testing experimental treatments.
Germline-Dependent Antibody Paratope States and Pairing Specific VH-VL Interface Dynamics
Authors: Fernández-Quintero Monica L. , Kroell Katharina B. , Bacher Lisa M. , Loeffler Johannes R. , Quoika Patrick K. , Georges Guy , Bujotzek Alexander , Kettenberger Hubert , Liedl Klaus R.
Published: August 2021

Antibodies have emerged as one of the fastest growing classes of biotherapeutic proteins. To improve the rational design of antibodies, we investigate the conformational diversity of 16 different germline combinations, which are composed of 4 different kappa light chains paired with 4 different heavy chains. In this study, we systematically show that different heavy and light chain pairings strongly influence the paratope, interdomain interaction patterns and the relative VH-VLinterface orientations. We observe changes in conformational diversity and substantial population shifts of the complementarity determining region (CDR) loops, resulting in distinct dominant solution structures and differently favored canonical structures. Additionally, we identify conformational changes in the structural diversity of the CDR-H3 loop upon different heavy and light chain pairings, as well as upon changes in sequence and structure of the neighboring CDR loops, despite having an identical CDR-H3 loop amino acid sequence. These results can also be transferred to all CDR loops and to the relative VH-VLorientation, as certain paratope states favor distinct interface angle distributions. Furthermore, we directly compare the timescales of sidechain rearrangements with the well-described transition kinetics of conformational changes in the backbone of the CDR loops. We show that sidechain flexibilities are strongly affected by distinct heavy and light chain pairings and decipher germline-specific structural features co-determining stability. These findings reveal that all CDR loops are strongly correlated and that distinct heavy and light chain pairings can result in different paratope states in solution, defined by a characteristic combination of CDR loop conformations and VH-VLinterface orientations. Thus, these results have broad implications in the field of antibody engineering, as they clearly show the importance of considering paired heavy and light chains to understand the antibody binding site, which is one of the key aspects in the design of therapeutics.
Targeted Immunotherapies in Gastrointestinal Cancer: From Molecular Mechanisms to Implications
Authors: Wang Ding-Kang , Zuo Qian , He Qing-Yu , Li Bin
Published: August 2021

Gastrointestinal cancer is a leading cause of cancer-related mortality and remains a major challenge for cancer treatment. Despite the combined administration of modern surgical techniques and chemoradiotherapy (CRT), the overall 5-year survival rate of gastrointestinal cancer patients in advanced stage disease is less than 15%, due to rapid disease progression, metastasis, and CRT resistance. A better understanding of the mechanisms underlying cancer progression and optimized treatment strategies for gastrointestinal cancer are urgently needed. With increasing evidence highlighting the protective role of immune responses in cancer initiation and progression, immunotherapy has become a hot research topic in the integrative management of gastrointestinal cancer. Here, an overview of the molecular understanding of colorectal cancer, esophageal cancer and gastric cancer is provided. Subsequently, recently developed immunotherapy strategies, including immune checkpoint inhibitors, chimeric antigen receptor T cell therapies, tumor vaccines and therapies targeting other immune cells, have been described. Finally, the underlying mechanisms, fundamental research and clinical trials of each agent are discussed. Overall, this review summarizes recent advances and future directions for immunotherapy for patients with gastrointestinal malignancies.
Crosstalk Between Plasma Cytokines, Inflammation, and Liver Damage as a New Strategy to Monitoring NAFLD Progression
Authors: Fontes-Cal Tereza C. M. , Mattos Rafael T. , Medeiros Nayara I. , Pinto Bruna F. , Belchior-Bezerra Mayara , Roque-Souza Bruna , Dutra Walderez O. , Ferrari Teresa C. A. , Vidigal Paula V. T. , Faria Luciana C. , Couto Cláudia A. , Gomes Juliana A. S.
Published: August 2021

Cytokines are involved in the immunopathogenesis of nonalcoholic fatty liver disease (NAFLD), but the relationship between them and clinical parameters of NAFLD progression is still unknown. Using flow cytometry, we evaluated the plasma levels of IL-1β, IL-6, IL-12, TNF and IL-10 and their association with clinical and biochemical parameters of liver function during simple steatosis (NAFL) and nonalcoholic steatohepatitis (NASH) in biopsy-proven patients. The NASH patients showed higher levels of IL-6 associated with a lower IL-10/IL-6 ratio. Besides heatmaps were similar in the NAFL and NASH groups, the same did not occur in signature curves, the NASH patients were high producers to IL-12 and IL-6 while the NAFL patients were not high producers of any cytokines evaluated. Integrative biomarker network analysis revealed that cytokines are differently correlated with clinical parameters, while IL-12, IL-10 presented moderate and negative correlations with glycemic and lipid profile in the NAFL group. The NASH group IL-12 and TNF revealed stronger and positive correlations with transient elastography parameters and NAFLD liver fibrosis score. These data suggest that IL-6 and IL-10 might act in chronic inflammation and insulin resistance whereas IL-12 and TNF may be involved in promoting liver damage and NAFLD progression. Plasma concentration analysis of these molecules and their association with clinical parameters can be used as new biomarkers to monitoring NAFLD progression and to reflect NASH development.
IgG Immune Complexes Inhibit Naïve T Cell Proliferation and Suppress Effector Function in Cytotoxic T Cells
Authors: Charab Wissam , Rosenberger Matthew G. , Shivram Haridha , Mirazee Justin M. , Donkor Moses , Shekhar Soumya R. , Gjuka Donjeta , Khoo Kimberly H. , Kim Jin Eyun , Iyer Vishwanath R. , Georgiou George
Published: August 2021

Elevated levels of circulating immune complexes are associated with autoimmunity and with worse prognoses in cancer. Here, we examined the effects of well-defined, soluble immune complexes (ICs) on human peripheral T cells. We demonstrate that IgG-ICs inhibit the proliferation and differentiation of a subset of naïve T cells but stimulate the division of another naïve-like T cell subset. Phenotypic analysis by multi-parameter flow cytometry and RNA-Seq were used to characterize the inhibited and stimulated T cells revealing that the inhibited subset presented immature features resembling those of recent thymic emigrants and non-activated naïve T cells, whereas the stimulated subset exhibited transcriptional features indicative of a more differentiated, early memory progenitor with a naïve-like phenotype. Furthermore, we show that while IgG1-ICs do not profoundly inhibit the proliferation of memory T cells, IgG1-ICs suppress the production of granzyme-β and perforin in cytotoxic memory T cells. Our findings reveal how ICs can link humoral immunity and T cell function.
Tumor Secretome to Adoptive Cellular Immunotherapy: Reduce Me Before I Make You My Partner
Authors: Etxebeste-Mitxeltorena Mikel , del Rincón-Loza Inés , Martín-Antonio Beatriz
Published: August 2021

Adoptive cellular immunotherapy using chimeric antigen receptor (CAR)-modified T cells and Natural Killer (NK) cells are common immune cell sources administered to treat cancer patients. In detail, whereas CAR-T cells induce outstanding responses in a subset of hematological malignancies, responses are much more deficient in solid tumors. Moreover, NK cells have not shown remarkable results up to date. In general, immune cells present high plasticity to change their activity and phenotype depending on the stimuli they receive from molecules secreted in the tumor microenvironment (TME). Consequently, immune cells will also secrete molecules that will shape the activities of other neighboring immune and tumor cells. Specifically, NK cells can polarize to activities as diverse as angiogenic ones instead of their killer activity. In addition, tumor cell phagocytosis by macrophages, which is required to remove dying tumor cells after the attack of NK cells or CAR-T cells, can be avoided in the TME. In addition, chemotherapy or radiotherapy treatments can induce senescence in tumor cells modifying their secretome to a known as “senescence-associated secretory phenotype” (SASP) that will also impact the immune response. Whereas the SASP initially attracts immune cells to eliminate senescent tumor cells, at high numbers of senescent cells, the SASP becomes detrimental, impacting negatively in the immune response. Last, CAR-T cells are an attractive option to overcome these events. Here, we review how molecules secreted in the TME by either tumor cells or even by immune cells impact the anti-tumor activity of surrounding immune cells.
Transient Depletion of Foxp3+ Regulatory T Cells Selectively Promotes Aggressive β Cell Autoimmunity in Genetically Susceptible DEREG Mice
Authors: Watts Deepika , Janßen Marthe , Jaykar Mangesh , Palmucci Francesco , Weigelt Marc , Petzold Cathleen , Hommel Angela , Sparwasser Tim , Bonifacio Ezio , Kretschmer Karsten
Published: August 2021

Type 1 diabetes (T1D) represents a hallmark of the fatal multiorgan autoimmune syndrome affecting humans with abrogated Foxp3+regulatory T (Treg) cell function due toFoxp3gene mutations, but whether the loss of Foxp3+Treg cell activity is indeed sufficient to promote β cell autoimmunity requires further scrutiny. As opposed to human Treg cell deficiency, β cell autoimmunity has not been observed in non-autoimmune-prone mice with constitutiveFoxp3deficiency or after diphtheria toxin receptor (DTR)-mediated ablation of Foxp3+Treg cells. In the spontaneous nonobese diabetic (NOD) mouse model of T1D, constitutive Foxp3 deficiency did not result in invasive insulitis and hyperglycemia, and previous studies on Foxp3+Treg cell ablation focused on Foxp3DTRNOD mice, in which expression of a transgenic BDC2.5 T cell receptor (TCR) restricted the CD4+TCR repertoire to a single diabetogenic specificity. Here we revisited the effect of acute Foxp3+Treg cell ablation on β cell autoimmunity in NOD mice in the context of a polyclonal TCR repertoire. For this, we took advantage of the well-established DTR/GFP transgene of DEREG mice, which allows for specific ablation of Foxp3+Treg cells without promoting catastrophic autoimmune diseases. We show that the transient loss of Foxp3+Treg cells in prediabetic NOD.DEREG mice is sufficient to precipitate severe insulitis and persistent hyperglycemia within 5 days after DT administration. Importantly, DT-treated NOD.DEREG mice preserved many clinical features of spontaneous diabetes progression in the NOD model, including a prominent role of diabetogenic CD8+T cells in terminal β cell destruction. Despite the severity of destructive β cell autoimmunity, anti-CD3 mAb therapy of DT-treated mice interfered with the progression to overt diabetes, indicating that the novel NOD.DEREG model can be exploited for preclinical studies on T1D under experimental conditions of synchronized, advanced β cell autoimmunity. Overall, our studies highlight the continuous requirement of Foxp3+Treg cell activity for the control of genetically pre-installed autoimmune diabetes.
Differences in Pneumococcal and Haemophilus influenzae Natural Antibody Development in Papua New Guinean Children in the First Year of Life
Authors: Martinovich Kelly M. , Rahman Tasmina , de Gier Camilla , Seppanen Elke J. , Orami Tilda , Granland Caitlyn M. , Francis Jacinta , Yoannes Mition , Corscadden Karli J. , Ford Rebecca , Jacoby Peter , van den Biggelaar Anita H. J. , Bakaletz Lauren O. , Cripps Allan W. , Lehmann Deborah , Richmond Peter C. , Pomat William S. , Kirkham Lea-Ann S. , Thornton Ruth B.
Published: August 2021

Background

Development of vaccines to prevent disease and death from Streptococcus pneumoniae, and nontypeable Haemophilus influenzae (NTHi), the main pathogens that cause otitis media, pneumonia, meningitis and sepsis, are a global priority. Children living in low and lower-middle income settings are at the highest risk of contracting and dying from these diseases. Improved vaccines with broader coverage are required. Data on the natural development of antibodies to putative vaccine antigens, especially in high-risk settings, can inform the rational selection of the best antigens for vaccine development.

Methods

Serum IgG titres to four pneumococcal proteins (PspA1, PspA2, CbpA, and Ply) and five NTHi antigens (P4, P6, OMP26, rsPilA and ChimV4) were measured in sera collected from 101 Papua New Guinean children at 1, 4, 9, 10, 23 and 24 months of age using multiplexed bead-based immunoassays. Carriage density of S. pneumoniae and H. influenzae were assessed by quantitative PCR on genomic DNA extracted from nasopharyngeal swabs using species-specific primers and probes. All data were log-transformed for analysis using Student’s unpaired t-tests with geometric mean titre (GMT) or density (GMD) calculated with 95% confidence intervals (CI).

Results

Serum -pneumococcal protein-specific IgG titres followed a “U” shaped pattern, with a decrease in presumably maternally-derived IgG titres between 1 and 4 months of age and returning to similar levels as those measured at 1 month of age by 24 months of age. In contrast, NTHi protein-specific IgG titres steadily increased with age. There was no correlation between antibody titres and carriage density for either pathogen.

Conclusion

This longitudinal study indicates that the waning of maternally- derived antibodies that is usually observed in infants, after infants does not occur for NTHi antigens in Papua New Guinean infants. Whether NTHi antigen IgG can be transferred maternally remains to be determined. Vaccines that are designed to specifically increase the presence of protective NTHi antibodies in the first few months of life may be most effective in reducing NTHi disease.

Clinical Trial Registration

https://clinicaltrials.gov/, identifier NCT01619462.
Coastal Ocean Observing and Modeling Systems in Brazil: Initiatives and Future Perspectives
Authors: Franz Guilherme , Garcia Carlos A. E. , Pereira Janini , de Freitas Assad Luiz Paulo , Rollnic Marcelo , Garbossa Luis Hamilton P. , da Cunha Letícia Cotrim , Lentini Carlos A. D. , Nobre Paulo , Turra Alexander , Trotte-Duhá Janice R. , Cirano Mauro , Estefen Segen F. , Lima José Antonio M. , Paiva Afonso M. , Noernberg Mauricio A. , Tanajura Clemente A. S. , Moutinho José Luiz , Campuzano Francisco , Pereira Ella S. , Lima André Cunha , Mendonça Luís F. F. , Nocko Helder , Machado Leandro , Alvarenga João B. R. , Martins Renato P. , Böck Carina Stefoni , Toste Raquel , Landau Luiz , Miranda Tiago , dos Santos Francisco , Pellegrini Júlio , Juliano Manuela , Neves Ramiro , Polejack Andrei
Published: August 2021

Coastal ocean observing and modeling systems (coastal observatories), connected with regional and global ocean systems, improve the quality of information and forecasts for effective management of safe and sustainable maritime activities. The public availability of systematic and long-term information of the ocean is an engine for the Blue Economy, boosting economic growth, employment, and innovation. An overview of some Brazilian initiatives is presented in this paper, involving universities, private companies, federal and state agencies, covering institutions from south to north of Brazil. Although these initiatives focus mainly on ocean physics, integrated efforts can extend the scope to include biogeochemistry and marine biodiversity, helping to address interdisciplinary problems. Existing initiatives can be connected, and new ones fostered, to fill in the gaps of temporal and spatial coverage of ocean monitoring in the vast oceanic area under Brazilian jurisdiction (nationally referred to as the Blue Amazon, in reference to the similar richness of the Amazon Forest). The alignment among national and regional initiatives, as well as with international programs, can be promoted if coordinated by a national-level organization, maximizing the return of public investment and socioeconomic benefits. In light of international examples, possible future institutional arrangements are discussed, leveraging from existing national public policies and international cooperation that Brazil is taking part. The United Nations Decade of Ocean Science for Sustainable Development is a timely opportunity to encourage an institutional arrangement to support and articulate an integrated network of coastal observatories in Brazil.
Stable Isotope Analysis of Juvenile White Sharks Inside a Nursery Area Reveals Foraging in Demersal-Inshore Habitats and Trophic Overlap With Sympatric Sharks
Authors: García-Rodríguez Emiliano , Herzka Sharon Z. , Sosa-Nishizaki Oscar , Lowe Christopher G. , O’Sullivan John B.
Published: August 2021

Knowledge about top predators’ trophic ecology is crucial for defining their role in ecosystems, understanding habitat preferences, characterizing life stage-specific feeding habits, and evaluating their interaction with fisheries. In the northeastern Pacific, white sharks (Carcharodon carcharias) occupy coastal habitats during the early life stages, including Bahía Sebastián Vizcaíno (BSV) in Mexico, which is a known nursery area. Although BSV presumably provides high prey abundance, the trophic ecology of immature white sharks is poorly understood. Carbon and nitrogen bulk stable isotope analyses (SIA) were used to explore the trophic relationship of early life stages with their potential prey and to infer dietary overlap with sympatric sharks, while SIA of amino acids were used to estimate trophic position. Muscle samples from young white sharks and inshore demersal prey commonly found in their stomach contents were sampled. Demersal prey and literature-derived isotope ratios for pelagic and offshore species were incorporated into mixing models with a Bayesian framework to estimate their contribution to white shark tissues. Nearshore demersal prey had the highest contribution for all life stages (between 35 and 47%), consistent with previous reports based on gut content analysis. The contribution of pelagic (between 26 and 37%) and offshore (between 14 and 32%) prey was smaller and suggests potential periodic changes in foraging grounds and the presence of a maternal-derived isotopic signature. A high contribution of demersal prey indicates a high level of interaction with local fisheries that target those species and catch white sharks incidentally and is consistent with immature shark movement patterns. Isotope ratios of two sympatric sharks, smooth hammerhead Sphyrna zygaena and copper sharks Carcharhinus brachyurus, were used to estimate the overlap in isotopic niche space. Immature white sharks had the smallest isotopic niche, while the highest was for copper sharks. Overlap was greatest between white sharks and hammerheads (∼45%), while overlap with copper sharks was limited (<20%), suggesting less potential for competition. Trophic position estimates were similar to those previously reported for the species. These results highlight the importance of coastal demersal prey heavily targeted by local fisheries for the diet of young white sharks and support the importance of BSV as a nursery habitat.
Evaluation of the Dietary Black Soldier Fly Larvae Meal (Hermetia illucens) on Growth Performance, Intestinal Health, and Disease Resistance to Vibrio parahaemolyticus of the Pacific White Shrimp (Litopenaeus vannamei)
Authors: Chen Yongkang , Chi Shuyan , Zhang Shuang , Dong Xiaohui , Yang Qihui , Liu Hongyu , Tan Beiping , Xie Shiwei
Published: August 2021

The present study evaluated the effects of the dietary black soldier fly larvae meal (BSF) on growth performance, intestinal health, and susceptibility to Vibrio parahaemolyticus in the Pacific white shrimp Litopenaeus vannamei. The basal diet was formulated to contain 25% fish meal (FM), and then the FM was replaced with BSF for 10, 20, and 30% of the FM protein in the experimental diets, which are referred to as FM, BSF10, BSF20, and BSF30, respectively. Four hundred and eighty healthy and uniform-sized shrimp (~0.88 g) were distributed among four groups of three replicates, each with 40 shrimp in a 300-L tank and they were fed four times daily for 7 weeks. The results showed that the growth performance did not change significantly in shrimp fed with BSF10 and BSF20 diets, but significantly decreased in those fed with BSF30 diet compared to the ones fed with FM diet. After feeding trial and sampling, a V. parahaemolyticus infection challenge trial was conducted on shrimp. The results showed that the survival rate of shrimp fed with BSF10 was significantly higher than those fed with FM. The results of the midgut histology showed that the width and height of intestinal mucosal folds decreased significantly in shrimp fed with BSF20 and BSF30, and the early signs of apoptosis in the intestinal cells were found in shrimp fed with BSF30. The mRNA levels of non-specific immune-related genes dorsal and relish were downregulated in shrimp fed with BSF20 and BSF30 diets. The mRNA levels of antimicrobial peptides–related genes alf (anti-lipopolysaccharide factor) were upregulated in shrimp fed with BSF10 but downregulated in shrimp fed with BSF30. The mRNA level pen3 (penaeidins 3) was upregulated in shrimp fed with BSF10 and BSF20 diets. The intestinal bacterial communities on operational taxonomic unit levels among groups were not significantly differentiated according to the beta diversity analysis. At the genus levels, a decrease in Vibrio, Photobacterium, and Candidatus_Bacilloplasma, as well as the increase in Bacillus and Pseudoalteromonas abundance, indicated the improvement of intestinal microbiota in shrimp fed with dietary BSF. Therefore, the use of BSF in shrimp diet should be controlled at a dosage of 20% of the FM, which can improve the intestinal microbiota without causing any negative effects.
A Clinicopathological Analysis of Melanocytic Nevi: A Retrospective Series
Authors: Liu Panpan , Su Juan , Zheng Xuanwei , Chen Mingliang , Chen Xiang , Li Jie , Peng Cong , Kuang Yehong , Zhu Wu
Published: August 2021

Purpose: Melanocytic nevi are common cutaneous lesions. This study aimed to demonstrate the concordance and discordance between clinical and histopathological diagnoses of melanocytic nevi and the importance of histological evaluation in differentiating malignant lesions from diseases with similar clinical manifestations.

Patients and Methods: We studied 4,561 consecutive patients with a clinical diagnosis of melanocytic nevi from 2014 to 2019. We compared the clinical diagnosis with the histopathological diagnosis to establish a histopathological concordance rate and then investigated the effects of clinical characteristics and the reasons for removal on misclassification.

Results: Among 4,561 patients who were clinically diagnosed with melanocytic nevi, the overall histopathological concordance rate was 82.11% (3,745 of 4,561 patients), while the histopathological discordance rate was 17.89% (816 of 4,561 patients). The histopathological concordance included 90.25% common acquired melanocytic nevi (3,380 of 3,745 patients) and 9.75% other benign melanocytic neoplasms (365 of 3,745 patients). The most common diagnostic change was to seborrheic keratosis (n = 470, 10.30%), followed by basal cell carcinoma (n = 64, 1.40%), vascular tumor (n = 53, 1.16%), fibroma (n = 43, 0.94%), epidermoid cyst (n = 34, 0.75%), wart (n = 30, 0.66%), melanoma (n = 24, 0.53%), Bowen's disease (n = 16, 0.35%), squamous cell carcinoma (n = 4, 0.09%), keratoacanthoma (n = 2, 0.04%), and other neoplasms (n = 76, 1.67%). Male sex, old age, location of the lesion, and the reasons for removal have a potential effect on misclassification. The percentages of misclassified lesions on the trunk and limbs and the perineum and buttocks were higher than those in lesions without a change in diagnosis. Importantly, locations of lesions on the head and neck were significantly related to a change in diagnosis to non-melanoma skin cancer, while locations on the hands and feet were significantly related to a change in diagnosis to melanoma. In addition to a typical clinical features, removal due to lesion changes or repeated stimulation was significantly associated with a change in diagnosis to melanoma.

Conclusions: Our study emphasizes the clinical differential diagnosis of melanocytic nevi, especially the possibility of malignant tumors. The occurrence of clinical features associated with clinicopathological discordance should raise the clinical suspect and be carefully differentiated from malignant tumors.
A Review of the Efficacy and Safety for Biologic Agents Targeting IL-23 in Treating Psoriasis With the Focus on Tildrakizumab
Authors: Ghazawi Feras M. , Mahmood Farhan , Kircik Leon , Poulin Yves , Bourcier Marc , Vender Ronald , Wiseman Marni C. , Lynde Charles , Litvinov Ivan V.
Published: August 2021

Psoriasis is a chronic and debilitating inflammatory immune-mediated skin disorder. Several cytokines including interleukin (IL)-23 were demonstrated to play a central role in the pathogenesis of this disease. Treatment options for psoriasis range from topical to systemic modalities, depending on the extent, anatomical locations involved and functional impairment level. Targeting cytokines or their cognate receptors that are involved in disease pathogenesis such as IL-12/23 (i.e., targeting the IL-12p40 subunit shared by these cytokines), IL-17A, IL-17F, IL-17RA, and TNF-α using biologic agents emerged in recent years as a highly effective therapeutic option for patients with moderate-to-severe disease. This review provides an overview of the important role of IL-23 signaling in the pathogenesis of psoriasis. We describe in detail the available IL-23 inhibitors for chronic plaque psoriasis. The efficacy, pharmacokinetic properties, and the safety profile of one of the most recent IL-23 biologic agents (tildrakizumab) are evaluated and reviewed in depth.
Label-Free Quantitative Proteomic Analysis of the Global Response to Indole-3-Acetic Acid in Newly Isolated Pseudomonas sp. Strain LY1
Authors: Zhao Shuxue , Chen Xi , Sun Qianshu , Wang Fei , Hu Chunhui , Guo Lizhong , Bai Jie , Yu Hao
Published: August 2021

Indole-3-acetic acid (IAA), known as a common plant hormone, is one of the most distributed indole derivatives in the environment, but the degradation mechanism and cellular response network to IAA degradation are still not very clear. The objective of this study was to elucidate the molecular mechanisms of IAA degradation at the protein level by a newly isolated strain Pseudomonas sp. LY1. Label-free quantitative proteomic analysis of strain LY1 cultivated with IAA or citrate/NH4Cl was applied. A total of 2,604 proteins were identified, and 227 proteins have differential abundances in the presence of IAA, including 97 highly abundant proteins and 130 less abundant proteins. Based on the proteomic analysis an IAA degrading (iad) gene cluster in strain LY1 containing IAA transformation genes (organized as iadHABICDEFG), genes of the β-ketoadipate pathway for catechol and protocatechuate degradation (catBCA and pcaABCDEF) were identified. The iadA, iadB, and iadE-disrupted mutants lost the ability to grow on IAA, which confirmed the role of the iad cluster in IAA degradation. Degradation intermediates were analyzed by HPLC, LC-MS, and GC-MS analysis. Proteomic analysis and identified products suggested that multiple degradation pathways existed in strain LY1. IAA was initially transformed to dioxindole-3-acetic acid, which was further transformed to isatin. Isatin was then transformed to isatinic acid or catechol. An in-depth data analysis suggested oxidative stress in strain LY1 during IAA degradation, and the abundance of a series of proteins was upregulated to respond to the stress, including reaction oxygen species (ROS) scavenging, protein repair, fatty acid synthesis, RNA protection, signal transduction, chemotaxis, and several membrane transporters. The findings firstly explained the adaptation mechanism of bacteria to IAA degradation.
Construction of an Artificial Biosynthetic Pathway for the Styrylpyrone Compound 11-Methoxy-Bisnoryangonin Produced in Engineered Escherichia coli
Authors: Heo Kyung Taek , Lee Byeongsan , Jang Jae-Hyuk , Ahn Jung-Oh , Hong Young-Soo
Published: August 2021

A cDNA clone (named pnpks), which shows high homology to the known chalcone synthase (CHS)-like type III PKS, was obtained from the leaves of Piper nigrum. The PnPKS protein with ferulic acid catalyzed lactonization instead of chalcone or stilbene formation. The new product was characterized as a styrylpyrone, 11-methoxy-bisnoryangonin, which is the lactonization compound of a linear triketide formed as the reaction product of PnPKS protein with ferulic acid. These results show that pnpks encodes a styrylpyrone synthase (SPS)-like PKS that catalyzes two-chain elongation with feruloyl CoA-linked starter substrates. Although these styrylpyrone compounds are promising for use in human healthcare, they are mainly obtained by extraction from raw plant or mushroom sources. For de novo synthesis of 11-methoxy-bisnoryangonin in the heterologous host Escherichia coli from a simple sugar as a starter, the artificial biosynthetic pathway contained five genes: optal, sam5, com, and 4cl2nt, along with the pnpks gene. The engineered L-tyrosine overproducing E. coli ∆COS1 strain, in which five biosynthetic genes were cloned into two vectors, pET-opT5M and pET22-4P, was cultured for 24 h in a minimal glucose medium containing ampicillin and kanamycin. As a result, 11-methoxy-bisnoryangonin production of up to 52.8 mg/L was achieved, which is approximately 8.5-fold higher than that in the parental E. coli strain harboring a plasmid for 11-methoxy-bisnoryangonin biosynthesis. As a potential styrylpyrone compound, 11-methoxy-bisnoryangonin, was successfully produced in E. coli from a simple glucose medium, and its production titer was also increased using engineered strains. This study provides a useful reference for establishing the biological manufacture of styrylpyrone compounds.