bluuebunny/crossref_metadata_2025 huggingface dataset:
Renal Ciliopathies: Sorting Out Therapeutic Approaches for Nephronophthisis
Authors: Stokman Marijn F. , Saunier Sophie , Benmerah Alexandre
Published: May 2021

Nephronophthisis (NPH) is an autosomal recessive ciliopathy and a major cause of end-stage renal disease in children. The main forms, juvenile and adult NPH, are characterized by tubulointerstitial fibrosis whereas the infantile form is more severe and characterized by cysts. NPH is caused by mutations in over 20 different genes, most of which encode components of the primary cilium, an organelle in which important cellular signaling pathways converge. Ciliary signal transduction plays a critical role in kidney development and tissue homeostasis, and disruption of ciliary signaling has been associated with cyst formation, epithelial cell dedifferentiation and kidney function decline. Drugs have been identified that target specific signaling pathways (for example cAMP/PKA, Hedgehog, and mTOR pathways) and rescue NPH phenotypes in in vitro and/or in vivo models. Despite identification of numerous candidate drugs in rodent models, there has been a lack of clinical trials and there is currently no therapy that halts disease progression in NPH patients. This review covers the most important findings of therapeutic approaches in NPH model systems to date, including hypothesis-driven therapies and untargeted drug screens, approached from the pathophysiology of NPH. Importantly, most animal models used in these studies represent the cystic infantile form of NPH, which is less prevalent than the juvenile form. It appears therefore important to develop new models relevant for juvenile/adult NPH. Alternative non-orthologous animal models and developments in patient-based in vitro model systems are discussed, as well as future directions in personalized therapy for NPH.
Validation of a Novel Fgf10Cre–ERT2 Knock-in Mouse Line Targeting FGF10Pos Cells Postnatally
Authors: Chu Xuran , Taghizadeh Sara , Vazquez-Armendariz Ana Ivonne , Herold Susanne , Chong Lei , Chen Chengshui , Zhang Jin-San , El Agha Elie , Bellusci Saverio
Published: May 2021

Fgf10 is a key gene during development, homeostasis and repair after injury. We previously reported a knock-in Fgf10Cre–ERT2 line (with the Cre-ERT2 cassette inserted in frame with the start codon of exon 1), called thereafter Fgf10Ki–v1, to target FGF10Pos cells. While this line allowed fairly efficient and specific labeling of FGF10Pos cells during the embryonic stage, it failed to target these cells after birth, particularly in the postnatal lung, which has been the focus of our research. We report here the generation and validation of a new knock-in Fgf10Cre–ERT2 line (called thereafter Fgf10Ki–v2) with the insertion of the expression cassette in frame with the stop codon of exon 3. Fgf10Ki−v2/+ heterozygous mice exhibited comparable Fgf10 expression levels to wild type animals. However, a mismatch between Fgf10 and Cre expression levels was observed in Fgf10Ki–v2/+ lungs. In addition, lung and limb agenesis were observed in homozygous embryos suggesting a loss of Fgf10 functional allele in Fgf10Ki–v2 mice. Bioinformatic analysis shows that the 3′UTR, where the Cre-ERT2 cassette is inserted, contains numerous putative transcription factor binding sites. By crossing this line with tdTomato reporter line, we demonstrated that tdTomato expression faithfully recapitulated Fgf10 expression during development. Importantly, Fgf10Ki–v2 mouse is capable of significantly targeting FGF10Pos cells in the adult lung. Therefore, despite the aforementioned limitations, this new Fgf10Ki–v2 line opens the way for future mechanistic experiments involving the postnatal lung.
miR-212/132-Enriched Extracellular Vesicles Promote Differentiation of Induced Pluripotent Stem Cells Into Pancreatic Beta Cells
Authors: Bai Chunyu , Ren Qiwei , Liu Haifeng , Li Xiangchen , Guan Weijun , Gao Yuhua
Published: May 2021

Pancreatic beta cell transplantation is the ideal method for treatment of type 1 diabetes mellitus (T1DM), and the generation of beta cells from induced pluripotent stem cells (iPSCs) of patients is a promising strategy. In this study, we improved a previous strategy to produce beta cells using extracellular vesicles (EVs) derived from mature beta cells and differentiated beta cells from iPSCs (i-Beta cells), which secreted insulin under glucose stimulation in vitro and ameliorated hyperglycemia in vivo. Mechanistic analyses revealed that EV-carried microRNA (miR)-212/132 (EV-miR-212/132) directly bound to the 3′ UTR of FBW7 to prevent its translation and FBW7 combined with NGN3 to accelerate its proteasomal degradation. EV-miR-212/132 stabilized NGN3 expression to promote differentiation of endocrine cells from induced iPSCs. Moreover, NGN3 bound to PDX1 to enhance transcription of endogenous miR-212/132 and formed a positive regulatory circuit that maintained the functions of mature pancreatic beta cells.

Conclusion

This study describes a novel approach for beta cell production and supports the use of iPSCs for cell replacement therapy of T1DM.
Protein Phosphatase 2A Mediates YAP Activation in Endothelial Cells Upon VEGF Stimulation and Matrix Stiffness
Authors: Jiang Xiao , Hu Jiandong , Wu Ziru , Cafarello Sarah Trusso , Di Matteo Mario , Shen Ying , Dong Xue , Adler Heike , Mazzone Massimiliano , Ruiz de Almodovar Carmen , Wang Xiaohong
Published: May 2021

Angiogenesis is an essential process during development. Abnormal angiogenesis also contributes to many disease conditions such as tumor and retinal diseases. Previous studies have established the Hippo signaling pathway effector Yes-associated protein (YAP) as a crucial regulator of angiogenesis. In ECs, activated YAP promotes endothelial cell proliferation, migration and sprouting. YAP activity is regulated by vascular endothelial growth factor (VEGF) and mechanical cues such as extracellular matrix (ECM) stiffness. However, it is unclear how VEGF or ECM stiffness signal to YAP, especially how dephosphorylation of YAP occurs in response to VEGF stimulus or ECM stiffening. Here, we show that protein phosphatase 2A (PP2A) is required for this process. Blocking PP2A activity abolishes VEGF or ECM stiffening mediated YAP activation. Systemic administration of a PP2A inhibitor suppresses YAP activity in blood vessels in developmental and pathological angiogenesis mouse models. Consistently, PP2A inhibitor also inhibits sprouting angiogenesis. Mechanistically, PP2A directly interacts with YAP, and this interaction requires proper cytoskeleton dynamics. These findings identify PP2A as a crucial mediator of YAP activation in ECs and hence as an important regulator of angiogenesis.
The First Insight Into the Supramolecular System of D,L-α-Difluoromethylornithine: A New Antiviral Perspective
Authors: Bojarska Joanna , New Roger , Borowiecki Paweł , Remko Milan , Breza Martin , Madura Izabela D. , Fruziński Andrzej , Pietrzak Anna , Wolf Wojciech M.
Published: May 2021

Targeting the polyamine biosynthetic pathway by inhibiting ornithine decarboxylase (ODC) is a powerful approach in the fight against diverse viruses, including SARS-CoV-2. Difluoromethylornithine (DFMO, eflornithine) is the best-known inhibitor of ODC and a broad-spectrum, unique therapeutical agent. Nevertheless, its pharmacokinetic profile is not perfect, especially when large doses are required in antiviral treatment. This article presents a holistic study focusing on the molecular and supramolecular structure of DFMO and the design of its analogues toward the development of safer and more effective formulations. In this context, we provide the first deep insight into the supramolecular system of DFMO supplemented by a comprehensive, qualitative and quantitative survey of non-covalent interactions via Hirshfeld surface, molecular electrostatic potential, enrichment ratio and energy frameworks analysis visualizing 3-D topology of interactions in order to understand the differences in the cooperativity of interactions involved in the formation of either basic or large synthons (Long-range Synthon Aufbau Modules, LSAM) at the subsequent levels of well-organized supramolecular self-assembly, in comparison with the ornithine structure. In the light of the drug discovery, supramolecular studies of amino acids, essential constituents of proteins, are of prime importance. In brief, the same amino-carboxy synthons are observed in the bio-system containing DFMO. DFT calculations revealed that the biological environment changes the molecular structure of DFMO only slightly. The ADMET profile of structural modifications of DFMO and optimization of its analogue as a new promising drug via molecular docking are discussed in detail.
Enhanced Electroluminescence Based on a π-Conjugated Heptazine Derivative by Exploiting Thermally Activated Delayed Fluorescence
Authors: Li Jie , Gong Heqi , Zhang Jincheng , Zhou Shiyi , Tao Li , Jiang Lihua , Guo Qiang
Published: May 2021

Heptazine derivatives have attracted much attention over the past decade by virtue of intriguing optical, photocatalytic as well as electronic properties in the fields of hydrogen evolution, organic optoelectronic technologies and so forth. Here, we report a simple π-conjugated heptazine derivative (HAP-3DF) possessing an n→π* transition character which exhibits enhanced electroluminescence by exploiting thermally activated delayed fluorescence (TADF). Green-emitting HAP-3DF shows relatively low photoluminescence quantum efficiencies (Φp) of 0.08 in toluene and 0.16 in doped film with bis(2-(diphenylphosphino)phenyl) ether oxide (DPEPO) as the matrix. Interestingly, the organic light-emitting diode (OLED) incorporating 8 wt% HAP-3DF:DPEPO as an emitting layer achieved a high external quantum efficiency (EQE) of 3.0% in view of the fairly low Φp of 0.16, indicating the presence of TADF stemming from n→π* transitions. As the matrix changing from DPEPO to 1,3-di (9H-carbazol-9-yl)benzene (mCP), a much higher Φp of 0.56 was found in doped film accompanying yellow emission. More importantly, enhanced electroluminescence was observed from the OLED containing 8 wt% HAP-3DF:mCP as an emitting layer, and a rather high EQE of 10.8% along with a low roll-off was realized, which should be ascribed to the TADF process deriving from exciplex formation.
Lipid Secretion by Parasitic Cells of Coccidioides Contributes to Disseminated Disease
Authors: Peláez-Jaramillo Carlos Alberto , Jiménez-Alzate Maria Del Pilar , Araque-Marin Pedronel , Hung Chiung-Yu , Castro-Lopez Natalia , Cole Garry T.
Published: May 2021

Coccidioides is a soil-borne fungal pathogen and causative agent of a human respiratory disease (coccidioidomycosis) endemic to semi-desert regions of southwestern United States, Mexico, Central and South America. Aerosolized arthroconidia inhaled by the mammalian host first undergo conversion to large parasitic cells (spherules, 80–100 μm diameter) followed by endosporulation, a process by which the contents of spherules give rise to multiple endospores. The latter are released upon rupture of the maternal spherules and establish new foci of lung infection. A novel feature of spherule maturation prior to endosporulation is the secretion of a lipid-rich, membranous cell surface layer shed in vivo during growth of the parasitic cells and secretion into liquid culture medium during in vitro growth. Chemical analysis of the culture derived spherule outer wall (SOW) fraction showed that it is composed largely of phospholipids and is enriched with saturated fatty acids, including myristic, palmitic, elaidic, oleic, and stearic acid. NMR revealed the presence of monosaccharide- and disaccharide-linked acylglycerols and sphingolipids. The major sphingolipid components are sphingosine and ceramide. Primary neutrophils derived from healthy C57BL/6 and DBA/2 mice incubated with SOW lipids revealed a significant reduction in fungicidal activity against viable Coccidioides arthroconidia compared to incubation of neutrophils with arthroconidia alone. Host cell exposure to SOW lipids had no effect on neutrophil viability. Furthermore, C57BL/6 mice that were challenged subcutaneously with Coccidioides arthroconidia in the presence of the isolated SOW fraction developed disseminated disease, while control mice challenged with arthroconidia alone by the same route showed no dissemination of infection. We hypothesize that SOW lipids contribute to suppression of inflammatory response to Coccidioides infection. Studies are underway to characterize the immunosuppressive mechanism(s) of SOW lipids.
Wearable Devices for Gait Analysis in Intelligent Healthcare
Authors: Liu Xin , Zhao Chen , Zheng Bin , Guo Qinwei , Duan Xiaoqin , Wulamu Aziguli , Zhang Dezheng
Published: May 2021

In this study, we review the role of wearable devices in tracking our daily locomotion. We discuss types of wearable devices that can be used, methods for gait analyses, and multiple healthcare-related applications aided by artificial intelligence. Impaired walking and locomotion are common resulting from injuries, degenerative pathologies, musculoskeletal disorders, and various neurological damages. Daily tracking and gait analysis are convenient and efficient approaches for monitoring human walking, where concreate and rich data can be obtained for examining our posture control mechanism during body movement and providing enhanced clinical pieces of evidence for diagnoses and treatments. Many sensors in wearable devices can help to record data of walking and running; spatiotemporal and kinematic variables can be further calculated in gait analysis. We report our previous works in gait analysis, discussing applications of wearable devices for detecting foot and ankle lesions, supporting surgeons in early diagnosis, and helping physicians with rehabilitation.
The True Identity of Putative Tooth Alveoli in a Cenozoic Crown Bird, the Gastornithid Omorhamphus
Authors: Louchart Antoine , Bhullar Bhart-Anjan , Riamon Ségolène , Field Daniel J.
Published: May 2021

All extant birds are toothless, and recent molecular evidence suggests that edentulism in extant birds is the product of a single evolutionary transition to toothlessness on the line to crown birds in the Cretaceous. However, a fossil crown bird premaxilla from the Palaeogene of North America (assigned to the gastornithid Omorhamphus storchii) has been interpreted as bearing alveoli for teeth, an observation that would cast doubt on a single loss of teeth preceding the extant avian radiation. However, the identity of these putative alveoli has never been reinvestigated in detail. Here, we re-examine this problematic juvenile specimen, using non-invasive x-ray microtomography, enabling the assessment of the true identity of the large, alveolus-like pits on the ventral side of this premaxilla. Although superficially alveolus-like, we illustrate that these pits represent openings of large neurovascular canals communicating with both the medullary cavity as well as other canals opening along the dorsal and lateral surfaces of the upper jaw, and that none of these openings appear to represent tooth alveoli. Further, we demonstrate that claims of an adult gastornithid specimen (Gastornis parisiensis) exhibiting tooth alveoli are similarly unfounded. By rejecting the hypothesis of dentition in these gastornithids, we eliminate any lingering uncertainty regarding the persistence of teeth within the avian crown group. We illustrate the presence of similar large vascular openings along the ventral surface of the beak of juvenile Gastornis russelli/parisiensis, and smaller versions in the juvenile premaxillae of Sylviornis neocaledoniae. We suggest that the large vascular canals in gastornithid specimens such as O. storchii are a feature associated with rapid growth of the juvenile beak, allowing the attainment of a large and dorsoventrally deep beak early in ontogeny. This may have enabled young gastornithids to become autonomous early, consistent with a presumably precocial developmental strategy.
The Probable Critical Role of Early Holocene Monsoon Activity in Siting the Origins of Rice Agriculture in China
Authors: Dodson John , Hung Hsiao-chun , Li Chenzi , Li Jianyong , Lu Fengyan , Yan Hong
Published: May 2021

The long process of rice domestication likely started 10,000–8,000 years ago in China, and the pre-existing hunter-gatherer communities gradually adopted more sedentary lifestyles with the dependence of rice agricultural economies. The archeological evidence builds a strong case for the first domestication of rice to Oryza sativa centered in the Middle-Lower Yangtze Valley during the early Holocene. The genetic evidence identifies the main ancestor of O. sativa was O. rufipogon, however, this now occurs naturally south of the Yangtze where its distribution is limited by summer temperatures and mean annual temperature. The mismatch between occurrence of ancestors and presumed sites of early cultivation leads to a number of hypotheses. These include that first domestication actually took place further south, such as in the Pearl River valley but archeological evidence is currently lacking for this. Or domestication took place, when O. rufipogon had a more extensive natural range in the past. Early to mid-Holocene palaeoclimate reconstructions show that the East Asian Summer Monsoon was more active in the early Holocene and estimates show that the temperature requirements for O. rufipogon were met for a substantial area of northeast China at the time. This would mean that earliest known domestication sites and presumed ancestor distribution coincided for several millennia. Thus early records of rice farming in Henan and Shandong were easily accommodated by early to mid Holocene climates.
Teacher and Student Practices Associated with Performance in the PISA Reading Literacy Evaluation
Authors: Rojas-Torres Luis , Ordóñez Graciela , Calvo Karen
Published: May 2021

This article aims at finding teacher’s and student’s practices that relate to performance in PISA reading literacy evaluations and that are feasible to intervene in order to assist the improvement of reading competency. To achieve this purpose, the study was developed with data collected from the population of Costa Rica that took the PISA evaluation in 2018 (n = 4691, 2340 men, and 2351 women). A linear regression of the reading score was performed utilizing plausible values and sampling weights. The predictors of the regression were contextual factors, teacher practices, and student habits. Time spent and interest in reading showed a positive and relevant association with student’s performance in reading, controlling important background aspects like economic resources and parents' education. Moreover, 28.19% to the obtained variance explanation of the reading literacy (27%) was only due to the teacher’s and student’s practices. These results provide favorable information to design interventions for the improvement of reading competency.
Development and Evaluation of a Framework for the Performance-Based Testing of ICT Skills
Authors: Engelhardt Lena , Naumann Johannes , Goldhammer Frank , Frey Andreas , Horz Holger , Hartig Katja , Wenzel S. Franziska C.
Published: May 2021

This paper addresses the development of performance-based assessment items for ICT skills, skills in dealing with information and communication technologies, a construct which is rather broadly and only operationally defined. Item development followed a construct-driven approach to ensure that test scores could be interpreted as intended. Specifically, ICT-specific knowledge as well as problem-solving and the comprehension of text and graphics were defined as components of ICT skills and cognitive ICT tasks (i.e., accessing, managing, integrating, evaluating, creating). In order to capture the construct in a valid way, design principles for constructing the simulation environment and response format were formulated. To empirically evaluate the very heterogeneous items and detect malfunctioning items, item difficulties were analyzed and behavior-related indicators with item-specific thresholds were developed and applied. The 69 item’s difficulty scores from the Rasch model fell within a comparable range for each cognitive task. Process indicators addressing time use and test-taker interactions were used to analyze whether most test-takers executed the intended processes, exhibited disengagement, or got lost among the items. Most items were capable of eliciting the intended behavior; for the few exceptions, conclusions for item revisions were drawn. The results affirm the utility of the proposed framework for developing and implementing performance-based items to assess ICT skills.
Case Report: MDM4 Amplified in a Thymoma Patient With Autoimmune Enteropathy and Myocarditis
Authors: Du Xin , Yu Lei , Li Fei , Yu Zhen , Yang Xing-guo , Jiang Yu-xuan , Yu Xin-tao
Published: May 2021

Introduction

Thymoma is a type of mediastinal malignant tumors which always associated with autoimmune diseases. Although surgery is the predominant treatment method for thymoma, the pathogenesis of thymoma and thymoma-associated autoimmune diseases is still unknown. However, the case study here provided a possible pathogenesis and treatment to cure the thymoma with autoimmune enteropathy and myocarditis.

Case presentation

A thymoma case with autoimmune enteropathy and myocarditis undergoing surgery was reported. The symptoms and laboratory results of the patient had dramatically fluctuated after tumor resection and gradually alleviated. The whole exome sequencing found MDM4 amplified in tumor cells. Immunohistochemistry indicated that thymoma cells were positive for MDM4. The result of drug sensitivity tests showed thymoma cells were highly sensitive to Nutlin-3a.

Conclusion

MDM4 could play an important role in the pathogenesis of this thymoma case with autoimmune enteropathy and myocarditis. This discovery may provide a novel idea of pathogenesis and treatment for thymoma and autoimmune diseases.
Risk of All-Cause Mortality in Levothyroxine-Treated Hypothyroid Patients: A Nationwide Korean Cohort Study
Authors: Sohn Seo Young , Seo Gi Hyeon , Chung Jae Hoon
Published: May 2021

Background

Although hypothyroidism is associated with various comorbidities, its relationship with increased all-cause mortality remains controversial. The aim of this nationwide retrospective cohort study was to investigate whether hypothyroid patients treated with levothyroxine had increased mortality compared to controls.

Methods

Hypothyroid subjects were identified through the Korean National Health Insurance Service Claims database between 2008 and 2017. Hypothyroidism in this study was defined as overt hypothyroidism treated with long-term prescription of levothyroxine (>6 months). After 1:3 age-, sex- and index year-matching, 501,882 patients with newly diagnosed hypothyroidism and 1,505,646 controls without hypothyroidism were included.

Results

During a mean follow-up of 6 years, 25,954 (5.2%) hypothyroid patients and 59,105 (3.9%) controls died. Hypothyroidism was significantly associated with increased all-cause mortality (adjusted hazard ratio [HR], 1.14; 95% confidence interval [CI] 1.12–1.16) even with levothyroxine treatment. When stratified by age, sex, and cardiovascular disease risk, independent associations between hypothyroidism and mortality remained significant in all subgroups. The risk of mortality was higher in the < 65 age group (HR: 1.25, 95% CI: 1.22–1.29), men (HR: 1.28, 95% CI: 1.25–1.31), and the high cardiovascular disease risk group (HR: 1.31, 95% CI: 1.29–1.34). The mortality rate of hypothyroid patients was highest within 1 year of treatment and decreased with time.

Conclusion

This nationwide, population-based cohort study showed that all-cause mortality was significantly higher in levothyroxine-treated hypothyroid patients than in non-hypothyroid controls. This association remained significant regardless of age, sex, and cardiovascular disease risk.
The Potential Application of Giant Reed (Arundo donax) in Ecological Remediation
Authors: Zhang Deng , Jiang QianWen , Liang DanYang , Huang Shixun , Liao Jianxiong
Published: May 2021

Giant reed is known as one of the most important energy plants as a consequence of its huge dry biomass production. It can be used for bioenergy or biopolymer production. Thus, it can replace maize and reduce the production cost of biomass and electricity. Giant reed and its products have different uses in industry. The use of giant reed as a raw material to obtain cellulose past for the production of rayon viscose and paper. Thanks to the flexible and strong of the material, giant reed can be used in the manufacture of fishing rods, brass musical instruments, canes and construction supplies. One of the most important characteristics of giant reed is that it shows strong growth capability in different soils with wide ranges of pH, salinity and high heavy metal contents and can be used for ecological remediation. Giant reed was able not only to decontaminate polluted soils with heavy metals, but also to purify the wastewater and decrease the pH and make red mud safer. Here, we review the available evidence regarding the utilization of giant reed in the field of phytoremediation and discuss the potential application of giant reed combined with advanced remediation technologies in ecological remediation.
The Ghost of the Hawk: Top Predator Shaping Bird Communities in Space and Time
Authors: Burgas Daniel , Ovaskainen Otso , Blanchet F. Guillaume , Byholm Patrik
Published: May 2021

Despite the wide recognition that strongly interacting species can influence distributions of other species, species interactions are often disregarded when assessing or projecting biodiversity distributions. In particular, it remains largely uncharted the extent to which the disappearance of a keystone species cast repercussions in the species composition of future communities. We tested whether an avian top predator can exert both positive and negative effects on spatial distribution of other species, and if these effects persist even after the predator disappeared. We acquired bird count data at different distances from occupied and non-occupied nests of Northern goshawks Accipiter gentilis. Using a Bayesian joint species distribution model, we found that large bird species (preferred prey) are less abundant in the proximity of nests occupied by goshawks, whereas smaller species –expected to get protection from subordinate predators displaced by goshawks– more often showed an opposite association. These spatial differences level off gradually, but still persist for years after the goshawks have disappeared. This indicates that the composition of local bird populations and communities might be conditional on past species interactions. Therefore, endeavors centered around species distributions could largely benefit from acknowledging the local extinction of keystone species.
Medicinal Plants and Isolated Molecules Demonstrating Immunomodulation Activity as Potential Alternative Therapies for Viral Diseases Including COVID-19
Authors: Alhazmi Hassan A. , Najmi Asim , Javed Sadique A. , Sultana Shahnaz , Al Bratty Mohammed , Makeen Hafiz A. , Meraya Abdulkarim M. , Ahsan Waquar , Mohan Syam , Taha Manal M. E. , Khalid Asaad
Published: May 2021

Plants have been extensively studied since ancient times and numerous important chemical constituents with tremendous therapeutic potential are identified. Attacks of microorganisms including viruses and bacteria can be counteracted with an efficient immune system and therefore, stimulation of body’s defense mechanism against infections has been proven to be an effective approach. Polysaccharides, terpenoids, flavonoids, alkaloids, glycosides, and lactones are the important phytochemicals, reported to be primarily responsible for immunomodulation activity of the plants. These phytochemicals may act as lead molecules for the development of safe and effective immunomodulators as potential remedies for the prevention and cure of viral diseases. Natural products are known to primarily modulate the immune system in nonspecific ways. A number of plant-based principles have been identified and isolated with potential immunomodulation activity which justify their use in traditional folklore medicine and can form the basis of further specified research. The aim of the current review is to describe and highlight the immunomodulation potential of certain plants along with their bioactive chemical constituents. Relevant literatures of recent years were searched from commonly employed scientific databases on the basis of their ethnopharmacological use. Most of the plants displaying considerable immunomodulation activity are summarized along with their possible mechanisms. These discussions shall hopefully elicit the attention of researchers and encourage further studies on these plant-based immunomodulation products as potential therapy for the management of infectious diseases, including viral ones such as COVID-19.
Neoantigen Specific T Cells Derived From T Cell-Derived Induced Pluripotent Stem Cells for the Treatment of Hepatocellular Carcinoma: Potential and Challenges
Authors: Lu Fei , Ma Xiao-Jing-Nan , Jin Wei-Lin , Luo Yang , Li Xun
Published: May 2021

Immunotherapy has become an indispensable part of the comprehensive treatment of hepatocellular carcinoma (HCC). Immunotherapy has proven effective in patients with early HCC, advanced HCC, or HCC recurrence after liver transplantation. Clinically, the most commonly used immunotherapy is immune checkpoint inhibition using monoclonal antibodies, such as CTLA-4 and PD-1. However, it cannot fundamentally solve the problems of a weakened immune system and inactivation of immune cells involved in killing tumor cells. T cells can express tumor antigen-recognizing T cell receptors (TCRs) or chimeric antigen receptors (CARs) on the cell surface through gene editing to improve the specificity and responsiveness of immune cells. According to previous studies, TCR-T cell therapy is significantly better than CAR-T cell therapy in the treatment of solid tumors and is one of the most promising immune cell therapies for solid tumors so far. However, its application in the treatment of HCC is still being researched. Technological advancements in induction and redifferentiation of induced pluripotent stem cells (iPSCs) allow us to use T cells to induce T cell-derived iPSCs (T-iPSCs) and then differentiate them into TCR-T cells. This has allowed a convenient strategy to study HCC models and explore optimal treatment strategies. This review gives an overview of the major advances in the development of protocols to generate neoantigen-specific TCR-T cells from T-iPSCs. We will also discuss their potential and challenges in the treatment of HCC.
Identification of Ecological Hotspots for the Seagrass Posidonia oceanica via Metapopulation Modeling
Authors: Mari Lorenzo , Melià Paco , Gatto Marino , Casagrandi Renato
Published: May 2021

The seagrassPosidonia oceanicais a benthic foundation species endemic to the Mediterranean Sea. It is a key component of coastal seascapes across the Mediterranean large marine ecosystem, where it plays fundamental ecological, physical, and economic roles. Despite the importance of this iconic seagrass species, a quantitative assessment of the interplay between local dynamics and basin-wide dispersal patterns is still lacking. Here we propose a Mediterranean-scale metapopulation model forP. oceanica, accounting for both demographic processes (inter-annual survival, vegetative growth, fruit production, seed establishment) and the spatial connectivity provided by current-driven dispersal of seagrass fruits. Model simulations are used to identify hotspots of seagrass population abundance, realized connectivity, and long-distance dispersal. Our results indicate thatP. oceanicamulti-functional hotspots, defined as species-suitable areas that rank high in all of the considered functional roles, are unevenly distributed in the four main sub-basins of the Mediterranean Sea, and along both the European and the African coastline. Our analysis also allows us to outline a remarkable geographical gap in protection: in fact, while many of the hotspots located along European coasts occur close to protected sites, the great majority of the hotspots lying on African coasts lack any form of protection. The identification of hotspots ofP. oceanicametapopulation dynamics can thus help select regions that may serve as priority candidates for focusing conservation efforts.
Impacts of the Marine Hatchery Built Environment, Water and Feed on Mucosal Microbiome Colonization Across Ontogeny in Yellowtail Kingfish, Seriola lalandi
Authors: Minich Jeremiah J. , Nowak Barbara , Elizur Abigail , Knight Rob , Fielder Stewart , Allen Eric E.
Published: May 2021

The fish gut microbiome is impacted by a number of biological and environmental factors including fish feed formulations. Unlike mammals, vertical microbiome transmission is largely absent in fish and thus little is known about how the gut microbiome is initially colonized during hatchery rearing nor the stability throughout growout stages. Here we investigate how various microbial-rich surfaces from the built environment “BE” and feed influence the development of the mucosal microbiome (gill, skin, and digesta) of an economically important marine fish, yellowtail kingfish, Seriola lalandi, over time. For the first experiment, we sampled gill and skin microbiomes from 36 fish reared in three tank conditions, and demonstrate that the gill is more influenced by the surrounding environment than the skin. In a second experiment, fish mucous (gill, skin, and digesta), the BE (tank side, water, inlet pipe, airstones, and air diffusers) and feed were sampled from indoor reared fish at three ages (43, 137, and 430 dph; n = 12 per age). At 430 dph, 20 additional fish were sampled from an outdoor ocean net pen. A total of 304 samples were processed for 16S rRNA gene sequencing. Gill and skin alpha diversity increased while gut diversity decreased with age. Diversity was much lower in fish from the ocean net pen compared to indoor fish. The gill and skin are most influenced by the BE early in development, with aeration equipment having more impact in later ages, while the gut “allochthonous” microbiome becomes increasingly differentiated from the environment over time. Feed had a relatively low impact on driving microbial communities. Our findings suggest that S. lalandi mucosal microbiomes are differentially influenced by the BE with a high turnover and rapid succession occurring in the gill and skin while the gut microbiome is more stable. We demonstrate how individual components of a hatchery system, especially aeration equipment, may contribute directly to microbiome development in a marine fish. In addition, results demonstrate how early life (larval) exposure to biofouling in the rearing environment may influence fish microbiome development which is important for animal health and aquaculture production.
Influence of the NaIO4 Concentration on the Gelation and the Adhesive Strength of Pyrocatechol/Pyrogallol Containing Gelatin Hydrogels
Authors: Back Florence , Ball Vincent , Arntz Youri
Published: May 2021

The presence of catechol groups in hydrogels, either grafted to the constituting polymers or added in the gel formulation allow to increase the adhesion strength of such hydrogels. In this investigation, we add pyrocatechol (1,2-benzenediol) and pyrogallol (1,2,3-benzenetriol) in gelatin solution to form hydrogels using sodium periodate as an oxidant with the aim to induce interactions between pyrocatechol/pyrogallol and the gelatin chains. The gelation kinetics of the hydrogels as well as their adhesion strength and toughness are evaluated as a function of the concentration in NaIO4 for a constant concentration-10 mM-in pyrocatechol/pyrogallol. It came out that the addition of pyrogallol to gelatin (10% w/v) did not improve the adhesion strength on stainless steel when compared to a pristine gelatin gel. As an interesting finding, the addition of pyrocatechol to gelatin allowed for a major improvement of the adhesive strength between two stainless steel plates and allowed to stabilize the gel up to 50°C. However, the pyrogallol modified gelatin gels displayed no thermal stabilization compared to pristine gelatin. The major differences between pyrocatechol and pyrogallol modified gels are explained on the basis of the electrophilicity of the oxidized polyphenols. In addition, the self-healing behavior of the gelatin based gels was investigated as a function of their composition.
Rewarming From Hypothermic Cardiac Arrest Applying Extracorporeal Life Support: A Systematic Review and Meta-Analysis
Authors: Bjertnæs Lars J. , Hindberg Kristian , Næsheim Torvind O. , Suborov Evgeny V. , Reierth Eirik , Kirov Mikhail Y. , Lebedinskii Konstantin M. , Tveita Torkjel
Published: May 2021

Introduction:This systematic review and meta-analysis aims at comparing outcomes of rewarming after accidental hypothermic cardiac arrest (HCA) with cardiopulmonary bypass (CPB) or/and extracorporeal membrane oxygenation (ECMO).

Material and Methods:Literature searches were limited to references with an abstract in English, French or German. Additionally, we searched reference lists of included papers. Primary outcome was survival to hospital discharge. We assessed neurological outcome, differences in relative risks (RR) of surviving, as related to the applied rewarming technique, sex, asphyxia, and witnessed or unwitnessed HCA. We calculated hypothermia outcome prediction probability score after extracorporeal life support (HOPE) in patients in whom we found individual data.P< 0.05 considered significant.

Results:Twenty-three case observation studies comprising 464 patients were included in a meta-analysis comparing outcomes of rewarming with CPB or/and ECMO. One-hundred-and-seventy-two patients (37%) survived to hospital discharge, 76 of 245 (31%) after CPB and 96 of 219 (44 %) after ECMO; 87 and 75%, respectively, had good neurological outcomes. Overall chance of surviving was 41% higher (P= 0.005) with ECMO as compared with CPB. A man and a woman had 46% (P= 0.043) and 31% (P= 0.115) higher chance, respectively, of surviving with ECMO as compared with CPB. Avalanche victims had the lowest chance of surviving, followed by drowning and people losing consciousness in cold environments. Assessed by logistic regression, asphyxia, unwitnessed HCA, male sex, high initial body temperature, low pH and high serum potassium (s-K+) levels were associated with reduced chance of surviving. In patients displaying individual data, overall mean predictive surviving probability (HOPE score;n= 134) was 33.9 ± 33.6% with no significant difference between ECMO and CPB-treated patients. We also surveyed 80 case reports with 96 victims of HCA, who underwent resuscitation with CPB or ECMO, without including them in the meta-analysis.

Conclusions:The chance of surviving was significantly higher after rewarming with ECMO, as compared to CPB, and in patients with witnessed compared to unwitnessed HCA. Avalanche victims had the lowest probability of surviving. Male sex, high initial body temperature, low pH, and high s-K+were factors associated with low surviving chances.
Brain Tumor Segmentation via Multi-Modalities Interactive Feature Learning
Authors: Wang Bo , Yang Jingyi , Peng Hong , Ai Jingyang , An Lihua , Yang Bo , You Zheng , Ma Lin
Published: May 2021

Automatic segmentation of brain tumors from multi-modalities magnetic resonance image data has the potential to enable preoperative planning and intraoperative volume measurement. Recent advances in deep convolutional neural network technology have opened up an opportunity to achieve end-to-end segmenting the brain tumor areas. However, the medical image data used in brain tumor segmentation are relatively scarce and the appearance of brain tumors is varied, so that it is difficult to find a learnable pattern to directly describe tumor regions. In this paper, we propose a novel cross-modalities interactive feature learning framework to segment brain tumors from the multi-modalities data. The core idea is that the multi-modality MR data contain rich patterns of the normal brain regions, which can be easily captured and can be potentially used to detect the non-normal brain regions, i.e., brain tumor regions. The proposed multi-modalities interactive feature learning framework consists of two modules: cross-modality feature extracting module and attention guided feature fusing module, which aim at exploring the rich patterns cross multi-modalities and guiding the interacting and the fusing process for the rich features from different modalities. Comprehensive experiments are conducted on the BraTS 2018 benchmark, which show that the proposed cross-modality feature learning framework can effectively improve the brain tumor segmentation performance when compared with the baseline methods and state-of-the-art methods.
The Development of Extra-Articular Manifestations in Children With Enthesitis-Related Arthritis: Natural Course or Different Disease Entity?
Authors: Pagnini Ilaria , Scavone Mariangela , Maccora Ilaria , Mastrolia Maria Vincenza , Marrani Edoardo , Bertini Federico , Lamot Lovro , Simonini Gabriele
Published: May 2021

Introduction: Enthesitis-related Arthritis (ERA) is a specific category of juvenile idiopathic arthritis (JIA) characterized by axial and/or peripheral arthritis, and enthesitis, although other different extra-articular manifestations may encompass its clinical spectrum.

Materials and Methods: In order to examine if ERA-JIA with extra-articular involvement may represent a different entity from ERA without extra-articular involvement, we performed a retrospective, observational, monocentric study, in a cohort of ERA patients followed between 2001 and September 2020 at the Pediatric Rheumatology Unit of Meyer Children Hospital of Florence. We analyzed the demographic, clinical, laboratory and imaging data at the disease onset, as well as after 3, 6, and 12 months follow up.

Results: We have enrolled 53 patients, 33 males. At the time of diagnosis, average age was 10.9 years, 53 patients had active arthritis and 25 active enthesitis. The middle foot involvement was present in 20 patients. Twenty-five children achieved clinical remission on medication. Extra-articular manifestations were observed in 14 patients, of whom 3 had inflammatory bowel disease, 5 uveitis, one uveitis associated with Crohn disease, 4 SAPHO syndrome, one celiac disease. The cohort was stratified according to the presence/absence of extra-articular manifestations. It was observed that middle foot involvement was more frequent in patients with no extra-articular manifestations (18/39 vs. 2/14; χ2 = 4.45, p = 0.05). Additionally, patients presenting extra-articular manifestation needed more frequently (12/14 vs. 21/39, χ2= 4.45, p = 0.05), and preciously (months: 3.7 ± 5.4 vs. 16.7 ± 26.5, p = 0.02), treatment with biologic agents. Finally, these patients achieved belatedly (months: 31.6 ± 32.3 vs. 22.9 ± 18.3, p = 0.01) and less frequently (3/14 vs. 22/39; χ2= 5.50, p = 0.03) the clinical remission on medication. Eventually, extra-articular involvement inversely correlated with the middle-foot arthritis (ρs −0.29, p = 0.03), the chance to achieve remission on medication (ρs −0.31 e p = 0.02), as well as the chance to keep overall remission, with and without medication (ρs −0.28, p = 0.04).

Conclusion: In our cohort, children diagnosed with ERA-JIA at the onset of disease and then developed extra-articular manifestations show the absence of middle foot involvement and worse prognosis with an early need for the use of biologic agents, and overall low chance to achieve remission.
Energy Starvation Induces a Cell Cycle Arrest in Escherichia coli by Triggering Degradation of the DnaA Initiator Protein
Authors: Charbon Godefroid , Mendoza-Chamizo Belén , Campion Christopher , Li Xiaobo , Jensen Peter Ruhdal , Frimodt-Møller Jakob , Løbner-Olesen Anders
Published: May 2021

During steady-state Escherichia coli growth, the amount and activity of the initiator protein, DnaA, controls chromosome replication tightly so that initiation only takes place once per origin in each cell cycle, regardless of growth conditions. However, little is known about the mechanisms involved during transitions from one environmental condition to another or during starvation stress. ATP depletion is one of the consequences of long-term carbon starvation. Here we show that DnaA is degraded in ATP-depleted cells. A chromosome replication initiation block is apparent in such cells as no new rounds of DNA replication are initiated while replication events that have already started proceed to completion.
Electroacupuncture Ameliorates Acute Pancreatitis: A Role for the Vagus Nerve–Mediated Cholinergic Anti-Inflammatory Pathway
Authors: Zhang Luyao , Wu Zhiyang , Zhou Jing , Lu Shengfeng , Wang Chaofan , Xia Yiqiu , Ren Hongyan , Tong Zhihui , Ke Lu , Li Weiqin
Published: May 2021

Organ failure resulting from excessive inflammation is the leading cause of death in the early phase of acute pancreatitis (AP). The autonomic nervous system was reported to be involved in AP, and the vagus nerve could exert anti-inflammatory effects through α7 nicotinic acetylcholine receptor (α7nAChR) signaling. Acupuncture has been widely used in traditional Asian medicine, and recent studies suggested the inflammation modulating effect of electroacupuncture (EA) might be mediated by the autonomic nervous system. In this study, we aimed to investigate the effects of EA in AP animal models. Two independent AP mouse models were used, namely, caerulein hyperstimulation and pancreatic duct ligation. We found that EA at Zusanli acupoint increased vagus nerve activity, suppressed systemic inflammation, and alleviated the histopathological manifestations and leukocyte infiltrations of the pancreas. Induction of AP resulted in a remarkable decrease in the frequency of α7nAchR+ macrophages in the pancreas, while EA counteracted this phenomenon. The anti-inflammatory, pancreatic protective and upregulation of α7nAchR effects of EA were reduced in mice with vagotomy. Moreover, the therapeutic effects of EA were attenuated in mice treated with methyllycaconitine citrate, a selective α7nAChR antagonist. Taken together, EA could modulate inflammation, thereby exerting protective effects in AP. The mechanism may include activating the vagus nerve through the cholinergic anti-inflammatory pathway.
CCDC137 Is a Prognostic Biomarker and Correlates With Immunosuppressive Tumor Microenvironment Based on Pan-Cancer Analysis
Authors: Guo Lihao , Li Boxin , Lu Zhaohong , Liang Hairong , Yang Hui , Chen Yuting , Zhu Shiheng , Zeng Minjuan , Wei Yixian , Liu Tonggong , Jiang Tikeng , Xuan Mei , Tang Huanwen
Published: May 2021

Background

The coiled-coil domain containing (CCDC) family proteins have important biological functions in various diseases. However, the coiled-coil domain containing 137 (CCDC137) was rarely studied. We aim to investigate the role of CCDC137 in pan-cancer.

Methods

CCDC137 expression was evaluated in RNA sequence expression profilers of pan-cancer and normal tissues from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) database. The influence of CCDC137 on the prognosis of tumor patients was analyzed using clinical survival data from TCGA. Function and pathway enrichment analysis was performed to explore the role of CCDC137 using the R package “clusterProfiler.” We further analyzed the correlation of immune cell infiltration score of TCGA samples and CCDC137 expression using TIMER2 online database.

Results

CCDC137 was over-expressed and associated with worse survival status in various tumor types. CCDC137 expression was positively correlated with tumor associated macrophages (TAMs) and cancer associated fibroblasts (CAFs) in Lower Grade Glioma (LGG) and Uveal Melanoma (UVM). In addition, high CCDC137 expression was positively correlated with most immunosuppressive genes, including TGFB1, PD-L1, and IL10RB in LGG and UVM.

Conclusions

Our study identified CCDC137 as an oncogene and predictor of worse survival in most tumor types. High CCDC137 may contribute to elevated infiltration of TAMs and CAFs and be associated with tumor immunosuppressive status.