bluuebunny/crossref_metadata_2025 huggingface dataset:
Imaging Unique DNA Sequences in Individual Cells Using a CRISPR-Cas9-Based, Split Luciferase Biosensor
Authors: Heath Nicholas G. , O’Geen Henriette , Halmai Nicole B. , Corn Jacob E. , Segal David J.
Published: March 2022

An extensive arsenal of biosensing tools has been developed based on the clustered regularly interspaced short palindromic repeat (CRISPR) platform, including those that detect specific DNA sequences both in vitro and in live cells. To date, DNA imaging approaches have traditionally used full fluorescent reporter-based fusion probes. Such “always-on” probes differentiate poorly between bound and unbound probe and are unable to sensitively detect unique copies of a target sequence in individual cells. Herein we describe a DNA biosensor that provides a sensitive readout for such low-copy DNA sequences through proximity-mediated reassembly of two independently optimized fragments of NanoLuc luciferase (NLuc), a small, bright luminescent reporter. Applying this “turn-on” probe in live cells, we demonstrate an application not easily achieved by fluorescent reporter-based probes, detection of individual endogenous genomic loci using standard epifluorescence microscopy. This approach could enable detection of gene edits during ex vivo editing procedures and should be a useful platform for many other live cell DNA biosensing applications.
Integrative Pathway Analysis of SNP and Metabolite Data Using a Hierarchical Structural Component Model
Authors: Jung Taeyeong , Jung Youngae , Moon Min Kyong , Kwon Oran , Hwang Geum-Sook , Park Taesung
Published: March 2022

Integrative multi-omics analysis has become a useful tool to understand molecular mechanisms and drug discovery for treatment. Especially, the couplings of genetics to metabolomics have been performed to identify the associations between SNP and metabolite. However, while the importance of integrative pathway analysis is increasing, there are few approaches to utilize pathway information to analyze phenotypes using SNP and metabolite. We propose an integrative pathway analysis of SNP and metabolite data using a hierarchical structural component model considering the structural relationships of SNPs, metabolites, pathways, and phenotypes. The proposed method utilizes genome-wide association studies on metabolites and constructs the genetic risk scores for metabolites referred to as genetic metabolomic scores. It is based on the hierarchical model using the genetic metabolomic scores and pathways. Furthermore, this method adopts a ridge penalty to consider the correlations between genetic metabolomic scores and between pathways. We apply our method to the SNP and metabolite data from the Korean population to identify pathways associated with type 2 diabetes (T2D). Through this application, we identified well-known pathways associated with T2D, demonstrating that this method adds biological insights into disease-related pathways using genetic predispositions of metabolites.
Tumor Microenvironment-Mediated Immune Profiles Characterized by Distinct Survival Outcome and Immunotherapeutic Efficacy in Breast Cancer
Authors: Xu Lijun , Hu Yaomin , Liu Wenwen
Published: March 2022

Background: Numerous reports have highlighted that the tumor microenvironment (TME) is closely linked to survival outcome and therapeutic efficacy. However, a comprehensive investigation of the TME feature in breast cancer (BC) has not been performed.

Methods: Here, we performed consensus clustering analysis based on TME cell expression profiles to construct TME pattern clusters and TME-related gene signature in BC. GSVA combined with CIBERSORT and ssGSEA algorithms were applied to evaluate the differences in biological pathway and immune cell infiltration level, respectively. The PCA method was employed to construct TME-score to quantify the TME-mediated pattern level in individual BC patients.

Results: We determined two distinct TME gene clusters among 3,738 BC samples, which exhibited distinct survival outcome and enriched biological processes. The TME features demonstrated that these two clusters corresponded to the established immune profiles: hot and cold tumor phenotypes, respectively. Based on TME-related signature genes, we constructed the TME-score and stratified BC patients into low and high TME-score groups. Patients with high TME-score exhibited favorable outcome and increased infiltration of immune cells. Further investigation revealed that high TME-score was also related with high expression of immunosuppressive molecules, decreased tumor mutation burden (TMB), and high rate of mutation in significantly mutated genes (SMGs) (e.g., PIK3CA and CDH1).

Conclusion: Assessing the TME-mediated pattern level of individual BC patients will assist us in better understanding the responses of BC patients to immunotherapies and directing more effective immunotherapeutic approaches.
Monitoring Menstrual Health Knowledge: Awareness of Menstruation at Menarche as an Indicator
Authors: Hennegan Julie , Swe Zay Yar , Than Kyu Kyu , Smith Calum , Sol Lidwien , Alberda Hilda , Bukenya Justine N. , Kibira Simon P. S. , Makumbi Fredrick E. , Schwab Kellogg J. , Azzopardi Peter S.
Published: March 2022

As initiatives to support menstrual health are implemented globally, monitoring progress through a set of comprehensive indicators provides important feedback to direct policies and programs. One proposed core indicator is awareness of menstruation at menarche. That is, at the time of menarche an adolescent girl knowing that menstrual bleeding is something she will experience. In this investigation, we undertook secondary analysis of data collected across four studies to support interpretation of this indicator. We (1) describe the proportion of each sample aware of menstruation at menarche, (2) test variations in awareness according to sociodemographic characteristics, and (3) describe the associations between this indicator and self-reported experience at menarche, social support, and confidence to manage menstruation. Studies included cross-sectional survey data from 421 schoolgirls in Magway, Myanmar, 537 schoolgirls in Soroti, Uganda, 1,359 schoolgirls in Netrokona, Bangladesh, and 599 adult women working in Mukono, Uganda. Awareness of menstruation at menarche varied from 84% in Myanmar to 34% in Bangladesh. Older age at menarche was associated with awareness. Awareness at menarche was not associated with household poverty in the adolescent samples, but greater poverty was associated with lower levels of awareness among adult women. In Myanmar, girls aware of menstruation had significantly higher odds of reporting that they felt prepared (2.85 95% CI 1.34–6.08), happy (OR = 3.81 95% CI 1.74–8.37) and knew what was happening at menarche (OR = 2.37 95% CI 1.34–4.19). However, they also reported higher levels of embarrassment (OR = 1.76 95% CI 1.04–2.97) and did not report significantly less fear (OR = 1.24 95% CI 0.82–1.85). Awareness of menstruation at menarche was associated with higher scores on a menstrual knowledge quiz in both Myanmar (b = 9.51 95% CI 3.99–15.04) and Bangladesh (b = 4.78 95% CI 1.70–7.87). In these studies girls aware of menstruation at menarche also had higher odds of reporting they felt confident discussing menstruation with support sources and managing menstruation at school, while these differences were not significant among schoolgirls in Uganda. Findings support the usefulness of awareness of menstruation at menarche as an indicator to describe minimal knowledge of menstruation and suggest that awareness may signal greater knowledge, social support, and confidence in some settings.
Preclinical Studies on Convalescent Human Immune Plasma-Derived Exosome: Omics and Antiviral Properties to SARS-CoV-2
Authors: Taşlı Neslihan Pakize , Gönen Zeynep Burçin , Kırbaş Oğuz Kaan , Gökdemir Nur Seda , Bozkurt Batuhan Turhan , Bayrakcı Buse , Sağraç Derya , Taşkan Ezgi , Demir Sevda , Ekimci Gürcan Nur , Bayındır Bilgiç Melike , Bayrak Ömer Faruk , Yetişkin Hazel , Kaplan Büşra , Pavel Shaikh Terkıs Islam , Dinç Gökçen , Serhatlı Müge , Çakırca Gamze , Eken Ahmet , Aslan Vedat , Yay Mehmet , Karakukcu Musa , Unal Ekrem , Gül Fethi , Basaran Kemal Erdem , Ozkul Yusuf , Şahin Fikrettin , Jones Olcay Y. , Tekin Şaban , Özdarendeli Aykut , Cetin Mustafa
Published: March 2022

The scale of the COVID-19 pandemic forced urgent measures for the development of new therapeutics. One of these strategies is the use of convalescent plasma (CP) as a conventional source for passive immunity. Recently, there has been interest in CP-derived exosomes. In this report, we present a structural, biochemical, and biological characterization of our proprietary product, convalescent human immune plasma-derived exosome (ChipEXO), following the guidelines set forth by the Turkish Ministry of Health and the Turkish Red Crescent, the Good Manufacturing Practice, the International Society for Extracellular Vesicles, and the Gene Ontology Consortium. The data support the safety and efficacy of this product against SARS-CoV-2 infections in preclinical models.
Update for Advance CAR-T Therapy in Solid Tumors, Clinical Application in Peritoneal Carcinomatosis From Colorectal Cancer and Future Prospects
Authors: Qian Siyuan , Villarejo-Campos Pedro , Guijo Ismael , Hernández-Villafranca Sergio , García-Olmo Damián , González-Soares Sara , Guadalajara Héctor , Jiménez-Galanes Santos , Qian Cheng
Published: March 2022

Latest advances in the field of cancer immunotherapy have developed the (Chimeric Antigen Receptor) CAR-T cell therapy. This therapy was first used in hematological malignancies which obtained promising results; therefore, the use of CAR-T cells has become a popular approach for treating non-solid tumors. CAR-T cells consist of T-lymphocytes that are engineered to express an artificial receptor against any surface antigen of our choice giving us the capacity of offering precise and personalized treatment. This leaded to the development of CAR-T cells for treating solid tumors with the hope of obtaining the same result; however, their use in solid tumor and their efficacy have not achieved the expected results. The reason of these results is because solid tumors have some peculiarities that are not present in hematological malignancies. In this review we explain how CAR-T cells are made, their mechanism of action, adverse effect and how solid tumors can evade their action, and also we summarize their use in colorectal cancer and peritoneal carcinomatosis.
Association Between Endophthalmitis and the Incidence of Acute Coronary Syndrome in Patients With Ankylosing Spondylitis: A Nationwide, Population-Based Cohort Study
Authors: Lin Ting-Yi , Lai Yi-Fen , Chien Wu-Chien , Chen Yi-Hao , Sun Chien-An , Chung Chi-Hsiang , Chen Jiann-Torng , Chen Ching-Long
Published: March 2022

Purpose

Ankylosing spondylitis (AS) is a risk factor for acute coronary syndrome (ACS). However, the influence of infectious insults, such as endophthalmitis, on the risk of ACS among AS patients has not been studied yet. In this study, we aimed to investigate the relationship between endophthalmitis in patients with AS and the incidence of ACS.

Methods

This retrospective cohort study extracted medical records from the Taiwan Longitudinal Health Insurance Database (LHID) from January 1, 2000, to December 31, 2015. The primary outcome was the incidence of ACS. Univariate and multivariate Cox regression analyses with and without Fine and Gray’s competing risk model and Kaplan–Meier survival curve were used for the analyses. Spearman’s rank correlation coefficient was performed for sensitivity analysis.

Results

We identified 530 AS patients with endophthalmitis and 2,120 AS patients without endophthalmitis for comparison. The incidence rate of endophthalmitis in our study population was 2.66%. The overall incidence rate of ACS was 1,595.96 per 100,000 person-years in AS patients with endophthalmitis and 953.96 per 100,000 person-years in AS patients without endophthalmitis (adjusted HR = 1.787; 95% CI: 1.594–2.104, p < 0.001). In comparison to those without comorbidities, higher adjusted HRs were found in AS patients with endophthalmitis and comorbidities such as diabetes mellitus, hyperlipidemia, hypertension, cerebrovascular accident, congestive heart failure, chronic obstructive pulmonary disease, asthma, and coronary artery disease. Besides, the age ≥ 60 years revealed a high risk for ACS in AS patients with endophthalmitis.

Conclusion

Endophthalmitis was found to be an independent risk factor for ACS in patients with AS. Further clinical studies are required to elucidate the underlying mechanisms and status of systemic inflammation during endophthalmitis.
Investigating the Anti-Inflammatory Effects of RCI001 for Treating Ocular Surface Diseases: Insight Into the Mechanism of Action
Authors: Kim Seunghoon , Jang Ye Won , Ku Young-ah , Shin Yungyeong , Rahman Md Mahbubur , Chung Myung-Hee , Kim Yong Ho , Kim Dong Hyun
Published: March 2022

The ocular surface is continuously exposed to various environmental factors, and innate and adaptive immunity play crucial roles in ocular surface diseases (OSDs). Previously, we have reported that the topical application of RCI001 affords excellent anti-inflammatory and antioxidant effects in dry eye disease and ocular chemical burn models. In this study, we examined the inhibitory effects of RCI001 on the Rac1 and NLRP3 inflammasomes in vitro and in vivo. Following RCI001 application to RAW264.7 and Swiss 3T3 cells, we measured Rac1 activity using a glutathione-S-transferase (GST) pull-down assay and G-protein activation assay kit. In addition, we quantified the expression of inflammatory cytokines (interleukin [IL]-1β, IL-6, and tumor necrosis factor [TNF]-α) in lipopolysaccharide (LPS)-stimulated RAW264.7 cells using ELISA and real-time PCR. In the mouse ocular alkali burn model, RCI001 was administered via eye drops (10 mg/mL, twice daily) for 5 days, and 1% prednisolone acetate (PDE) ophthalmic suspension was used as a positive control. Corneal epithelial integrity (on days 0-5) and histological examinations were performed, and transcript and protein levels of Rac1, NLRP3, caspase-1, and IL-1β were quantified using real-time PCR and western blotting in corneal tissues collected on days 3 and 5. We observed that RCI001 dose-dependently inhibited Rac1 activity and various inflammatory cytokines in LPS-stimulated murine macrophages. Furthermore, RCI001 restored corneal epithelial integrity more rapidly than corticosteroid treatment in chemically injured corneas. Compared to the saline group, activation of Rac1 and the NLRP3 inflammasome/IL-1β axis was suppressed in the RCI001 group, especially during the early phase of the ocular alkali burn model. Topical RCI001 suppressed the expression of activated Rac1 and inflammatory cytokines in vitro and rapidly restored the injured cornea by inhibiting activation of Rac1 and the NLRP inflammasome/IL-1β axis in vivo. Accordingly, RCI001 could be a promising therapeutic agent for treating OSDs.
PLX5622 Reduces Disease Severity in Lethal CNS Infection by Off-Target Inhibition of Peripheral Inflammatory Monocyte Production
Authors: Spiteri Alanna G. , Ni Duan , Ling Zheng Lung , Macia Laurence , Campbell Iain L. , Hofer Markus J. , King Nicholas J. C.
Published: March 2022

PLX5622 is a CSF-1R inhibitor and microglia-depleting reagent, widely used to investigate the biology of this central nervous system (CNS)-resident myeloid population, but the indirect or off-target effects of this agent remain largely unexplored. In a murine model of severe neuroinflammation induced by West Nile virus encephalitis (WNE), we showed PLX5622 efficiently depleted both microglia and a sub-population of border-associated macrophages in the CNS. However, PLX5622 also significantly depleted mature Ly6Chi monocytes in the bone marrow (BM), inhibiting their proliferation and lethal recruitment into the infected brain, reducing neuroinflammation and clinical disease scores. Notably, in addition, BM dendritic cell subsets, plasmacytoid DC and classical DC, were depleted differentially in infected and uninfected mice. Confirming its protective effect in WNE, cessation of PLX5622 treatment exacerbated disease scores and was associated with robust repopulation of microglia, rebound BM monopoiesis and markedly increased inflammatory monocyte infiltration into the CNS. Monoclonal anti-CSF-1R antibody blockade late in WNE also impeded BM monocyte proliferation and recruitment to the brain, suggesting that the protective effect of PLX5622 is via the inhibition of CSF-1R, rather than other kinase targets. Importantly, BrdU incorporation in PLX5622-treated mice, suggest remaining microglia proliferate independently of CSF-1 in WNE. Our study uncovers significantly broader effects of PLX5622 on the myeloid lineage beyond microglia depletion, advising caution in the interpretation of PLX5622 data as microglia-specific. However, this work also strikingly demonstrates the unexpected therapeutic potential of this molecule in CNS viral infection, as well as other monocyte-mediated diseases.
BET Protein Inhibition Regulates Macrophage Chromatin Accessibility and Microbiota-Dependent Colitis
Authors: Hoffner O’Connor Michelle , Berglind Ana , Kennedy Ng Meaghan M. , Keith Benjamin P. , Lynch Zachary J. , Schaner Matthew R. , Steinbach Erin C. , Herzog Jeremy , Trad Omar K. , Jeck William R. , Arthur Janelle C. , Simon Jeremy M. , Sartor R. Balfour , Furey Terrence S. , Sheikh Shehzad Z.
Published: March 2022

Introduction

In colitis, macrophage functionality is altered compared to normal homeostatic conditions. Loss of IL-10 signaling results in an inappropriate chronic inflammatory response to bacterial stimulation. It remains unknown if inhibition of bromodomain and extra-terminal domain (BET) proteins alters usage of DNA regulatory elements responsible for driving inflammatory gene expression. We determined if the BET inhibitor, (+)-JQ1, could suppress inflammatory activation of macrophages in Il10-/- mice.

Methods

We performed ATAC-seq and RNA-seq on Il10-/- bone marrow-derived macrophages (BMDMs) cultured in the presence and absence of lipopolysaccharide (LPS) with and without treatment with (+)-JQ1 and evaluated changes in chromatin accessibility and gene expression. Germ-free Il10-/- mice were treated with (+)-JQ1, colonized with fecal slurries and underwent histological and molecular evaluation 14-days post colonization.

Results

Treatment with (+)-JQ1 suppressed LPS-induced changes in chromatin at distal regulatory elements associated with inflammatory genes, particularly in regions that contain motifs for AP-1 and IRF transcription factors. This resulted in attenuation of inflammatory gene expression. Treatment with (+)-JQ1 in vivo resulted in a mild reduction in colitis severity as compared with vehicle-treated mice.

Conclusion

We identified the mechanism of action associated with a new class of compounds that may mitigate aberrant macrophage responses to bacteria in colitis.
A Detoxification Enzyme for Apis mellifera Newly Characterized by Recombinant Expression: 10-Formyl Tetrahydrofolate Dehydrogenase
Authors: Mating Moritz , Sharbati Soroush , Einspanier Ralf
Published: March 2022

Honeybees are important managed pollinators that perform important ecological and economic functions. In recent decades, the obligate ectoparasite Varroa destructor severely affected survival of honeybees as it either feeds on hemolymph and fat bodies or acts as a vector for viruses. A common treatment against the varroa mite is formic acid, which has been used for many years by beekeepers. This treatment is known to be effective, but the therapeutic index is very narrow. Many beekeepers report negative effects of formic acid on bees, which include damage to brood, worker bee mortality, and queen loss. Little is yet known about the molecular mechanisms of formic acid detoxification in honeybees. Our previous study shows the upregulation of predicted 10-formyl tetrahydrofolate dehydrogenase (10-FTHFDH) transcripts in honeybees exposed to formic acid. Here, the predicted honeybee-specific 10-FTHFDH is recombinantly expressed, and its hydrolase and dehydrogenase activities are investigated. As a result, the enzyme shows similar dehydrogenase activity in comparison to known 10-FTHFDHs. This study provides further knowledge to better understand the detoxification mechanisms of formic acid in Apis mellifera.
Phytoplankton Response to Different Light Colors and Fluctuation Frequencies
Authors: Neun Sebastian , Hintz Nils Hendrik , Schröder Matthias , Striebel Maren
Published: March 2022

The natural environment of phytoplankton is variable in manifold ways. Light, as essential resource for photosynthetic phytoplankton, fluctuates in its intensity (quantity) as well as spectrum (quality) over great temporal scales in aquatic ecosystems. To elucidate the significance of temporal heterogeneity in available light spectrum for phytoplankton, we analyzed the growth of four marine North Sea species (chlorophyte Tetraselmis sp., cryptophyte Rhodomonas salina, cyanobacteria Pseudanabaena sp., raphidophyte Fibrocapsa japonica), in monoculture as well as the dynamics of these species in pairwise competition experiments under blue and green light. These species were chosen as they differ in their absorption of light, the colors were chosen to contrast the absorption by chlorophylls (blue), carotenoids (partially green) and phycobiliproteins (green). Light colors were either supplied constantly or along a gradient of fluctuation frequencies (hourly to weekly alternation) between blue and green but always with the same photon flux density. When constantly supplied (no change in color), the color of light led to significant differences in growth rates and carrying capacities of the species, with Pseudanabaena sp. being the only one profiting from green light. Under alternating light color, the maximum growth rate of R. salina was higher with faster light color fluctuations, but lower for Pseudanabaena sp. and did not show significant trends for F. japonica and Tetraselmis sp. Accordingly, competition was significantly affected by the light color treatments, under constant as well as fluctuating supply conditions. However, we did not detect considerable changes in competitive outcomes between fluctuating light colors vs. constant light color supply. As the underwater light in natural ecosystems is rather variable than constant, our results of fluctuations within the light spectrum highlight their frequency-dependent effects on growth and competition. While fluctuating light colors affect the growth and capacity of species, our tested fluctuations did not have major effects on species competition.
Biofouling Role in Mariculture Environment Restoration: An Example in the Mar Grande of Taranto (Mediterranean Sea)
Authors: Arduini Daniele , Borghese Jacopo , Gravina Maria Flavia , Trani Roberta , Longo Caterina , Pierri Cataldo , Giangrande Adriana
Published: March 2022

The biodiversity of macrobenthic invertebrates of two artificial hard substrates close to a mariculture plant was assessed in order to understand the effect on the fouling community of an innovative Integrated Multi-Trophic Aquaculture (IMTA) system. The examined hard substrates were (i) vertical bare collectors that are placed around the cages as new colonizable substrates, which were investigated from the early colonization and (ii) artificial hard substrates already present under the cages analyzed over time to observe changes due to the action on the water column by filter feeder organisms colonizing the above vertical collectors. Overall, 186 taxa were collected (both the substrates), of which 99 as sessile habitat-former or structuring macroinvertebrates and 87 as associated fauna, mostly vagile forms. On the vertical collectors 121 taxa were collected, among which 44 sessile structuring species and 77 vagile-associated taxa; on the artificial hard substrates under the cages, 124 taxa were identified, 95 belong to the first category and 29 as associated taxa. The two analyzed substrates shared 43% of sessile species (40) and 22% of associated species (19). At the end of the first year of experimentation, the study revealed Sabella spallanzanii and mussels as the most abundant taxa. Lastly, the communities under the cages showed an increase in biodiversity after the placement of collectors. The changes were attributed to the decrease in particulate matter originating as wastes from the breeding cage, which was intercepted by the filter feeder community developed on the vertical collectors.
Distribution of Benthic Foraminifera in Intertidal Sabkha of Al-Kharrar Lagoon, Saudi Arabia: Tools to Study Past Sea-Level Changes
Authors: Al-Dubai Talha A. , Bantan Rashad A. , Abu-Zied Ramadan H. , Al-Zubieri Aaid G. , Jones Brian G.
Published: March 2022

Contemporary foraminiferal sediment samples were collected from the intertidal sabkha of Al-Kharrar Lagoon, Saudi Arabia, to study the vertical distribution of foraminifers and, based on a modern training set, their potential to develop a predictor of former sea-level changes in the area. Based on hierarchical cluster analysis, the intertidal sabkha is divided into three vertical zones (A, B, and C) represented by three foraminiferal assemblages, where agglutinated species occupied Zone A and calcareous species occupied the other two zones. In Zone A (high intertidal), Agglutinella compressa, Clavulina angularis and C. multicamerata are dominant species with a minor presence of Peneroplis planatus, Coscinospira hemprichii, Sorites orbiculus, Quinqueloculina lamarckiana, Q. seminula, Ammonia convexa and A. tepida. In contrast, in Zone B (middle intertidal) the most abundant species are P. planatus, C. hemprichii, S. orbiculus, Q. lamarckiana, Q. seminula and Q. laevigata, while Zone C (low intertidal) is characterized by C. hemprichii, Q. costata, S. orbiculus, P. planatus, A. convexa, A. tepida, Spiroloculina communis, and S. costigera. A transfer function for sea-level reconstruction was developed using a modern dataset of 75 contemporary sediment samples and 99 species collected from several transects across the sabkha. The model provided an error of 0.12 m, suggesting that intertidal foraminifers can be used to assess past sea-level changes with high precision in Al-Kharrar Lagoon, and adjacent regions.
Unification and Coordination of Maritime Jurisdiction: Providing a Judicial Guarantee for International Trade and Marine Transport
Authors: Fu Ben-Chao
Published: March 2022

Maritime jurisdiction plays an important role in international trade and marine transport. It involves special kinds of rules that vary among different countries and legal systems. Thus, in international maritime jurisdiction, the coordination and settlements of jurisdictional conflicts are vital for the uniformity of international maritime law. This study provides a comparative analysis of maritime jurisdiction in international trade and marine transport. First, it introduces the concept, category, and legal characteristics of maritime jurisdiction based on historical sources. Then, we conduct a comparative analysis of the civil law system, common law system, international conventions, and Chinese maritime jurisdiction provisions, focusing on their differences and the existing legal problems. Among other suggestions for the improvement of the rules of maritime jurisdiction, this study proposes the unification and coordination of maritime jurisdiction, which could impact international trade and marine transport.
Functional Characterization of Cfap206 for Bivalve Ciliogenesis by RNAi and CRISPR/Cas9 Technologies
Authors: Wang Yinghui , Zhu Xiaomei , Lian Shanshan , Li Yiran , Hu Naina , Hu Xiaoli , Bao Zhenmin , Wang Shi
Published: March 2022

Cilia are organelles located on the surface of eukaryotic cells and play important roles in numerous physiological and developmental processes. Cilia- and flagella-associated proteins (CFAP family) are well known due to their close relation to the assembly and functionalization of both cilia and flagella. In vertebrates, Cfap206 is reported to function during motile cilia assembly, and its abolished expression could lead to abnormal ciliary beating and decreased sperm motility. However, there is scarcely any information on the function of Cfap206 in marine invertebrates. Here, through using an ideal shellfish research model, the dwarf surf calm Mulinia lateralis, we explored the role of Cfap206 during embryonic ciliogenesis as well as during male gametogenesis. In trochophore larvae, effective knocking down or knocking out of Cfap206 was detected respectively through RNAi and CRISPR/Cas9 technology, showing an obviously decreased number of cilia. During the period of gonadal maturation, we managed to deliver the dsRNA of Cfap206 to male individuals for 14 days through carrier vector feeding. Significant suppression of Cfap206 was observed, together with impaired sperm motility and aberrant sperm tail assembly. The present study provided valuable information on gene function exploration methods in M. lateralis and further enriched the understanding of Cfap206 on ciliogenesis in marine invertebrates. Furthermore, by revealing the relationship between Cfap206 and spermatozoa flagellum, it is possible to generate male sterile populations in hermaphroditic marine organisms to improve crossbreeding efficiency.
In-Situ Study of Microstructure Evolution of Spinodal Decomposition in an Al-Rich High-Entropy Alloy
Authors: Jorgensen Cameron S. , Santodonato Louis J. , Littrell Kenneth C. , Kuo Chih Hsiang , Lee Chanho , Unocic Raymond R. , Liaw Peter K. , Gilbert Dustin A. , DeBeer-Schmitt Lisa M.
Published: March 2022

High-entropy alloys (HEAs) are materials which leverage the entropy of mixing to motivate the formation of single-phase solid solutions, even of immiscible elements. While these materials are well-recognized for their application to structural engineering, there is increasing interest in the use of HEAs for functional applications such as memory storage and energy devices. The current work investigates the HEA Al1.3CoCrCuFeNi, which has been previously shown to be single-phase at high temperatures, but undergoes phase separation at lower temperatures, transforming the structural and the functional properties. This phase separation is investigated at high temperatures with in-situ small angle neutron scattering (SANS) and scanning transmission electron microscopy (EDS). These techniques show that increasing the temperature up to 800°C, the microstructure of the HEA adiabatically disorders and abruptly homogenizes near 700°C, which is consistent with spinodal decomposition. Overall, the microstructural evolution proceeds mainly by the atomistic redistribution of the constituent elements within simple crystal lattices, producing coherent phase mixtures.
Temperature-Dependence Corrosion Behavior of Ti6Al4V in the Presence of HCl
Authors: Yu Fei , Addison Owen , Davenport Alison
Published: March 2022

Ti alloys have been widely used in biomedical field due to good compatibility and corrosion resistance. However, corrosion-related failures of implanted Ti devices and prostheses have been regularly reported within the medical literature. The corrosion of Ti alloys has attracted much attention in vivo and in vitro. In the current study, the corrosion behavior of Ti6Al4V alloy was investigated using surface analysis and electrochemical tests. Corrosion of Ti6Al4V in 2 M hydrochloric acid is temperature dependent within the temperature range studied. It has found that the steady state current density at −510 mV vs. SCE (the primary passivation potential at the physiological temperature of 37°C) becomes higher with increasing temperature. The α phase of Ti6Al4V is preferentially dissolved relative to the β phase after potentiostatic measurement at primary passivation potential in 2 M HCl at 37°C. This investigation provides novel and useful information for Ti corrosion-related failures of biomedical implants and prostheses.
Longevity of Humoral Response Six Months Following BNT162b2 Vaccine in Dialysis Patients
Authors: Agur Timna , Ben-Dor Naomi , Herman-Edelstein Michal , Steinmetz Tali , Lichtenberg Shelly , Schneider Shira , Yahav Dafna , Rozen-Zvi Benaya , Zingerman Boris
Published: March 2022

Background

End-stage kidney disease substantially increases the risk of severe COVID-19. However, despite early robust immunogenicity of the mRNA-SARS-CoV-2 vaccination in patients with hemodialysis, the longevity of humoral response in this high-risk population is still unknown.

Methods

A prospective cohort study aimed to evaluate the longevity of serologic response in patients with hemodialysis, compared with a control group, 6 months following the second dose of the BNT162b2 vaccine. We assessed antibody response by quantitative measurement of IgG antibodies against the receptor-binding domain of the Spike protein (anti-S1-RBD IgG). Study outcomes were defined as a seropositivity rate and log-transformed anti-S1-RBD IgG levels at 6 months, and the change in antibody levels between 3 and 6 months.

Findings

The cohort included 104 patients with hemodialysis and 84 controls. At a median time of 184 days (IQR, 183–188) following the second dose of the vaccine, 83/104 (79.8%) patients with hemodialysis maintained seropositivity for the anti-S1-RBD IgG level compared to 83/84 (98.8%) in the control group (p < 0.001). The log-transformed antibody level was significantly lower in the hemodialysis group (2.23 ± 0.39 log AU/ml vs. 2.69 ± 0.65 log AU/ml, respectively, p < 0.001). Older age and hypoalbuminemia were the only variables that were found to be associated with reduced log-transformed antibody levels in univariate and multivariate analysis. There was no interaction between dialysis status and an antibody-level decline rate (p = 0.972).

Conclusion

Among patients with hemodialysis, a seropositivity rate and anti-S1-RBD antibody titers were substantially reduced compared with a control group, at 6 months following the second dose of the BNT162b2 vaccine. These findings support the prioritization of patients with hemodialysis for a third “booster” dose.
Transformed Health Ecosystems—Challenges for Security, Privacy, and Trust
Authors: Ruotsalainen Pekka , Blobel Bernd
Published: March 2022

A transformed health ecosystem is a multi-stakeholder coalition that collects, stores, and shares personal health information (PHI) for different purposes, such as for personalized care, prevention, health prediction, precise medicine, personal health management, and public health purposes. Those services are data driven, and a lot of PHI is needed not only from received care and treatments, but also from a person’s normal life. Collecting, processing, storing, and sharing of the huge amount of sensitive PHI in the ecosystem cause many security, privacy, and trust challenges to be solved. The authors have studied those challenges from different perspectives using existing literature and found that current security and privacy solutions are insufficient, and for the user it is difficult to know whom to trust, and how much. Furthermore, in today’s widely used privacy approaches, such as privacy as choice or control and belief or perception based trust does not work in digital health ecosystems. The authors state that it is necessary to redefine the way privacy and trust are understood in health, to develop new legislation to support new privacy and approaches, and to force the stakeholders of the health ecosystem to make their privacy and trust practices and features of their information systems available. The authors have also studied some candidate solutions for security, privacy, and trust to be used in future health ecosystems.
Spontaneous Spinal Epidural Hematoma Complicated by Pulmonary Embolism During Pregnancy: A Case Report
Authors: Jiang Wei , Tan Xuan-Yu , Li Jia-Ai , Dong Ming
Published: March 2022

Background

Spontaneous spinal epidural hematoma, without discernable underlying conditions, is considered a neurological emergency, and is rare during pregnancy.

Case Presentation

We report the case of a 24-year-old patient at 37 weeks of gestation. She had back pain that progressed to paraplegia of both lower limbs within 2 days. Thoracic magnetic resonance imaging revealed a lesion behind the spinal cord at the T5–T6 level, suggestive of spontaneous spinal epidural hematoma. Due to the rapid recovery of muscle strength in her lower limbs after an emergency cesarean section, we used methylprednisolone therapy to reduce spinal edema rather than decompression of the spinal canal. We incidentally found that the patient’s left pulmonary artery was occluded. In consideration of spontaneous spinal epidural hematoma as relative contraindication to anticoagulation, and in the absence of pulmonary embolism symptoms, including good partial oxygen pressure, we did not administer anticoagulant therapy. The patient’s condition improved rapidly in the following week.

Conclusion

Spontaneous spinal epidural hematoma concomitant with pulmonary artery embolism is an extremely rare manifestation during pregnancy. As exemplified by our case, desirable treatment outcomes are possible under such cases.
A Novel Mutation in the Membrane Frizzled-Related Protein Gene for Posterior Microphthalmia, Non-pigmented Retinitis Pigmentosa, Optic Nerve Drusen, and Retinoschisis in a Consanguineous Family
Authors: Ren Xiang , Gao Yunxia , Lin Yu , Fu Xiangyu , Xiao Lirong , Wang Xiaoyue , Zeng Zhibing , Bao Li , Yan Naihong , Zhang Ming , Tang Li
Published: March 2022

Background

Microphthalmos (MCO) is a rare developmental defect characterized by small malformed eyes. Our study aimed to describe the clinical characteristics of posterior microphthalmos syndrome caused by a novel variant in MFRP gene in a Chinese patient.

Methods

Complete ophthalmologic examinations were performed for the proband and proband's family members. Whole exon sequencing (WES) and Sanger sequencing were used to identify the mutated genes, and bioinformatic analysis was undertaken to predict the effect of this variant.

Results

Clinical analysis showed that the proband had reduced axial length (17.95 and 17.98 mm) with normal-size corneas and shallow anterior chamber depth. Fundus photography showed scattered yellowish-white spots in the whole retina with cup-to-disc ratios of 0.95 in both eyes. Retinoschisis in the inner nuclear layer and reduced outer retina thickness were apparent on OCT examination, and optic nerve drusen demonstrated increased autofluorescence in fundus autofluorescence (FAF). Perimeter examination revealed a tubular visual field for the right eye, and electroretinography (ERG) revealed a moderately reduced rod response combined with compromised cone response. Ocular examinations of the patient's family members were unremarkable. WES revealed that the proband had homozygous mutations in c.55-1 (IVS1) G>A in intron 1 for the MFRP gene. Both the proband's parents and offspring were confirmed to be heterozygous by Sanger sequencing. Bioinformatic analysis showed this mutation was deleterious.

Conclusion

We reported autosomal recessive posterior microphthalmia, atypical retinitis pigmentosa, and retinoschisis caused by a novel mutation in the MFRP gene in this consanguineous marriage family. Our study further broadens the mutation and phenotype spectrum of the MFRP gene in microphthalmia.
A Study Protocol for Validation and Implementation of Whole-Genome and -Transcriptome Sequencing as a Comprehensive Precision Diagnostic Test in Acute Leukemias
Authors: Berglund Eva , Barbany Gisela , Orsmark-Pietras Christina , Fogelstrand Linda , Abrahamsson Jonas , Golovleva Irina , Hallböök Helene , Höglund Martin , Lazarevic Vladimir , Levin Lars-Åke , Nordlund Jessica , Norèn-Nyström Ulrika , Palle Josefine , Thangavelu Tharshini , Palmqvist Lars , Wirta Valtteri , Cavelier Lucia , Fioretos Thoas , Rosenquist Richard
Published: March 2022

Background

Whole-genome sequencing (WGS) and whole-transcriptome sequencing (WTS), with the ability to provide comprehensive genomic information, have become the focal point of research interest as novel techniques that can support precision diagnostics in routine clinical care of patients with various cancer types, including hematological malignancies. This national multi-center study, led by Genomic Medicine Sweden, aims to evaluate whether combined application of WGS and WTS (WGTS) is technically feasible and can be implemented as an efficient diagnostic tool in patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). In addition to clinical impact assessment, a health-economic evaluation of such strategy will be performed.

Methods and Analysis

The study comprises four phases (i.e., retrospective, prospective, real-time validation, and follow-up) including approximately 700 adult and pediatric Swedish AML and ALL patients. Results of WGS for tumor (90×) and normal/germline (30×) samples as well as WTS for tumors only will be compared to current standard of care diagnostics. Primary study endpoints are diagnostic efficiency and improved diagnostic yield. Secondary endpoints are technical and clinical feasibility for routine implementation, clinical utility, and health-economic impact.

Discussion

Data from this national multi-center study will be used to evaluate clinical performance of the integrated WGTS diagnostic workflow compared with standard of care. The study will also elucidate clinical and health-economic impacts of a combined WGTS strategy when implemented in routine clinical care.

Clinical Trial Registration

[https://doi.org/10.1186/ISRCTN66987142], identifier [ISRCTN66987142].
The Influence of Prior Statin Use on the Prevalence and Exacerbation of Chronic Obstructive Pulmonary Disease in an Adult Population
Authors: Kim Joo-Hee , Choi Hyo Geun , Kwon Mi Jung , Kim Ji Hee , Park Ji-Young , Hwang Yong Il , Jang Seung Hun , Jung Ki-Suck
Published: March 2022

Background

Statins have anti-inflammatory and antioxidant properties, and previous studies have reported the positive effects of statins on chronic obstructive pulmonary disease (COPD) outcomes. However, the effects of statins on the development and acute exacerbations of COPD remain unclear. Therefore, this study aimed to assess the relation between statin use and COPD occurrence in all participants and the link between statin use and COPD acute exacerbations in participants with COPD.

Methods

This case-control study comprised 26,875 COPD participants and 107,500 control participants who were 1:4 matched from the Korean National Health Insurance Service-Health Screening Cohort. Conditional logistic regression was used to evaluate the probability of COPD occurrence associated with previous statin use. In addition, unconditional logistic regression was employed to assess the risk of exacerbations related to statin use among COPD participants. These relations were estimated in subgroup analysis according to statin type (lipophilic vs. hydrophilic).

Results

The association between previous statin use and the occurrence of COPD did not reach statistical significance in the overall population (adjusted odds ratio [aOR] = 0.96, 95% confidence interval [CI] = 0.93–1.00, P = 0.059). However, statin use decreased the probability of exacerbations in participants with COPD (aOR = 0.79, 95% CI = 0.74–0.85, P < 0.001). Lipophilic statins decreased the probability of exacerbations, whereas hydrophilic statins were not associated with a decreased likelihood of exacerbations (aOR = 0.78, 95% CI = 0.72–0.84, P < 0.001 for lipophilic statins; aOR = 0.89, 95% CI = 0.78–1.02, P = 0.102 for hydrophilic statins).

Discussion

Statin use was not associated with the occurrence of COPD in the adult population. However, statin use was associated with a reduced probability of exacerbations in participants with COPD, with a greater risk reduction with lipophilic statin use.
Clinical Utility of SCALE-B to Predict Hepatitis B Virus Relapse, Hepatitis B Surface Antigen Loss After Antiviral Cessation in Asian Patients After 2-Year Follow-up
Authors: Kaewdech Apichat , Assawasuwannakit Suraphon , Sripongpun Pimsiri , Chamroonkul Naichaya , Tangkijvanich Pisit , Piratvisuth Teerha
Published: March 2022

Background

Discontinuation of antiviral therapy in chronic hepatitis B (CHB) patients leads to a higher hepatitis B surface antigen (HBsAg) loss; yet, clinical relapse (CR) may occur. SCALE-B score was developed to predict off-treatment CR; however, validation of SCALE-B beyond a 48-week follow-up is rare. We studied whether SCALE-B and hepatitis B virus ribonucleic acid (HBV RNA) could predict outcomes in CHB patients after a 2-year follow-up.

Methods

A total of 92 Thai CHB patients who stopped antiviral treatment were followed up; baseline characteristics, quantitative hepatitis B surface antigen (qHBsAg), hepatitis B core-related antigen (HBcrAg), and HBV RNA were collected at the time of discontinuation, and SCALE-B scores were calculated. Patients were followed up every 12 weeks for 48 weeks, and then, the intervals were upon primary doctors. Follow-up data regarding virological relapse (VR), CR, and HBsAg loss were obtained.

Results

The median follow-up duration was 142 weeks; the cumulative incidences of VR, CR, and HBsAg loss were 65.2, 33.7, and 7.6%, respectively. After 48 weeks, VR and CR plateaued, but HBsAg loss increased from 2.2 to 7.6%. According to the SCALE-B strata, VR, CR, and HBsAg loss were significantly different. The highest stratum (≥ 320) was associated with higher VR, CR, and lesser HBsAg loss when compared to the lowest stratum, with adjusted hazard ratios of 5.0 (95% CIs: 1.8–14.4), 10.44 (95% CIs: 1.4–79.1), and 0.04 (95% CIs: 0.004–0.43), respectively.

Conclusion

At a median follow-up of 2.5 years after discontinuing therapy, HBsAg loss in Thai patients was found to increase over time. SCALE-B is a valuable tool for predicting CR, VR, and HBsAg loss; HBV RNA is not significantly associated with long-term outcomes.

Clinical Trial Registration

[www.ClinicalTrials.gov], identifier [TCTR20180316007].
Organic Phosphorus Scavenging Supports Efficient Growth of Diazotrophic Cyanobacteria Under Phosphate Depletion
Authors: Rabouille Sophie , Tournier Lauralie , Duhamel Solange , Claquin Pascal , Crispi Olivier , Talec Amélie , Landolfi Angela , Oschlies Andreas
Published: March 2022

Considering the reported significant diazotrophic activities in open-ocean regions where primary production is strongly limited by phosphate, we explored the ability of diazotrophs to use other sources of phosphorus to alleviate the phosphate depletion. We tested the actual efficiency of the open-ocean, N2-fixer Crocosphaera watsonii to grow on organic phosphorus as the sole P source, and observed how the P source affects the cellular C, N, and P composition. We obtained equivalent growth efficiencies on AMP and DL-α-glycerophosphate as compared with identical cultures grown on phosphate, and survival of the population on phytic acid. Our results show that Crocosphaera cannot use all phosphomonoesters with the same efficiency, but it can grow without phosphate, provided that usable DOP and sufficient light energy are available. Also, results point out that organic phosphorus uptake is not proportional to alkaline phosphatase activity, demonstrating that the latter is not a suitable proxy to estimate DOP-based growth yields of organisms, whether in culture experiments or in the natural environment. The growth parameters obtained, as a function of the P source, will be critical to improve and calibrate mathematical models of diazotrophic growth and the distribution of nitrogen fixation in the global ocean.