bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Implications of Combinatorial Pharmacogenomic Tests Based on Cytochrome P450 Variant Selection
Authors: Sayer Michael , Duche Ashley , Nguyen Trang Jenny Tran , Le Michelle , Patel Kunj , Vu Jacqueline , Pham Danny , Vernick Brianne , Beuttler Richard , Roosan Don , Roosan Moom R.
Published: September 2021

Despite the potential to improve patient outcomes, the application of pharmacogenomics (PGx) is yet to be routine. A growing number of PGx implementers are leaning toward using combinatorial PGx (CPGx) tests (i.e., multigene tests) that are reusable over patients’ lifetimes. However, selecting a single best available CPGx test is challenging owing to many patient- and population-specific factors, including variant frequency differences across ethnic groups. The primary objective of this study was to evaluate the detection rate of currently available CPGx tests based on the cytochrome P450 (CYP) gene variants they target. The detection rate was defined as the percentage of a given population with an “altered metabolizer” genotype predicted phenotype, where a CPGx test targeted both gene variants a prospective diplotypes. A potential genotype predicted phenotype was considered an altered metabolizer when it resulted in medication therapy modification based on Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. Targeted variant CPGx tests found in the Genetic Testing Registry (GTR), gene selection information, and diplotype frequency data from the Pharmacogenomics Knowledge Base (PharmGKB) were used to determine the detection rate of each CPGx test. Our results indicated that the detection rate of CPGx tests covering CYP2C19, CYP2C9, CYP2D6, and CYP2B6 show significant variation across ethnic groups. Specifically, the Sub-Saharan Africans have 63.9% and 77.9% average detection rates for CYP2B6 and CYP2C19 assays analyzed, respectively. In addition, East Asians (EAs) have an average detection rate of 55.1% for CYP2C9 assays. Therefore, the patient’s ethnic background should be carefully considered in selecting CPGx tests.
Dystrophic Epidermolysis Bullosa: Secondary Disease Mechanisms and Disease Modifiers
Authors: Nyström Alexander , Bruckner-Tuderman Leena , Kiritsi Dimitra
Published: September 2021

The phenotypic presentation of monogenetic diseases is determined not only by the nature of the causative mutations but also is influenced by manifold cellular, microenvironmental, and external factors. Here, heritable extracellular matrix diseases, including dystrophic epidermolysis bullosa (DEB), are no exceptions. Dystrophic epidermolysis bullosa is caused by mutations in theCOL7A1gene encoding collagen VII. Deficiency of collagen VII leads to skin and mucosal fragility, which progresses from skin blistering to severe fibrosis and cancer. Clinical and pre-clinical studies suggest that targeting of secondary disease mechanisms or employment of natural disease modifiers can alleviate DEB severity and progression. However, since many of these mechanisms are needed for tissue homeostasis, informed, selective targeting is essential for safe and efficacious treatment. Here, we discuss a selection of key disease modifiers and modifying processes active in DEB, summarize the still scattered knowledge of them, and reflect on ways forward toward their utilization for symptom-relief or enhancement of curative therapies.
Transcriptome-Wide Association Study Provides Insights Into the Genetic Component of Gene Expression in Anxiety
Authors: Su Xi , Li Wenqiang , Lv Luxian , Li Xiaoyan , Yang Jinfeng , Luo Xiong-Jian , Liu Jiewei
Published: September 2021

Anxiety disorders are common mental disorders that often result in disability. Recently, large-scale genome-wide association studies (GWASs) have identified several novel risk variants and loci for anxiety disorders (or anxiety traits). Nevertheless, how the reported risk variants confer risk of anxiety remains unknown. To identify genes whose cis-regulated expression levels are associated with risk of anxiety traits, we conducted a transcriptome-wide association study (TWAS) by integrating genome-wide associations from a large-scale GWAS (N = 175,163) (which evaluated anxiety traits based on Generalized Anxiety Disorder 2-item scale (GAD-2) score) and brain expression quantitative trait loci (eQTL) data (from the PsychENCODE and GTEx). We identified 19 and 17 transcriptome-wide significant (TWS) genes in the PsychENCODE and GTEx, respectively. Intriguingly, 10 genes showed significant associations with anxiety in both datasets, strongly suggesting that genetic risk variants may confer risk of anxiety traits by regulating the expression of these genes. Top TWS genes included RNF123, KANSL1-AS1, GLYCTK, CRHR1, DND1P1, MAPT and ARHGAP27. Of note, 25 TWS genes were not implicated in the original GWAS. Our TWAS identified 26 risk genes whose cis-regulated expression were significantly associated with anxiety, providing important insights into the genetic component of gene expression in anxiety disorders/traits and new clues for future drug development.
Metabolic Program of Regulatory B Lymphocytes and Influence in the Control of Malignant and Autoimmune Situations
Authors: Iperi Cristian , Bordron Anne , Dueymes Maryvonne , Pers Jacques-Olivier , Jamin Christophe
Published: September 2021

Metabolic pathways have been studied for a while in eukaryotic cells. During glycolysis, glucose enters into the cells through the Glut1 transporter to be phosphorylated and metabolized generating ATP molecules. Immune cells can use additional pathways to adapt their energetic needs. The pentose phosphate pathway, the glutaminolysis, the fatty acid oxidation and the oxidative phosphorylation generate additional metabolites to respond to the physiological requirements. Specifically, in B lymphocytes, these pathways are activated to meet energetic demands in relation to their maturation status and their functional orientation (tolerance, effector or regulatory activities). These metabolic programs are differentially involved depending on the receptors and the co-activation molecules stimulated. Their induction may also vary according to the influence of the microenvironment, i.e. the presence of T cells, cytokines … promoting the expression of particular transcription factors that direct the energetic program and modulate the number of ATP molecule produced. The current review provides recent advances showing the underestimated influence of the metabolic pathways in the control of the B cell physiology, with a particular focus on the regulatory B cells, but also in the oncogenic and autoimmune evolution of the B cells.
IL-17+ Mast Cell/T Helper Cell Axis in the Early Stages of Acne
Authors: Eliasse Yoan , Leveque Edouard , Garidou Lucile , Battut Louise , McKenzie Brienne , Nocera Thérèse , Redoules Daniel , Espinosa Eric
Published: September 2021

Acne is a multifactorial disease driven by physiological changes occurring during puberty in the pilosebaceous unit (PSU) that leads to sebum overproduction and a dysbiosis involving notably Cutibacterium acnes. These changes in the PSU microenvironment lead to a shift from a homeostatic to an inflammatory state. Indeed, immunohistochemical analyses have revealed that inflammation and lymphocyte infiltration can be detected even in the infraclinical acneic stages, highlighting the importance of the early stages of the disease. In this study, we utilized a robust multi-pronged approach that included flow cytometry, confocal microscopy, and bioinformatics to comprehensively characterize the evolution of the infiltrating and resident immune cell populations in acneic lesions, beginning in the early stages of their development. Using a discovery cohort of 15 patients, we demonstrated that the composition of immune cell infiltrate is highly dynamic in nature, with the relative abundance of different cell types changing significantly as a function of clinical lesion stage. Within the stages examined, we identified a large population of CD69+ CD4+ T cells, several populations of activated antigen presenting cells, and activated mast cells producing IL-17. IL-17+ mast cells were preferentially located in CD4+ T cell rich areas and we showed that activated CD4+ T cells license mast cells to produce IL-17. Our study reveals that mast cells are the main IL-17 producers in the early stage of acne, underlying the importance of targeting the IL-17+ mast cell/T helper cell axis in therapeutic approaches.
What Basophil Testing Tells Us About CSU Patients – Results of the CORSA Study
Authors: Marcelino João , Baumann Katrine , Skov Per Stahl , Pereira Santos Maria Conceição , Wyroslak Inga , Scheffel Jörg , Altrichter Sabine , Woetmann Anders , Pereira-Barbosa Manuel , Costa Célia , Maurer Marcus
Published: September 2021

Basophil testing is the most effective single approach for diagnosing type-IIb autoimmune chronic spontaneous urticaria (TIIbaiCSU). A positive basophil test has been linked to long disease duration, higher disease activity, a poor response to antihistamines and omalizumab, and a better response to cyclosporine and fenebrutinib. As of now it is unclear what other features are connected to a positive basophil test in chronic spontaneous urticaria (CSU). We aimed to identify features of basophil test-positive CSU patients. We performed a cross-sectional study of 85 CSU patients. Basophil testing was done with the basophil activation test (BAT) and the basophil histamine release assay (BHRA). Data were analysed using SPSS: Student’s t-test, Chi-square test, Odds Ratio, Spearman’s correlation test. Of 85 CSU patients, 44% and 28% tested positive with the BAT and BHRA, respectively. These patients showed higher disease activity and impact, lower levels of disease control and total serum IgE, as well as higher rates of having a positive autologous serum skin test (ASST), angioedema, nocturnal symptoms, symptoms for >5 days/week, and thyroid autoantibodies. The ASST, by itself, was not a good predictor of basophil test results, but it predicted a positive basophil test in up to 100% of cases when combined with angioedema, thyroid autoantibodies or low IgE. In conclusion, a positive basophil test is linked to known features of TIIbaiCSU and novel characteristics including nocturnal symptoms. Further studies on basophil test-positive and -negative CSU patients can help to better understand CSU endotypes and to develop better management approaches.
MHC Variants Associated With Symptomatic Versus Asymptomatic SARS-CoV-2 Infection in Highly Exposed Individuals
Authors: Castelli Erick C. , de Castro Mateus V. , Naslavsky Michel S. , Scliar Marilia O. , Silva Nayane S. B. , Andrade Heloisa S. , Souza Andreia S. , Pereira Raphaela N. , Castro Camila F. B. , Mendes-Junior Celso T. , Meyer Diogo , Nunes Kelly , Matos Larissa R. B. , Silva Monize V. R. , Wang Jaqueline Y. T. , Esposito Joyce , Coria Vivian R. , Bortolin Raul H. , Hirata Mario H. , Magawa Jhosiene Y. , Cunha-Neto Edecio , Coelho Verônica , Santos Keity S. , Marin Maria Lucia C. , Kalil Jorge , Mitne-Neto Miguel , Maciel Rui M. B. , Passos-Bueno Maria Rita , Zatz Mayana
Published: September 2021

Despite the high number of individuals infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who develop coronavirus disease 2019 (COVID-19) symptoms worldwide, many exposed individuals remain asymptomatic and/or uninfected and seronegative. This could be explained by a combination of environmental (exposure), immunological (previous infection), epigenetic, and genetic factors. Aiming to identify genetic factors involved in immune response in symptomatic COVID-19 as compared to asymptomatic exposed individuals, we analyzed 83 Brazilian couples where one individual was infected and symptomatic while the partner remained asymptomatic and serum-negative for at least 6 months despite sharing the same bedroom during the infection. We refer to these as “discordant couples”. We performed whole-exome sequencing followed by a state-of-the-art method to call genotypes and haplotypes across the highly polymorphic major histocompatibility complex (MHC) region. The discordant partners had comparable ages and genetic ancestry, but women were overrepresented (65%) in the asymptomatic group. In the antigen-presentation pathway, we observed an association between HLA-DRB1 alleles encoding Lys at residue 71 (mostly DRB1*03:01 and DRB1*04:01) and DOB*01:02 with symptomatic infections and HLA-A alleles encoding 144Q/151R with asymptomatic seronegative women. Among the genes related to immune modulation, we detected variants in MICA and MICB associated with symptomatic infections. These variants are related to higher expression of soluble MICA and low expression of MICB. Thus, quantitative differences in these molecules that modulate natural killer (NK) activity could contribute to susceptibility to COVID-19 by downregulating NK cell cytotoxic activity in infected individuals but not in the asymptomatic partners.
Dysfunctional Immune Regulation in Autoimmune Hepatitis: From Pathogenesis to Novel Therapies
Authors: Vuerich Marta , Wang Na , Kalbasi Ahmadreza , Graham Jonathon J. , Longhi Maria Serena
Published: September 2021

Autoimmune hepatitis (AIH) is a chronic inflammatory disorder characterized by hypergammaglobulinemia, presence of serum autoantibodies and histological features of interface hepatitis. AIH therapeutic management still relies on the administration of corticosteroids, azathioprine and other immunosuppressants like calcineurin inhibitors and mycophenolate mofetil. Withdrawal of immunosuppression often results in disease relapse, and, in some cases, therapy is ineffective or associated with serious side effects. Understanding the mechanisms underlying AIH pathogenesis is therefore of paramount importance to develop more effective and well tolerated agents capable of restoring immunotolerance to liver autoantigens. Imbalance between effector and regulatory cells permits liver damage perpetuation and progression in AIH. Impaired expression and regulation of CD39, an ectoenzyme key to immunotolerance maintenance, have been reported in Tregs and effector Th17-cells derived from AIH patients. Interference with these altered immunoregulatory pathways may open new therapeutic avenues that, in addition to limiting aberrant inflammatory responses, would also reconstitute immune homeostasis. In this review, we highlight the most recent findings in AIH immunopathogenesis and discuss how these could inform and direct the development of novel therapeutic tools.
α-Hemolysin-Aided Oligomerization of the Spike Protein RBD Resulted in Improved Immunogenicity and Neutralization Against SARS-CoV-2 Variants
Authors: Zou Jintao , Jing Haiming , Zhang Xiaoli , Liu Yiheng , Zhao Zhuo , Duan Lianli , Yuan Yue , Chen Zhifu , Gou Qiang , Xiong Qingshan , Li Sisi , Yang Feng , Zeng Hao , Zou Quanming , Zhang Jinyong
Published: September 2021

The increase in confirmed COVID-19 cases and SARS-CoV-2 variants calls for the development of safe and broad cross-protective vaccines. The RBD of the spike protein was considered to be a safe and effective candidate antigen. However, the low immunogenicity limited its application in vaccine development. Herein, we designed and obtained an RBD heptamer (mHla-RBD) based on a carrier protein-aided assembly strategy. The molecular weight of mHla-RBD is up to 450 kDa, approximately 10 times higher than that of the RBD monomer. When formulated with alum adjuvant, mHla-RBD immunization significantly increased the immunogenicity of RBD, as indicated by increased titers of RBD-specific antibodies, neutralizing antibodies, Th2 cellular immune response, and pseudovirus neutralization activity, when compared to RBD monomer. Furthermore, we confirmed that RBD-specific antibodies predominantly target conformational epitopes, which was approximately 200 times that targeting linear epitopes. Finally, a pseudovirus neutralization assay revealed that neutralizing antibodies induced by mHla-RBD against different SARS-CoV-2 variants were comparable to those against the wild-type virus and showed broad-spectrum neutralizing activity toward different SARS-CoV-2 variants. Our results demonstrated that mHla-RBD is a promising candidate antigen for development of SARS-CoV-2 vaccines and the mHla could serve as a universal carrier protein for antigen design.
Promoting Ocean Literacy in Elementary School Students Through Investigation Activities and Citizen Science
Authors: Boaventura Diana , Neves Ana Teresa , Santos Jaime , Pereira Paula Colares , Luís Cristina , Monteiro António , Cartaxana Alexandra , Hawkins Stephen John , Caldeira Maria Filomena , Ponces de Carvalho António
Published: September 2021

To enable the process of energy transition towards carbon neutrality, it is important to educate the community on the need for social, economic, environmental and institutional transformation, and to educate and inform citizens to participate proactively in this change. This study evaluated the effectiveness of participation by elementary school students in educational activities and citizen science actions in enhancing their scientific knowledge and skills related to Ocean Literacy in the context of climate change. The activities were directed to children (aged 9–11) and involved pre-service teachers, in-service teachers and researchers, in formal and non-formal contexts. A total of 329 elementary school students participated in interdisciplinary science activities, focusing on the cause & effect of climate change in the ocean. They learned to identify rocky shore marine species used to monitor climate change and acquired ICT skills by inserting species observations in a biodiversity mapping platform. Finally, students worked collaboratively to communicate to the community what they have learned through an exhibition at the Museum João de Deus. To assess the impact of the activities on acquisition of scientific knowledge and skills by the students, a mixed methodology was applied using pre and post-tests, analysis of the data inserted by students in the platform, and content analysis of the students’ work for the museum exhibition. The results of pre and post-tests revealed a significant increase in knowledge of the effects of climate change on the rocky shore species distribution, as well as of the importance of monitoring these species distribution. The data from the online biodiversity platform showed that 42% of the species identifications made by the students were correct. The ability of the students to communicate their learning to the wider community was evaluated by the scientific content, structure, presentation and creativity and of posters, models, videos and games produced. Most of students focused their communications and creations on the greenhouse effect, cause & effect of climate change in the ocean and biodiversity. This study reinforces the importance of addressing Ocean Literacy and climate change through formal and non-formal educational activities with an investigative nature.
Cyclical Patterns and a Regime Shift in the Character of Phytoplankton Blooms in a Restricted Sub-Tropical Lagoon, Indian River Lagoon, Florida, United States
Authors: Phlips Edward J. , Badylak Susan , Nelson Natalie G. , Hall Lauren M. , Jacoby Charles A. , Lasi Margaret A. , Lockwood Jean C. , Miller Janice D.
Published: September 2021

This paper examines the character of phytoplankton blooms in a restricted sub-tropical lagoon along the Atlantic coast of central Florida. The results of the 23-year study (1997–2020) provide evidence for multiple types of variability in bloom activity, including cyclical patterns, stochastic events, and most prominently a regime shift in composition and intensity. Cyclical patterns (e.g., El Niño/La Niña periods) and stochastic events (e.g., tropical storms) influenced rainfall levels, which in turn impacted nutrient concentrations in the water column and the timing and intensity of blooms. In 2011, a major change occurred in the character of blooms, with a dramatic increase in peak biomass levels of blooms and the appearance of new dominant taxa, including the brown tide speciesAureoumbra lagunensisand other nanoplanktonic species. Results of quantitative analyses reveal system behavior indicative of a regime shift. The shift coincided with widespread losses of seagrass community and reduced drift algae biomass. A combination of exceptionally low water temperatures in the winters of 2009/2010 and 2010/2011, hypersaline conditions associated with drought conditions, and high light attenuation caused by blooms appear to have contributed to the widespread and protracted decline in seagrass and drift macroalgal communities in the lagoon, leading to shifts in distribution of internal and external nutrient sources toward phytoplankton.
Novel Non-paralytic Shellfish Toxin and Non-spirolide Toxicity to Finfish, Brine Shrimp, and Rotifer Observed in a Culture of the Dinoflagellate Alexandrium insuetum Isolated From the Coastal Water of China
Authors: Song Xiaoying , Zhai Xinyu , Hao Shuang , Shang Lixia , Deng Yunyan , Chai Zhaoyang , Chen Junhui , Hu Zhangxi , Tang Ying Zhong
Published: September 2021

The genus Alexandrium is one of the major harmful algal blooms (HABs)-forming dinoflagellate group and at least half of ~40 described species have been reported to produce paralytic shellfish toxins (PSTs). The potentially harmful species Alexandrium insuetum has been reported from many countries of Asia and Europe, and to have paralytic shellfish poisoning toxicity, but no mortality of marine animals was observed during its bloom. Therefore, it is ecologically important to characterize the possible toxicity and toxins of this organism. In this study, based on the establishment of two clonal cultures through cyst germination collected from the Yellow Sea, we identified A. insuetum from China as the first record via light microscopy (LM) and scanning electron microscopy (SEM) observations and phylogenetic analyses. The cultures of A. insuetum were further observed to be toxic to finfish and zooplankton and deleterious to rotifer eggs via laboratory bioassays. The exposure bioassays using rotifer (Brachionus plicatilis), brine shrimp (Artemia salina), and larval finfish (Oryzias melastigma) demonstrated that A. insuetum caused significant lethal effects on finfish and zooplankton species. Rotifer bioassays using cell-free culture medium, heat-treated cultures, and water, methanol, and trichloromethane extracts of algal cells revealed that A. insuetum produced heat-labile, water-soluble toxin(s) that could be excreted from A. insuetum cells and steadily accumulated in the medium during the growth phases. Hatching success of rotifer eggs was also found to be seriously affected by the exposure to A. insuetum. Importantly, ultra-high performance liquid chromatography-tandem mass spectrometry [UPLC (or LC)-MS-MS] analyses suggest the above-described toxicity of A. insuetum was caused by neither PSTs nor spiroimines (13-desmethyl spirolide C and gymnodimine). Collectively, our findings demonstrated the novel toxicity to finfish and zooplankton in A. insuetum, which is ecologically important in not only possibly contributing to population dynamics and even the formation of HABs of the species, but also affecting the on-the-spot survival and the reproduction potency of marine animals. The present work is believed to set a cornerstone for the monitoring and risk assessment of the species along the coastal waters of China and for understanding the general ecology of A. insuetum.
Interactive Immunomodulation in the Mediterranean Mussel Mytilus galloprovincialis Under Thermal Stress and Cadmium Exposure
Authors: Nardi Alessandro , Benedetti Maura , Gorbi Stefania , Regoli Francesco
Published: September 2021

Marine bivalves are frequently exposed to multiple co-occurring challenges such as temperature extremes and anthropogenic pollution. These stressors can elicit negative effects on several biological pathways, including antioxidant and neuroendocrine-immune (NEI) systems, leading to immune disorders and altered immunocytes functionality. Since interactive mechanisms of action and resulting outcomes are still scarcely explored, we examined the single and combined effects of increased temperature (+5°C) and cadmium (20 μg/L) in the Mediterranean mussel Mytilus galloprovincialis. Analyzed parameters included cholinergic system in gills and hemolymph (acetylcholinesterase activity, AChE), total oxyradical scavenging capacity in gills and key functional processes in hemocytes, including lysosomal membrane stability, hemocytes subpopulations ratio, phagocytosis capacity, and onset of genotoxic damage. Results highlighted interactive inhibition of AChE activity along to a concomitant increased total oxyradical scavenging capacity, confirming neuroendocrine-immune system (NEI) disturbance and oxidative pressure. In hemocytes, lysosomal membrane stability and granulocytes:hyalinocytes ratio revealed additive effects of stressors, while a consistent reduction of phagocytosis was caused by temperature stress, with a slightly antagonistic effect of cadmium. Pearson’s correlation statistics provided either positive or negative relationships between investigated parameters and stressors, allowing to hypothesize putative mechanism of immune system functional alterations. The overall results suggest that the occurrence of short-term events of increased temperature and concomitant metal exposure could elicit interactive and negative effects on immune system efficiency of marine organisms.
Clinical Knowledge and Practice of “Ketofol” at University of Gondar Comprehensive Specialized Hospital
Authors: Woldekidan Nigist Alemayehu , Mohammed Ammas Siraj
Published: September 2021

Background: Ketamine and propofol in a single syringe are reported to create an admixture used for balancing cardiorespiratory effects during induction of general anesthesia. This study aimed to assess the clinical practice and knowledge of “ketofol” among anesthesia providers.

Methods: A cross-sectional institutional-based study was conducted among anesthesia providers. Data abstracted format was prepared and distributed to senior anesthetists, junior anesthetist postgraduate students, and undergraduate students. The study was conducted from January 1, 2019, to January 30, 2019. Descriptive statistics and binary logistic regression were performed for frequency distribution and to determine the association, respectively.

Result: From a total of 133 participants included in the study, the majority, 88 (66.2%), were men and 75 (56.9%) had 0–2 years of experience. More than two-thirds of participants, 105 (78.9%), have never had a seminar or educational session about combined use. Lack of experience among 11 participants (8.3%) was one of the reasons for not using “ketofol” followed by lack of knowledge among three (2.3%) participants. The majority of participants, 112 (84.2%), prefer ketamine and propofol to be administered one right after the other with separate syringes and the ratio to be 1:2, 64 (48.2). There was no significant association observed between sociodemographic and other characteristics and the practice of “ketofol.”

Conclusion: In this study, nearly half of the participants rated their knowledge at the average level, and the study identifies that there is clinical knowledge and practice gap among anesthesia providers working in the University of Gondar Comprehensive Specialized Hospital (UOGCSH). Preparing educational sessions regarding “ketofol” for addressing identified barriers is among the recommendations forwarded to UOGCSH.
Maternal and Neonatal Outcomes After Planned or Emergency Delivery for Placenta Accreta Spectrum: A Systematic Review and Meta-Analysis
Authors: Zhong Wei , Zhu Fang , Li Shengqiong , Chen Jin , He Fengya , Xin Jie , Yang Mei
Published: September 2021

Objective: To compare maternal and neonatal outcomes for women with placenta accreta syndrome (PAS) delivering via a planned or emergent approach.

Methods: A systematic search for relevant studies was conducted by screening the PubMed, Scopus, Web of Science, and Google Scholar electronic databases. Included studies should have been retrospective record-based or prospective in design. They must have compared maternal and/or neonatal outcomes for PAS patients delivering via planned and emergency procedures. Strength of association was presented as pooled adjusted relative risk (RR) for categorical outcomes and weighted mean difference (WMD) for continuous outcomes. Statistical analysis was done using STATA version 16.0.

Results: Nine articles were included in the meta-analysis. PAS patients undergoing planned deliveries had increased gestational ages, required fewer units of transfused blood, experienced shorter hospital stay durations, and presented reduced risks for maternal ICU admission and severe maternal morbidity. Neonates born to mothers undergoing planned deliveries had increased birth weights and decreased NICU admission risk.

Conclusion: These findings indicate a planned approach for delivery is better for maternal and neonatal outcomes compared to urgent/emergency delivery for PAS patients.
Pan-Genome of the Genus Streptomyces and Prioritization of Biosynthetic Gene Clusters With Potential to Produce Antibiotic Compounds
Authors: Caicedo-Montoya Carlos , Manzo-Ruiz Monserrat , Ríos-Estepa Rigoberto
Published: September 2021

Species of the genus Streptomyces are known for their ability to produce multiple secondary metabolites; their genomes have been extensively explored to discover new bioactive compounds. The richness of genomic data currently available allows filtering for high quality genomes, which in turn permits reliable comparative genomics studies and an improved prediction of biosynthetic gene clusters (BGCs) through genome mining approaches. In this work, we used 121 genome sequences of the genus Streptomyces in a comparative genomics study with the aim of estimating the genomic diversity by protein domains content, sequence similarity of proteins and conservation of Intergenic Regions (IGRs). We also searched for BGCs but prioritizing those with potential antibiotic activity. Our analysis revealed that the pan-genome of the genus Streptomyces is clearly open, with a high quantity of unique gene families across the different species and that the IGRs are rarely conserved. We also described the phylogenetic relationships of the analyzed genomes using multiple markers, obtaining a trustworthy tree whose relationships were further validated by Average Nucleotide Identity (ANI) calculations. Finally, 33 biosynthetic gene clusters were detected to have potential antibiotic activity and a predicted mode of action, which might serve up as a guide to formulation of related experimental studies.
Tumor-Associated Microbiota in Proximal and Distal Colorectal Cancer and Their Relationships With Clinical Outcomes
Authors: Jin Min , Shang Fumei , Wu Jingjing , Fan Qilin , Chen Chen , Fan Jun , Liu Li , Nie Xiu , Zhang Tao , Cai Kailin , Ogino Shuji , Liu Hongli
Published: September 2021

The proximal and distal subsites of colorectal cancer (CRC) have distinct differences in their embryonic origin, epidemiology, and prognosis. Therefore, they are not considered as the same disease. However, the possible difference in microbial characterization of the two subsites of CRC is still unclear. In this study, we explored tumor microbiota diversity and composition difference in patients with proximal (N = 187) and distal CRCs (N = 142). This was carried out on cancer tissues and adjacent tissues using bacterial 16S rRNA sequencing. The Kaplan–Meier method was used to analyze the correlation between differential flora and overall survival rate of the patients. It was found that there were significant differences in tumor microbial characteristics between the proximal and distal CRC tissues. The microbiota communities were distinctly richer in the proximal colon tumor tissues than in the distal CRC tissues. Microbial diversity and structure were relatively constant in the paracancerous normal tissues of the proximal and distal colorectum. Generally, microbial communities of CRC tumor tissues were composed of Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes. Alpha diversity in the proximal and distal CRC tumor tissues was closely related to specific microflora. The abundance of Fusobacteria was associated with age of patient, tumor diameter, and tumor microsatellite instability (MSI) status of the patients. Moreover, Fusobacteria enrichment was associated with poor prognosis especially in patients with proximal colon cancers, but not in patients with distal CRC. In conclusion, proximal and distal subsites of the CRC present distinct microbiota diversity and community structures. The differences indicate that there are different risk factors across anatomical subsites of CRC, which may provide a new strategy for precise prevention and treatment of CRC in the future.
Seroepidemiology of Chlamydia trachomatis Infection in the General Population of Northern China: The Jidong Community Cohort Study
Authors: Shui Jingwei , Xie Dongjie , Zhao Jianhui , Ao Cailing , Lin Hongqing , Liang Yuanhao , Wang Haiying , Dai Yingchun , Tang Shixing
Published: September 2021

A longitudinal serological study to investigate the seropositive frequency, incidence, and antibody dynamics ofChlamydia trachomatisinfection in the general population of China is urgently needed in order to optimize the strategies for surveillance and precise prevention ofC. trachomatisinfection. This longitudinal study enrolled 744 subjects aged 18–65 years from Jidong Community of Northern China from 2014 to 2018. Seropositive frequency, incidence, and reinfection ofC. trachomatiswere determined by detecting antibody againstC. trachomatisPgp3 using “in-house” luciferase immunosorbent assay (LISA). The dynamic of anti-Pgp3 antibody was analyzed using the Generalized Estimating Equation (GEE) model. The overall Pgp3 seropositive frequency among the 18–65-year-old population was 28.1% (95% CI 24.9–31.5), and significantly increased from 12.0% in those aged 18–29 years to 48.6% in the 60–65 years old. The seropositive frequency was slightly higher in women than in men (31.3% vs. 25.4%) without statistical significance. TheC. trachomatisincidence and reinfection rate were 11 and 14 per 1,000 person-years, respectively, and showed no significant difference with respect to age, gender, ethnicity, marital status, and education levels. Furthermore, anti-Pgp3 antibody remained detectable in 93.3% (195/209) of the seropositive subjects during the 5 years of follow-up. The overall decay rate for anti-Pgp3 antibody for CT-infected persons was −0.123 Log2 RLU/year, which was dramatically slower than in CT new infection (−3.34 Log2 RLU/year) or reinfection (−1.1 Log2 RLU/year). In conclusion, at least one quarter of the people aged 18–65 years have been infected withC. trachomatisover their lifetime while all age groups are susceptible toC. trachomatisinfection in the community of Northern China. Therefore, comprehensive prevention strategies are urgently needed.
Coronavirus Nsp1: Immune Response Suppression and Protein Expression Inhibition
Authors: Yuan Shuai , Balaji Shravani , Lomakin Ivan B. , Xiong Yong
Published: September 2021

Coronaviruses have brought severe challenges to public health all over the world in the past 20years. SARS-CoV-2, the causative agent of the COVID-19 pandemic that has led to millions of deaths, belongs to the genus beta-coronavirus. Alpha- and beta-coronaviruses encode a unique protein, nonstructural protein 1 (Nsp1) that both suppresses host immune responses and reduces global gene expression levels in the host cells. As a key pathogenicity factor of coronaviruses, Nsp1 redirects the host translation machinery to increase synthesis of viral proteins. Through multiple mechanisms, coronaviruses impede host protein expression through Nsp1, while escaping inhibition to allow the translation of viral RNA. In this review, we discuss current data about suppression of the immune responses and inhibition of protein synthesis induced by coronavirus Nsp1, as well as the prospect of live-attenuated vaccine development with virulence-attenuated viruses with mutations in Nsp1.
ORF3a Protein of Severe Acute Respiratory Syndrome Coronavirus 2 Inhibits Interferon-Activated Janus Kinase/Signal Transducer and Activator of Transcription Signaling via Elevating Suppressor of Cytokine Signaling 1
Authors: Wang Rong , Yang Xiaofeng , Chang Mingke , Xue Ziyang , Wang Weirong , Bai Liang , Zhao Sihai , Liu Enqi
Published: September 2021

Coronavirus disease 2019 (COVID-19) has caused a crisis to global public health since its outbreak at the end of 2019. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen of COVID-19, appears to efficiently evade the host immune responses, including interferon (IFN) signaling. Several SARS-CoV-2 viral proteins are believed to involve in the inhibition of IFN signaling. In this study, we discovered that ORF3a, an accessory protein of SARS-CoV-2, inhibited IFN-activated Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling via upregulating suppressor of cytokine signaling 1 (SOCS1), a negative regulator of cytokine signaling. ORF3a induced SOCS1 elevation in a dose- and time-dependent manner. RNAi-mediated silencing of SOCS1 efficiently abolished ORF3a-induced blockage of JAK/STAT signaling. Interestingly, we found that ORF3a also promoted the ubiquitin-proteasomal degradation of Janus kinase 2 (JAK2), an important kinase in IFN signaling. Silencing of SOCS1 by siRNA distinctly blocked ORF3a-induced JAK2 ubiquitination and degradation. These results demonstrate that ORF3a dampens IFN signaling via upregulating SOCS1, which suppressed STAT1 phosphorylation and accelerated JAK2 ubiquitin-proteasomal degradation. Furthermore, analysis of ORF3a deletion constructs showed that the middle domain of ORF3a (amino acids 70–130) was responsible for SOCS1 upregulation. These findings contribute to our understanding of the mechanism of SARS-CoV-2 antagonizing host antiviral response.
Emergent Differential Organization of Airway Smooth Muscle Cells on Concave and Convex Tubular Surface
Authors: Jin Yang , Liu Lei , Yu Peili , Lin Feng , Shi Xiaohao , Guo Jia , Che Bo , Duan Yiyuan , Li Jingjing , Pan Yan , Luo Mingzhi , Deng Linhong
Published: September 2021

Airway smooth muscle cells (ASMCs) exist in a form of helical winding bundles within the bronchial airway wall. Such tubular tissue provides cells with considerable curvature as a physical constraint, which is widely thought as an important determinant of cell behaviors. However, this process is difficult to mimic in the conventional planar cell culture system. Here, we report a method to develop chips with cell-scale tubular (concave and convex) surfaces from fused deposition modeling 3D printing to explore how ASMCs adapt to the cylindrical curvature for morphogenesis and function. Results showed that ASMCs self-organized into two distinctively different patterns of orientation on the concave and convex surfaces, eventually aligning either invariably perpendicular to the cylinder axis on the concave surface or curvature-dependently angled on the convex surface. Such oriented alignments of the ASMCs were maintained even when the cells were in dynamic movement during migration and spreading along the tubular surfaces. Furthermore, the ASMCs underwent a phenotype transition on the tubular (both concave and convex) surfaces, significantly reducing contractility as compared to ASMCs cultured on a flat surface, which was reflected in the changes of proliferation, migration and gene expression of contractile biomarkers. Taken together, our study revealed a curvature-induced pattern formation and functional modulation of ASMCs in vitro, which is not only important to better understanding airway smooth muscle pathophysiology, but may also be useful in the development of new techniques for airway disease diagnosis and therapy such as engineering airway tissues or organoids.
Nanopore Single-Molecule Sequencing for Mitochondrial DNA Methylation Analysis: Investigating Parkin-Associated Parkinsonism as a Proof of Concept
Authors: Lüth Theresa , Wasner Kobi , Klein Christine , Schaake Susen , Tse Ronnie , Pereira Sandro L. , Laß Joshua , Sinkkonen Lasse , Grünewald Anne , Trinh Joanne
Published: September 2021

Objective:To establish a workflow for mitochondrial DNA (mtDNA) CpG methylation using Nanopore whole-genome sequencing and perform first pilot experiments on affectedParkinbiallelic mutation carriers (Parkin-PD) and healthy controls.

Background:Mitochondria, including mtDNA, are established key players in Parkinson's disease (PD) pathogenesis. Mutations in Parkin, essential for degradation of damaged mitochondria, cause early-onset PD. However, mtDNA methylation and its implication in PD is understudied. Herein, we establish a workflow using Nanopore sequencing to directly detect mtDNA CpG methylation and compare mtDNA methylation between Parkin-related PD and healthy individuals.

Methods:To obtain mtDNA, whole-genome Nanopore sequencing was performed on blood-derived from five Parkin-PD and three control subjects. In addition, induced pluripotent stem cell (iPSC)-derived midbrain neurons from four of these patients with PD and the three control subjects were investigated. The workflow was validated, using methylated and unmethylated 897 bp synthetic DNA samples at different dilution ratios (0, 50, 100% methylation) and mtDNA without methylation. MtDNA CpG methylation frequency (MF) was detected using Nanopolish and Megalodon.

Results:Across all blood-derived samples, we obtained a mean coverage of 250.3X (SD ± 80.5X) and across all neuron-derived samples 830X (SD ± 465X) of the mitochondrial genome. We detected overall low-level CpG methylation from the blood-derived DNA (mean MF ± SD = 0.029 ± 0.041) and neuron-derived DNA (mean MF ± SD = 0.019 ± 0.035). Validation of the workflow, using synthetic DNA samples showed that highly methylated DNA molecules were prone to lower Guppy Phred quality scores and thereby more likely to fail Guppy base-calling. CpG methylation in blood- and neuron-derived DNA was significantly lower in Parkin-PD compared to controls (Mann-Whitney U-testp< 0.05).

Conclusion:Nanopore sequencing is a useful method to investigate mtDNA methylation architecture, including Guppy-failed reads is of importance when investigating highly methylated sites. We present a mtDNA methylation workflow and suggest methylation variability across different tissues and between Parkin-PD patients and controls as an initial model to investigate.
Cellular Senescence in Traumatic Brain Injury: Evidence and Perspectives
Authors: Schwab Nicole , Leung Emily , Hazrati Lili-Naz
Published: September 2021

Mild traumatic brain injury (mTBI) can lead to long-term neurological dysfunction and increase one's risk of neurodegenerative disease. Several repercussions of mTBI have been identified and well-studied, including neuroinflammation, gliosis, microgliosis, excitotoxicity, and proteinopathy – however the pathophysiological mechanisms activating these pathways after mTBI remains controversial and unclear. Emerging research suggests DNA damage-induced cellular senescence as a possible driver of mTBI-related sequalae. Cellular senescence is a state of chronic cell-cycle arrest and inflammation associated with physiological aging, mood disorders, dementia, and various neurodegenerative pathologies. This narrative review evaluates the existing studies which identify DNA damage or cellular senescence after TBI (including mild, moderate, and severe TBI) in both experimental animal models and human studies, and outlines how cellular senescence may functionally explain both the molecular and clinical manifestations of TBI. Studies on this subject clearly show accumulation of various forms of DNA damage (including oxidative damage, single-strand breaks, and double-strand breaks) and senescent cells after TBI, and indicate that cellular senescence may be an early event after TBI. Further studies are required to understand the role of sex, cell-type specific mechanisms, and temporal patterns, as senescence may be a pathway of interest to target for therapeutic purposes including prognosis and treatment.
Prevalence and Factors Related to Pathological Laughter and Crying in Patients With Amyotrophic Lateral Sclerosis
Authors: Wei Qian-Qian , Ou Ruwei , Lin Junyu , Zhang Lingyu , Hou Yanbing , Cao Bei , Chen Yongping , Yang Tianmi , Shang Huifang
Published: September 2021

Objective: This study aimed to explore the prevalence and clinical correlates of pathological laughter and crying (PLC) in patients with amyotrophic lateral sclerosis (ALS).

Methods: A total of 1,031 ALS patients were enrolled between August 2012 and August 2019. The PLC was recorded by a face-to-face interview. Other characteristics of patients, including depression, anxiety, cognition, and behavior function, were also evaluated. The potential associated factors of PLC were explored using forward binary regression analysis. Survival was analyzed in groups using propensity score matching (PSM) and Cox proportional hazards models.

Results: The prevalence of PLC was 11.4% in all patients at baseline. Bulbar-onset and female patients had higher prevalence of PLC. The multivariate regression analysis indicated that PLC in ALS was associated with bulbar onset (p < 0.001), late disease stage (p < 0.001), and higher score in the Hamilton Depression Rating Scale (HDRS) (p = 0.012). The higher score of HDRS was significantly and independently associated with PLC occurrence in bulbar-onset patients (p = 0.032). The late disease stage was related to PLC occurrence in spinal-onset patients (p < 0.001). After comparison with matched pairs by using PSM, PLC at baseline had no impact on survival.

Conclusion: PLC was not uncommon in ALS, especially in bulbar-onset and female patients. We highlighted that the emotional state other than cognitive function had possible relationship with PLC in ALS.
Modified Protocol to Enable the Study of Hemorrhage and Hematoma in a Traumatic Brain Injury Mouse Model
Authors: Joo Hyejin , Bae Jinhyun , Park Jae-Woo , Lee Beom-Joon , Lee Byoung Dae , Bu Youngmin
Published: September 2021

To date, many studies using the controlled cortical impact (CCI) mouse model of traumatic brain injury (TBI) have presented results without presenting the pathophysiology of the injury-core itself or the temporal features of hemorrhage (Hrr). This might be owing to the removal of the injury-core during the histological procedure. We therefore developed a modified protocol to preserve the injury-core. The heads of mice were obtained after perfusion and were post-fixed. The brains were then harvested, retaining the ipsilateral skull bone; these were post-fixed again and sliced using a cryocut. To validate the utility of the procedure, the temporal pattern of Hrr depending on the impacting depth was analyzed. CCI-TBI was induced at the following depths: 1.5 mm (mild Hrr), 2.5 mm (moderate Hrr), and 3.5 mm (severe Hrr). A pharmacological study was also conducted using hemodynamic agents such as warfarin (2 mg/kg) and coagulation factor VIIa (Coa-VIIa, 1 mg/kg). The current protocol enabled the visual observation of the Hrr until 7 days. Hrr peaked at 1–3 days and then decreased to the normal range on the seventh day. It expanded from the affected cortex (mild) to the periphery of the hippocampus (moderate) and the brain ventricle (severe). Pharmacological studies showed that warfarin pre-treatment produced a massively increased Hrr, concurrent with the highest mortality rate and brain injury. Coa-VIIa reduced the side effects of warfarin. Therefore, these results suggest that the current method might be suitable to conduct studies on hemorrhage, hematoma, and the injury-core in experiments using the CCI-TBI mouse model.