bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamics of SARS-CoV2 Infection and Multi-Drug Resistant Bacteria Superinfection in Patients With Assisted Mechanical Ventilation
Authors: Mazzariol Annarita , Benini Anna , Unali Ilaria , Nocini Riccardo , Smania Marcello , Bertoncelli Anna , De Sanctis Francesco , Ugel Stefano , Donadello Katia , Polati Enrico , Gibellini Davide
Published: August 2021

Objective

To investigate the presence of bacteria and fungi in bronchial aspirate (BA) samples from 43 mechanically ventilated patients with severe COVID-19 disease.

Methods

Detection of SARS-CoV-2 was performed using Allplex 2019-nCoV assay kits. Isolation and characterisation of bacteria and fungi were carried out in BA specimens treated with 1X dithiothreitol 1% for 30 min at room temperature, using standard culture procedures.

Results

Bacterial and/or fungal superinfection was detected in 25 out of 43 mechanically ventilated patients, generally after 7 days of hospitalisation in an intensive care unit (ICU). Microbial colonisation (colony forming units (CFU) <1000 colonies/ml) in BA samples was observed in 11 out of 43 patients, whereas only 7 patients did not show any signs of bacterial or fungal growth. Pseudomonas aeruginosa was identified in 17 patients. Interestingly, 11 out of these 17 isolates also showed carbapenem resistance. The molecular analysis demonstrated that resistance to carbapenems was primarily related to OprD mutation or deletion. Klebsiella pneumoniae was the second most isolated pathogen found in 13 samples, of which 8 were carbapenemase-producer strains.

Conclusion

These data demonstrate the detection of bacterial superinfection and antimicrobial resistance in severe SARS-CoV-2-infected patients and suggest that bacteria may play an important role in COVID-19 evolution. A prospective study is needed to verify the incidence of bacterial and fungal infections and their influence on the health outcomes of COVID-19 patients.
Forensic Analysis of Human Microbiome in Skin and Body Fluids Based on Geographic Location
Authors: Cho Hye-Won , Eom Yong-Bin
Published: August 2021

High-throughput DNA sequencing technologies have facilitated the in silico forensic analysis of human microbiome. Specific microbial species or communities obtained from the crime scene provide evidence of human contacts and their body fluids. The microbial community is influenced by geographic, ethnic, lifestyle, and environmental factors such as urbanization. An understanding of the effects of these external stressors on the human microbiome and determination of stable and changing elements are important in selecting appropriate targets for investigation. In this study, the Forensic Microbiome Database (FMD) (http://www.fmd.jcvi.org) containing the microbiome data of various locations in the human body in 35 countries was used. We focused on skin, saliva, vaginal fluid, and stool and found that the microbiome distribution differed according to the body part as well as the geographic location. In the case of skin samples, Staphylococcus species were higher than Corynebacterium species among Asians compared with Americans. Holdemanella and Fusobacterium were specific in the saliva of Koreans and Japanese populations. Lactobacillus was found in the vaginal fluids of individuals in all countries, whereas Serratia and Enterobacter were endemic to Bolivia and Congo, respectively. This study is the first attempt to collate and describe the observed variation in microbiomes from the forensic microbiome database. As additional microbiome databases are reported by studies worldwide, the diversity of the applications may exceed and expand beyond the initial identification of the host.
Identification of Natural Inhibitors Against SARS-CoV-2 Drugable Targets Using Molecular Docking, Molecular Dynamics Simulation, and MM-PBSA Approach
Authors: Kushwaha Prem Prakash , Singh Atul Kumar , Bansal Tanya , Yadav Akansha , Prajapati Kumari Sunita , Shuaib Mohd , Kumar Shashank
Published: August 2021

The present study explores the SARS-CoV-2 drugable target inhibition efficacy of phytochemicals from Indian medicinal plants using molecular docking, molecular dynamics (MD) simulation, and MM-PBSA analysis. A total of 130 phytochemicals were screened against SARS-CoV-2 Spike (S)-protein, RNA-dependent RNA polymerase (RdRp), and Main protease (Mpro). Result of molecular docking showed that Isoquercetin potentially binds with the active site/protein binding site of the Spike, RdRP, and Mpro targets with a docking score of -8.22, -6.86, and -9.73 kcal/mole, respectively. Further, MS 3, 7-Hydroxyaloin B, 10-Hydroxyaloin A, showed -9.57, -7.07, -8.57 kcal/mole docking score against Spike, RdRP, and Mpro targets respectively. The MD simulation was performed to study the favorable confirmation and energetically stable complex formation ability of Isoquercetin and 10-Hydroxyaloin A phytochemicals in Mpro-unbound/ligand bound/standard inhibitor bound system. The parameters such as RMSD, RMSF, Rg, SASA, Hydrogen-bond formation, energy landscape, principal component analysis showed that the lead phytochemicals form stable and energetically stabilized complex with the target protein. Further, MM-PBSA analysis was performed to compare the Gibbs free energy of the Mpro-ligand bound and standard inhibitor bound complexes. The analysis revealed that the His-41, Cys145, Met49, and Leu27 amino acid residues were majorly responsible for the lower free energy of the complex. Drug likeness and physiochemical properties of the test compounds showed satisfactory results. Taken together, the study concludes that that the Isoquercetin and 10-Hydroxyaloin A phytochemical possess significant efficacy to bind SARS-Cov-2 Mpro active site. The study necessitates further in vitro and in vivo experimental validation of these lead phytochemicals to assess their anti-SARS-CoV-2 potential.
The Association of Left Atrial Appendage Morphology to Atrial Fibrillation Recurrence After Radiofrequency Ablation
Authors: Gong Shiyu , Zhou Jian , Li Bingyu , Kang Sheng , Ma Xiaoye , Cai Ying , Guo Yang , Hu Rui , Zhang Xumin
Published: August 2021

Objective: The probability of late recurrent atrial fibrillation (AF) after radiofrequency ablation (RFA) has not yet been fully clarified. This study aims to study the association of left atrial appendage (LAA) morphology with AF recurrence after RFA.

Methods: We retrospectively enrolled 84 patients (24 patients had persistent AF, 60 patients had paroxysmal AF) who underwent RFA in Shanghai East Hospital from June 2014 to May 2018. The mean follow-up of these patients was 618.6 days. According to preoperative transesophageal echocardiography (TEE), the morphology feature of LAA was classified and evaluated by two classification methods. The first method was divided into chicken-wing, windsock, cactus, and cauliflower, and the second method was divided into one lobe, two lobes, and multiple lobes. The correlation between morphological feature of LAA and the recurrence rate of AF after RFA was analyzed.

Results: During follow-up, 12 patients (50%) and 10 patients (16.7%) had AF recurrence in persistent and paroxysmal AF, respectively. The LAA morphology was associated with the recurrence of AF after RFA with the chicken-wing highest recurrence risk (68.2%). The structure type of LAA was also related to the AF recurrence rate (p < 0.01). Compared with one lobe and multiple lobes, two lobes (recurrence, 47.6%) were more likely associated with the recurrence of AF (p < 0.02). Logistic regression analysis showed that the chicken-wing group had a higher risk of recurrence after RFA (OR = 8.13, p = 0.004), and the windsock group had a lower risk of recurrence (OR = 0.17, p = 0.002).

Conclusion: The morphological feature of LAA is related to the recurrence risk of AF after RFA. LAA morphology assessment can predict the risk of AF recurrence.
Blood Pressure Response in Miners Exposed to Chronic Intermittent Hypoxia in Chile
Authors: Lang Morin , Paéz Valeria , Maj Giacomo , Silva-Urra Juan , Labarca-Valenzuela Cristián , Caravita Sergio , Faini Andrea , Cantuarias Javier , Perez Oscar , Bilo Grzegorz , Parati Gianfranco
Published: August 2021

Introduction: Limited information is available on blood pressure (BP) behavior in workers exposed to chronic intermittent hypoxia (CIH), and even less is known regarding effects of CIH on 24-h ambulatory BP in those affected by arterial hypertension at sea level (SL). The aims of this study were to assess clinic and 24-h ambulatory BP at SL and at high altitude (HA; 3,870 m above SL) in workers exposed to CIH, and to compare BP response to HA exposure between normotensive and hypertensive workers.

Methods: Nineteen normotensive and 18 pharmacologically treated hypertensive miners acclimatized to CIH were included, whose work was organized according to a “7 days-on−7 days-off” shift pattern between SL and HA. All measurements were performed on the second and seventh day of their HA shift and after the second day of SL sojourn.

Results: Compared to SL, 24-h systolic BP (SBP) and diastolic BP (DBP) increased at HA [+14.7 ± 12.6 mmHg (p < 0.001) and +8.7 ± 7.2 mmHg (p < 0.001), respectively], and SBP nocturnal fall decreased consistently (−4.1 ± 9.8%; p < 0.05) in all participants, with hypertensives showing higher nocturnal DBP than normotensives (p < 0.05) despite the current therapy. Also, heart rate (HR) nocturnal fall tended to be reduced at HA. In addition, the 24-h SBP/DBP hypertension threshold of ≥130/80 mmHg was exceeded by 39% of workers at SL and by 89% at HA. Clinic HR, SBP, and DBP were significantly higher on the second day of work at HA compared with SL, the increase being more pronounced for SBP in hypertensives (p < 0.05) and accompanied by, on average, mild altitude sickness in both groups. These symptoms and the values of all cardiovascular variables decreased on the seventh day at HA (p < 0.05) regardless of CIH exposure duration.

Conclusion: Long history of work at HA according to scheduled CIH did not prevent the occurrence of acute cardiovascular changes at HA during the first days of exposure. The BP response to HA tended to be more pronounced in hypertensive than in normotensive workers despite being already treated; the BP changes were more evident for 24-h ambulatory BP. Twenty-four-hour ABP monitoring is a useful tool for an appropriate evaluation of BP in CIH workers.
Effect of SYTL3-SLC22A3 Variants, Their Haplotypes, and G × E Interactions on Serum Lipid Levels and the Risk of Coronary Artery Disease and Ischaemic Stroke
Authors: Zheng Peng-Fei , Yin Rui-Xing , Cao Xiao-Li , Chen Wu-Xian , Wu Jin-Zhen , Huang Feng
Published: August 2021

Background: The current study aimed to investigate the effects of synaptotagmin-like 3 (SYTL3) and solute carrier family 22 member 3 (SLC22A3) single nucleotide polymorphisms (SNPs) and gene-environment (G × E) interactions on blood lipid levels as well as the risk of coronary artery disease (CAD) and ischaemic stroke (IS) in the Southern Chinese Han population.

Methods: The genetic makeup of 6 SYTL3-SLC22A3 SNPs in 2269 unrelated participants (controls, 755; CAD, 758 and IS, 756) of Chinese Han ethnicity was detected by the next-generation sequencing techniques.

Results: The allele and genotype frequencies of the SYTL3 rs2129209 and SLC22A3 rs539298 SNPs were significantly different between the case and control groups. The SLC22A3 rs539298 SNP was correlated with total cholesterol (TC) levels in controls, the rs539298G allele carriers maintained lower TC levels than the rs539298G allele non-carriers. At the same time, the SLC22A3 rs539298 SNP interacted with alcohol consumption reduced the risk of CAD and IS. The SYTL3-SLC22A3 A-C-A-A-A-A, G-T-C-G-C-A and A-T-A-A-C-A haplotypes increased and the A-C-A-A-C-G haplotype reduced the risk of CAD, whereas the SYTL3-SLC22A3 A-C-A-A-A-A, G-T-C-G-A-G and A-T-A-A-C-A haplotypes increased and the A-C-A-A-A-G and A-C-A-A-C-G haplotypes reduced the risk of IS. In addition, several SNPs interacted with alcohol consumption, body mass index ≥ 24 kg/m2 and cigarette smoking to affect serum lipid parameters such as triglyceride, high-density lipoprotein cholesterol, TC, and apolipoprotein A1 levels.

Conclusions: Several SYTL3-SLC22A3 variants, especially the rs539298 SNP, several haplotypes, and G × E interactions, were related to blood lipid parameters and the risk of CAD and IS in the Southern Chinese Han population.
Direct Bilirubin Levels Predict Long-Term Outcomes in Patients With Acute Coronary Syndrome Under Different Glucose Metabolism Status: A 6.5-Year Cohort Study of Three-Vessel Disease
Authors: Liu Yue , Zhang Ce , Jiang Lin , Tian Jian , Zhao Xue-yan , Xu Jing-jing , Liu Ru , Xu Bo , Hui Ru-tai , Gao Run-lin , Yuan Jin-qing , Xu Lian-jun , Song Lei
Published: August 2021

Background: There is controversy over the relationship between bilirubin and coronary artery disease. This study aimed to evaluate the predictive value of direct bilirubin (DB) in patients with complex acute coronary syndrome (ACS).

Methods: From April 2004 to February 2011, 5,322 ACS patients presenting with three-vessel disease were consecutively enrolled. Disease severity and complexity were determined by SYNTAX score (SS) and SS II. The primary endpoint was all-cause death, and the secondary endpoints were major adverse cardiovascular and cerebrovascular events (MACCE). Stratification of normal glucose regulation, prediabetes, and diabetes was based on a previous diagnosis, hypoglycemic medications, fasting blood glucose, and hemoglobin A1c.

Results: Subjects were divided into quartiles according to baseline DB (μmol/L): Q1 (0–1.6), Q2 (1.61–2.20), Q3 (2.21–2.80), and Q4 (>2.80). Multivariable logistic regression analysis showed that DB was an independent predictor of intermediate–high SS. During a median follow-up time of 6.5 years, elevated DB was associated with more all-cause death (p < 0.001) but not MACCE. DB remained to be predictive of all-cause death in the multivariable Cox regression model (Q2 vs. Q1: HR 1.043, 95% CI 0.829–1.312, p = 0.719; Q3 vs. Q1: HR 1.248, 95% CI 1.001–1.155, p = 0.048; Q4 vs. Q1: HR 1.312, 95% CI 1.063–1.620, p = 0.011). When subjects are stratified according to glucose metabolism regulation and treatment strategies, the predictivity of DB was only profound in patients with diabetes or with conservative treatment. Additionally, incorporating DB further improved the discrimination and reclassification abilities of SS II for risk prediction.

Conclusion: DB is a potential biomarker for predicting lesion severity and long-term outcomes in ACS patients.
Clinical Characteristics, Prognosis, and Gender Disparities in Young Patients With Acute Myocardial Infarction
Authors: Lv Junxing , Ni Lin , Liu Kexin , Gao Xiaojin , Yang Jingang , Zhang Xuan , Ye Yunqing , Dong Qiuting , Fu Rui , Sun Hui , Yan Xinxin , Zhao Yanyan , Wang Yang , Yang Yuejin , Xu Haiyan
Published: August 2021

Background: Young people hold a stable or increasing percentage of patients with acute myocardial infarction (AMI) in many countries. However, data on clinical characteristics and outcomes of young AMI patients were insufficient. This study aimed to analyze clinical characteristics, prognosis, and gender disparities in patients aged ≤45 years with AMI.

Methods: A total of 24,125 patients from China Acute Myocardial Infarction registry were included in this study. Clinical characteristics, managements, and in-hospital and 2-year outcomes were compared between patients aged ≤45 years and those aged >45 years. Predictors of all-cause death were obtained using multivariate regression models. Gender disparities of AMI were analyzed among young patients.

Results: Of 24,125 patients, 2,042 (8.5%, 116 female) were aged ≤45 years. Compared with patients aged >45 years, young patients were more often male, current smokers, and more likely to have medical history of hyperlipidemia. Smoking (72.1%) was the major modifiable risk factor in patients aged ≤45 years. Young patients received more evidence-based medications and had significantly lower risk of both in-hospital and 2-year adverse events than older patients. Education level and left ventricular ejection fraction were independent predictors of 2-year mortality in young patients. Moreover, symptom onset to admission time of young women was significantly longer than that of young men. Young women were less likely to receive percutaneous coronary intervention and suffered higher risk of in-hospital adverse events than young men (adjusted odds ratio for death: 5.767, 95% confidence interval 1.580–21.049, p = 0.0080; adjusted odds ratio for the composite of death, re-infarction, and stroke: 3.981, 95% confidence interval 1.150–13.784, p = 0.0292). Young women who survived at discharge had a higher 2-year cumulative incidence of death (3.8 vs 1.4%, plog−rank = 0.0412).

Conclusions: Patients aged ≤45 years constituted a non-negligible proportion of AMI patients, with higher prevalence of smoking and hyperlipidemia but better care and prognosis compared with older patients. There were significant gender disparities of managements and outcomes in young patients. More efforts to improve quality of care in young women are needed.
A Policy-Driven Approach to Secure Extraction of COVID-19 Data From Research Papers
Authors: Elluri Lavanya , Piplai Aritran , Kotal Anantaa , Joshi Anupam , Joshi Karuna Pande
Published: August 2021

The entire scientific and academic community has been mobilized to gain a better understanding of the COVID-19 disease and its impact on humanity. Most research related to COVID-19 needs to analyze large amounts of data in very little time. This urgency has made Big Data Analysis, and related questions around the privacy and security of the data, an extremely important part of research in the COVID-19 era. The White House OSTP has, for example, released a large dataset of papers related to COVID research from which the research community can extract knowledge and information. We show an example system with a machine learning-based knowledge extractor which draws out key medical information from COVID-19 related academic research papers. We represent this knowledge in a Knowledge Graph that uses the Unified Medical Language System (UMLS). However, publicly available studies rely on dataset that might have sensitive data. Extracting information from academic papers can potentially leak sensitive data, and protecting the security and privacy of this data is equally important. In this paper, we address the key challenges around the privacy and security of such information extraction and analysis systems. Policy regulations like HIPAA have updated the guidelines to access data, specifically, data related to COVID-19, securely. In the US, healthcare providers must also comply with the Office of Civil Rights (OCR) rules to protect data integrity in matters like plasma donation, media access to health care data, telehealth communications, etc. Privacy policies are typically short and unstructured HTML or PDF documents. We have created a framework to extract relevant knowledge from the health centers’ policy documents and also represent these as a knowledge graph. Our framework helps to understand the extent to which individual provider policies comply with regulations and define access control policies that enforce the regulation rules on data in the knowledge graph extracted from COVID-related papers. Along with being compliant, privacy policies must also be transparent and easily understood by the clients. We analyze the relative readability of healthcare privacy policies and discuss the impact. In this paper, we develop a framework for access control decisions that uses policy compliance information to securely retrieve COVID data. We show how policy compliance information can be used to restrict access to COVID-19 data and information extracted from research papers.
Diabetes in Patients With Heart Failure With Reduced Ejection Fraction During Hospitalization: A Retrospective Observational Study
Authors: Zhou Yiling , Wang Miye , Wang Si , Li Nan , Zhang Shengzhao , Tang Siqi , Shi Qingyang , Zhao Yuliang , Li Jingwen , Zeng Yuping , Song Huan , Tian Haoming , Li Shuangqing , Li Sheyu
Published: August 2021

Background

Diabetes is prevalent worldwide including hospitalized patients with heart failure with reduced ejection fraction (HFrEF). This retrospective study investigated the association of diabetes with in-hospital adverse events in patients with HFrEF.

Methods

We analyzed data from electronic medical records of patients hospitalized with HFrEF in West China Hospital of Sichuan University from January 1, 2011, to September 30, 2018. Propensity score matching balances the baseline characteristics between patients with and without diabetes. Logistic and Poisson regressions investigated the association of diabetes with risks of intubation, cardiogenic shock, acute kidney injury (AKI), intensive care unit (ICU) admission and death during hospitalization, and length of ICU and hospital stay in the matched cases.

Results

Among 6,022 eligible patients (including 1,998 with diabetes), 1,930 patient pairs with and without diabetes were included by propensity score matching. Patients with diabetes had a significantly increased risk of intubation (odds ratio [OR], 2.69; 95% confidence interval [CI], 2.25–3.22; P<0.001), cardiogenic shock (OR, 2.01; 95% CI, 1.72–2.35; P<0.001), AKI at any stage (OR, 1.67; 95% CI, 1.44–1.94; P<0.001), ICU admission (OR, 1.89; 95% CI, 1.65–2.15; P<0.001), and death (OR, 4.25; 95% CI, 3.06–6.02; P<0.001) during hospitalization. Patients with diabetes had longer ICU (median difference, 1.47 days; 95% CI, 0.96–2.08; P<0.001) and hospital stay (2.20 days; 95% CI, 1.43–2.86; P<0.001) than those without diabetes. There were potential subgroup effects by age and by hypertension, and CKD status on the association of diabetes with risk of AKI at any stage; and subgroup effects by sex and CKD status on the association of diabetes with risk of intubation. The increase in length of hospital stay was larger in patients without hypertension than those with hypertension.

Conclusions

Among patients with HFrEF, those with diabetes have a worse prognosis, including a higher risk of in-hospital intubation, cardiogenic shock, AKI, ICU admission and death during hospitalization, and longer ICU and hospital stay.
Evaluating Invasive Marbled Crayfish as a Potential Livestock for Sustainable Aquaculture
Authors: Tönges Sina , Masagounder Karthik , Lenich Frank , Gutekunst Julian , Tönges Marvin , Lohbeck Jasmin , Miller Aubry K. , Böhl Florian , Lyko Frank
Published: August 2021

The marbled crayfish (Procambarus virginalis) is a recently discovered freshwater crayfish species, which reproduces by apomictic parthenogenesis, resulting in a monoclonal, and all-female population. The animals were widely distributed through the aquarium trade and have established numerous stable wild populations through anthropogenic releases. They are highly prevalent in Madagascar, where they have become a popular source of nutritional protein. As freshwater crayfish aquaculture in open systems is a thriving, but ecologically damaging global industry, alternatives are urgently needed. Although marbled crayfish are often branded by their invasive mode of reproduction, their overall invasiveness is not higher than for other cultured crayfish species. Furthermore, their resiliency and high adaptability provide a strong rationale for evaluating them for closed, and environmentally safe aquaculture approaches. Here we describe a novel population of marbled crayfish in a former German coal mining area that is characterized by acid and polluted water. Even under these adverse conditions, animals grew to sizes, and weights that are comparable to commercially farmed freshwater crayfish. Tailored feed development and laboratory testing demonstrated highly efficient feed conversion, suggesting a considerable capacity for sustainable production in closed systems. We further show that marbled crayfish meat can be readily introduced into European meals. Finally, chemical analysis of marbled crayfish exoskeletons revealed comparably high amounts of chitin, which is a valuable source for the synthesis of chitosan and bioplastics. Our results thus suggest that production of marbled crayfish in closed systems may represent a sustainable alternative for crayfish aquaculture.
Genetic Diversity, Structure and Effective Population Size of Old-Growth vs. Second-Growth Populations of Keystone and Long-Lived Conifer, Eastern White Pine (Pinus strobus): Conservation Value and Climate Adaptation Potential
Authors: Rajora Om P. , Zinck John W. R.
Published: August 2021

Whether old-growth (OG) forests have higher genetic diversity and effective population size, consequently higher conservation value and climate adaptive potential than second-growth (SG) forests, remain an unresolved issue. We have tested the hypothesis that old-growth forest tree populations have higher genetic diversity, effective population size (NE), climate adaptive potential and conservation value and lower genetic differentiation than second-growth forest tree populations, employing a keystone and long-lived conifer, eastern white pine (EWP; Pinus strobus). Genetic diversity and population structure of old-growth and second-growth populations of eastern white pine (EWP) were examined using microsatellites of the nuclear and chloroplast genomes and single nucleotide polymorphisms (SNPs) in candidate nuclear genes putatively involved in adaptive responses to climate and underlying multilocus genetic architecture of local adaptation to climate in EWP. Old-growth and second-growth EWP populations had statistically similar genetic diversity, inbreeding coefficient and inter-population genetic differentiation based on nuclear microsatellites (nSSRs) and SNPs. However, old-growth populations had significantly higher chloroplast microsatellites (cpSSRs) haploid diversity than second-growth populations. Old-growth EWP populations had significantly higher coalescence-based historical long-term NE than second-growth EWP populations, but the linkage disequilibrium (LD)-based contemporary NE estimates were statistically similar between the old-growth and second-growth EWP populations. Analyses of population genetic structure and inter-population genetic relationships revealed some genetic constitution differences between the old-growth and second-growth EWP populations. Overall, our results suggest that old-growth and second-growth EWP populations have similar genetic resource conservation value. Because old-growth and second-growth EWP populations have similar levels of genetic diversity in genes putatively involved in adaptive responses to climate, old-growth, and second-growth populations may have similar adaptive potential under climate change. Our results could potentially be generalized across most of the boreal and temperate conifer forest trees. Our study contributes to address a long-standing issue, advances research field and knowledge about conservation and ecological and climate adaptation of forest trees.
Identification of BRCA2 Cis Double Heterozygous Breast Cancer Cases Using Whole Exome Sequencing: Phenotypic Expression and Impact on Personalized Oncology
Authors: Hamdi Yosr , Boujemaa Maroua , Mighri Najah , Mejri Nesrine , Jaidane Olfa , Ben Nasr Sonia , Bouaziz Hanen , Hassouna Jamel Ben , Zribi Aref , Berrazaga Yossra , Rachdi Haifa , Daoud Nouha , El Benna Houda , Labidi Soumaya , Haddaoui Abderrazek , Rahal Khaled , Benna Farouk , Boussen Hamouda , Abdelhak Sonia , Boubaker Samir
Published: August 2021

BRCA1 and BRCA2 are the most commonly mutated breast cancer susceptibility genes that convey a high risk of breast and ovarian cancer. Most BRCA1 or BRCA2 mutation carriers have inherited a single heterozygous mutation. In recent years, very rare cases with biallelic or trans double heterozygous mutations on BRCA1 and or BRCA2 have been identified and seem to be associated with distinctive phenotypes. Given that this genotype-phenotype correlation in cancer predisposing hereditary conditions is of relevance for oncological prevention and genetic testing, it is important to investigate these rare BRCA genotypes for better clinical management of BRCA mutation carriers. Here we present the first report on Cis double heterozygosity (Cis DH) on BRCA2 gene identified using Whole exome sequencing (WES) in a Tunisian family with two BRCA2 mutations namely: c.632-1G>A and c.1310_1313DelAAGA that are both reported as pathogenic in ClinVar database. Subsequent analysis in 300 high-risk Tunisian breast cancer families detected this Cis double heterozygous genotype in 8 additional individuals belonging to 5 families from the same geographic origin suggesting a founder effect. Moreover, the observed Cis DH seems to be associated with an early age of onset (mean age = 35.33 years) and severe phenotype of the disease with high breast cancer grade and multiple cancer cases in the family. The identification of unusual BRCA genotypes in this Tunisian cohort highlights the importance of performing genetic studies in under-investigated populations. This will also potentially help avoiding erroneous classifications of genetic variants in African population and therefore avoiding clinical misdiagnosis of BRCA related cancers. Our findings will also have an impact on the genetic testing and the clinical management of North African breast cancer patients as well as patients from different other ethnic groups in regard to several emerging target therapies such as PARP inhibitors.
Diaphyseal and Metaphyseal Modeling Defects—Clinical Findings and Identification of WRAP53 Deficiency in Craniometadiaphyseal Dysplasia
Authors: Hao Yun , Wang Xiao-Lin , Xiao Jun , Jiao Chun-Lei , Meng Xin-Yao , Guo Jia-Chao , Shao Jing-Fan , Feng Jie-Xiong , He Jin-Peng
Published: August 2021

Background: Diaphyseal and metaphyseal modeling defects lead to severe changes in bone mass and shape, which are common features in osteoporosis that linked to non-vertebral fractures. Original mechanism of diaphyseal and metaphyseal modeling defects has proved elusive. Studying rare syndromes can elucidate mechanisms of common disorders and identify potential therapeutic targets.

Methods: We evaluated a family pedigree with craniometadiaphyseal dysplasia (CRMDD, OMIM 269300), a genetic disorder that is characterized by cortical-bone thinning, limb deformity, and absent of normal metaphyseal flaring and diaphyseal constriction. Systemic radiographic examination and serum hormone test were made for this rare disease. One patient and her two normal parents were examined by means of whole-exome sequencing (WES) to identify the candidate pathogenic gene and rule out mucopolysaccharidosis and Prader–Willi Syndrome by means of Sanger sequencing.

Results: There are several conspicuous radiographic characteristics: (1) bullet-shaped phalanges, (2) long and narrow pelvic inlet, absent of supra-acetabular constriction, (3) round rod-shaped long tubular bones, (4) prominent aiploic mastoid, (5) bending-shaped limb, genua varus and genu varum, and (6) congenital dislocation of elbow. Here, we did not find any wormian bones, and there are several typical clinical characteristics: (1) macrocephaly and wide jaw, (2) Avatar elf-shaped ears, pointed and protruding ears, (3) hypertrophy of limbs, (4) flat feet and giant hand phenomenon, (5) nail dystrophy, (6) limb deformity, (7) high-arched palate, (8) superficial hemangiomas, (9) tall stature, and intellectual disability. In this patient, we found biallelic frameshift deletion mutations in WRAP53, and those two mutations were transmitted from her parents respectively.

Conclusions: We describe her clinical and radiological findings and presented a new subtype without wormian bones and with a tall stature. Our study showed that craniometadiaphyseal dysplasia was caused by a deficiency of WRAP53 with autosomal recessive inheritance.
Case Report: Expanding the Digenic Variants Involved in Thyroid Hormone Synthesis−10 New Cases of Congenital Hypothyroidism and a Literature Review
Authors: Yang Rulai , Lu Yijun , Yang Chenxi , Wu Xiaoyu , Feng Junqi , Zhu Ling , Shu Qiang , Jiang Pingping
Published: August 2021

Congenital hypothyroidism (CH) is the most common neonatal metabolic disorder. Although it has been understood to be a monogenic disease, some CH patients are reported to carry two or more variants at different genes. Here, ten permanent congenital hypothyroidism (PCH) patients were retrospectively reviewed, with elevated levels of serum thyroid-stimulating hormone and levothyroxine dependence during follow-up between 2015 and 2019. Each affected individual carried digenic variants, which were heterozygous at two of pathogenic genes. In total, five pathogenic genes, TSHR, TG, TPO, DUOX2 and DUOXA2, were simultaneously identified in subjects that were involved in the same metabolic pathway: thyroid hormone biosynthesis. There were digenic variants at TSHR and DUOX2 combined in three patients, DUOX2 and TG combined in two patients, DUOX2 and DUOXA2 combined in two patients, TG and DUOXA2 combined in two patients, and TG and TPO combined in one patient. Additionally, seven novel variants, TSHR c.679G>A, DUOX2 c.127A>T, c.608-619del, c.959T>C, TG c.2307G>A, and c.6759_6765del, and DUOXA2 c.93T>G, were identified in these PCH patients. Along with a literature review on digenic variants in patients with CH, our findings illustrated the complexity of genetic etiology in CH.
Laminin Polymerization and Inherited Disease: Lessons From Genetics
Authors: Shaw Liam , Sugden Conor J. , Hamill Kevin J.
Published: August 2021

The laminins (LM) are a family of basement membranes glycoproteins with essential structural roles in supporting epithelia, endothelia, nerves and muscle adhesion, and signaling roles in regulating cell migration, proliferation, stem cell maintenance and differentiation. Laminins are obligate heterotrimers comprised of α, β and γ chains that assemble intracellularly. However, extracellularly these heterotrimers then assemble into higher-order networks via interaction between their laminin N-terminal (LN) domains. In vitro protein studies have identified assembly kinetics and the structural motifs involved in binding of adjacent LN domains. The physiological importance of these interactions has been identified through the study of pathogenic point mutations in LN domains that lead to syndromic disorders presenting with phenotypes dependent on which laminin gene is mutated. Genotype-phenotype comparison between knockout and LN domain missense mutations of the same laminin allows inferences to be drawn about the roles of laminin network assembly in terms of tissue function. In this review, we will discuss these comparisons in terms of laminin disorders, and the therapeutic options that understanding these processes have allowed. We will also discuss recent findings of non-laminin mediators of laminin network assembly and their implications in terms of basement membrane structure and function.
Retrospective Diagnosis of a Novel ACAN Pathogenic Variant in a Family With Short Stature: A Case Report and Review of the Literature
Authors: Mancioppi Valentina , Prodam Flavia , Mellone Simona , Ricotti Roberta , Giglione Enza , Grasso Nicolino , Vurchio Denise , Petri Antonella , Rabbone Ivana , Giordano Mara , Bellone Simonetta
Published: August 2021

Short stature is a frequent disorder in the pediatric population and can be caused by multiple factors. In the last few years, the introduction of Next Generation Sequencing (NGS) in the molecular diagnostic workflow led to the discovery of mutations in novel genes causing short stature including heterozygous mutations in ACAN gene. It encodes for aggrecan, a primary proteoglycan component specific for the structure of the cartilage growth plate, articular and intervertebral disc. We report a novel ACAN heterozygous pathogenic variant in a family with idiopathic short stature, early-onset osteoarthritis and osteoarthritis dissecans (SSOAOD). We also performed a literature review summarizing the clinical characteristic of ACAN's patients. The probands are two Caucasian sisters with a family history of short stature and osteoarthritis dissecans. They showed dysmorphic features such as mild midface hypoplasia, brachydactyly and broad thumbs, especially the great toes. The same phenotype was presented in the mother who had had short stature and suffered from intervertebral disc disease. DNA sequencing identified a heterozygous pathogenic variation (c.4390delG p.Val1464Ter) in the sisters, with a maternal inheritance. The nonsense mutation, located on exon 12, results in premature truncation and presumed loss of protein function. In terms of treatment, our patients underwent recombinant human growth hormone replacement therapy, associated with gonadotropin releasing hormone therapy, in order to block early growth cessation and therefore reach a better final height. Our case suggests that SSOAOD ACAN related should be considered in the differential diagnosis of children with autosomal dominant short stature and family history of joints disease.
Design of a Novel Multi-Epitope Vaccine Against Echinococcus granulosus in Immunoinformatics
Authors: Yu Mingkai , Zhu Yuejie , Li Yujiao , Chen Zhiqiang , Sha Tong , Li Zhiwei , Zhang Fengbo , Ding Jianbing
Published: August 2021

All the time, echinococcosis is a global zoonotic disease which seriously endangers public health all over the world. In order to speed up the development process of anti-Echinococcus granulosus vaccine, at the same time, it can also save economic cost. In this study, immunoinformatics tools and molecular docking methods were used to predict and screen the antigen epitopes of Echinococcus granulosus, to design a multi-epitope vaccine containing B- and T-cell epitopes. The multi-epitope vaccine could activate B lymphocytes to produce specific antibodies theoretically, which could protect the human body against Echinococcus granulosus infection. It also could activate T lymphocytes and clear the infected parasites in the body. In this study, four CD8+ T-cell epitopes, three CD4+ T-cell epitopes and four B-cell epitopes of Protein EgTeg were identified by immunoinformatics methods. Meanwhile, three CD8+ T-cell epitopes, two CD4+ T-cell epitopes and four B-cell epitopes of Protein EgFABP1 were identified. We constructed the multi-epitope vaccine using linker proteins. The study based on the traditional methods of antigen epitope prediction, further optimized the prediction results combined with molecular docking technology and improved the precision and accuracy of the results. Finally, in vivo and in vitro experiments had verified that the vaccine designed in this study had good antigenicity and immunogenicity.
ImmuCellDB: An Indicative Database of Immune Cell Composition From Different Tissues and Disease Conditions in Mouse and Human
Authors: Chen Ziyi , Na Han , Wu Aiping
Published: August 2021

Immune cell composition is highly divergent across different tissues and diseases. A comprehensive resource of tissue immune cells across different conditions in mouse and human will thus provide great understanding of the immune microenvironment of many diseases. Recently, computational methods for estimating immune cell abundance from tissue transcriptome data have been developed and are now widely used. Using these computational tools, large-scale estimation of immune cell composition across tissues and conditions should be possible using gene expression data collected from public databases. In total, 266 tissue types and 706 disease types in humans, as well as 143 tissue types and 61 disease types, and 206 genotypes in mouse had been included in a database we have named ImmuCellDB (http://wap-lab.org:3200/ImmuCellDB/). In ImmuCellDB, users can search and browse immune cell proportions based on tissues, disease or genotype in mouse or humans. Additionally, the variation and correlation of immune cell abundance and gene expression level between different conditions can be compared and viewed in this database. We believe that ImmuCellDB provides not only an indicative view of tissue-dependent or disease-dependent immune cell profiles, but also represents an easy way to pre-determine immune cell abundance and gene expression profiles for specific situations.
The Functions of Hepatitis B Virus Encoding Proteins: Viral Persistence and Liver Pathogenesis
Authors: Zhao Fenglin , Xie Xiaoyu , Tan Xu , Yu Hongli , Tian Miaomiao , Lv Huanran , Qin Chengyong , Qi Jianni , Zhu Qiang
Published: August 2021

About 250 million people worldwide are chronically infected with Hepatitis B virus (HBV), contributing to a large burden on public health. Despite the existence of vaccines and antiviral drugs to prevent infection and suppress viral replication respectively, chronic hepatitis B (CHB) cure remains a remote treatment goal. The viral persistence caused by HBV is account for the chronic infection which increases the risk for developing liver cirrhosis and hepatocellular carcinoma (HCC). HBV virion utilizes various strategies to escape surveillance of host immune system therefore enhancing its replication, while the precise mechanisms involved remain elusive. Accumulating evidence suggests that the proteins encoded by HBV (hepatitis B surface antigen, hepatitis B core antigen, hepatitis B envelope antigen, HBx and polymerase) play an important role in viral persistence and liver pathogenesis. This review summarizes the major findings in functions of HBV encoding proteins, illustrating how these proteins affect hepatocytes and the immune system, which may open new venues for CHB therapies.
Lactococcus lactis Expressing Type I Interferon From Atlantic Salmon Enhances the Innate Antiviral Immune Response In Vivo and In Vitro
Authors: Muñoz Carlos , González-Lorca Josue , Parra Mick , Soto Sarita , Valdes Natalia , Sandino Ana María , Vargas Rodrigo , González Alex , Tello Mario
Published: August 2021

In salmon farming, viruses are responsible for outbreaks that produce significant economic losses for which there is a lack of control tools other than vaccines. Type I interferon has been successfully used for treating some chronic viral infections in humans. However, its application in salmonids depends on the proper design of a vehicle that allows its massive administration, ideally orally. In mammals, administration of recombinant probiotics capable of expressing cytokines has shown local and systemic therapeutic effects. In this work, we evaluate the use of Lactococcus lactis as a type I Interferon expression system in Atlantic salmon, and we analyze its ability to stimulate the antiviral immune response against IPNV, in vivo and in vitro. The interferon expressed in L. lactis, even though it was located mainly in the bacterial cytoplasm, was functional, stimulating Mx and PKR expression in CHSE-214 cells, and reducing the IPNV viral load in SHK-1 cells. In vivo, the oral administration of this L. lactis producer of Interferon I increases Mx and PKR expression, mainly in the spleen, and to a lesser extent, in the head kidney. The oral administration of this strain also reduces the IPNV viral load in Atlantic salmon specimens challenged with this pathogen. Our results show that oral administration of L. lactis producing Interferon I induces systemic effects in Atlantic salmon, allowing to stimulate the antiviral immune response. This probiotic could have effects against a wide variety of viruses that infect Atlantic salmon and also be effective in other salmonids due to the high identity among their type I interferons.
The Clinical Aspect of Adaptor Molecules in T Cell Signaling: Lessons Learnt From Inborn Errors of Immunity
Authors: Dinur-Schejter Yael , Zaidman Irina , Mor-Shaked Hagar , Stepensky Polina
Published: August 2021

Adaptor molecules lack enzymatic and transcriptional activities. Instead, they exert their function by linking multiple proteins into intricate complexes, allowing for transmitting and fine-tuning of signals. Many adaptor molecules play a crucial role in T-cell signaling, following engagement of the T-cell receptor (TCR). In this review, we focus on Linker of Activation of T cells (LAT) and SH2 domain-containing leukocyte protein of 76 KDa (SLP-76). Monogenic defects in these adaptor proteins, with known roles in T-cell signaling, have been described as the cause of human inborn errors of immunity (IEI). We describe the current knowledge based on defects in cell lines, murine models and human patients. Germline mutations in Adhesion and degranulation adaptor protein (ADAP), have not resulted in a T-cell defect.
The Hunger Games: Aggregatibacter actinomycetemcomitans Exploits Human Neutrophils As an Epinephrine Source for Survival
Authors: Ozuna Hazel , Uriarte Silvia M. , Demuth Donald R.
Published: August 2021

Aggregatibacter actinomycetemcomitans is a gram-negative facultative anaerobe and an opportunistic oral pathogen, strongly associated with periodontitis and other inflammatory diseases. Periodontitis is a chronic inflammation of the periodontium resulting from the inflammatory response of the host towards the dysbiotic microbial community present at the gingival crevice. Previously, our group identified catecholamines and iron as the signals that activate the QseBC two-component system in A. actinomycetemcomitans, necessary for the organism to acquire iron as a nutrient to survive in the anaerobic environment. However, the source of catecholamines has not been identified. It has been reported that mouse neutrophils can release catecholamines. In periodontitis, large infiltration of neutrophils is found at the subgingival pocket; hence, we wanted to test the hypothesis that A. actinomycetemcomitans exploits human neutrophils as a source for catecholamines. In the present study, we showed that human neutrophils synthesize, store, and release epinephrine, one of the three main types of catecholamines. Human neutrophil challenge with A. actinomycetemcomitans induced exocytosis of neutrophil granule subtypes: secretory vesicles, specific granules, gelatinase granules, and azurophilic granules. In addition, by selectively inhibiting granule exocytosis, we present the first evidence that epinephrine is stored in azurophilic granules. Using QseC mutants, we showed that the periplasmic domain of the QseC sensor kinase is required for the interaction between A. actinomycetemcomitans and epinephrine. Finally, epinephrine-containing supernatants collected from human neutrophils promoted A. actinomycetemcomitans growth and induced the expression of the qseBC operon under anaerobic conditions. Based on our findings, we propose that A. actinomycetemcomitans promotes azurophilic granule exocytosis by neutrophils as an epinephrine source to promote bacterial survival.