bluuebunny/crossref_metadata_2025 huggingface dataset:
The small and large intestine contain transcriptionally related mesenchymal stromal cell subsets that derive from embryonic Gli1+ mesothelial cells
Authors: Pærregaard Simone , Schussek Sophie , Wulff Line , Niss Kristoffer , Mörbe Urs , Jendholm Johan , Wendland Kerstin , Andrusaite Anna , Brulois Kevin , Nibbs Robert , Sitnik Katarzyna , Mowat Allan , Butcher Eugene , Brunak Søren , Agace William
Published: October 2021

Intestinal fibroblasts (FB) play essential roles in intestinal homeostasis. Here we show that the small and large intestinal lamina propria (LP) contain similar FB subsets that locate in specific anatomical niches and express distinct arrays of epithelial support genes. However, there were tissue specific differences in the transcriptional profile of intestinal FB subsets in the two sites. All adult intestinal LP mesenchymal stromal cells (MSC), including FB, smooth muscle cells (SMC) and pericytes derive from Gli1-expressing embryonic precursors which we identify as mesothelial cells. Trajectory analysis suggested that adult SMC and FB derive from distinct embryonic intermediates, and that adult FB subsets develop in a linear trajectory from CD81+ FB. Finally, we show that colonic subepithelial PDGFRαhi FB comprise several functionally and anatomically distinct populations that originate from an Fgfr2-expressing FB intermediate. Collectively our results provide novel insights into MSC diversity, location, function and ontogeny, with implications for our understanding of intestinal development, homeostasis and disease.
The Neutrophil Percentage-to-Albumin Ratio is Associated with All-Cause Mortality in Critically Ill Patients with Acute Myocardial Infarction
Authors: Lin Ya , Lin Yanhan , Yue Juanqing , Zou Qianqian
Published: October 2021

Aim
In this study, we evaluated the utility of neutrophil percentage-to-albumin ratio (NPAR) in predicting in critically ill patients with acute myocardial infarction (AMI).
Methods
the information of patients were collected from Medical Information Mart for Intensive Care III (MIMIC III) database. Admission NPAR was calculated as neutrophil percentage divided by serum albumin. The endpoints of this study were 30-day, 90-day, 180-day, and 365-day all-cause mortality. Cox proportional hazards models and subgroup analyses were used to determine the relationship between admission NPAR and these endpoints.
Results
798 critically ill patients with AMI were enrolled in. After adjustments for age, race and gender, higher admission NPAR was associated with increased risk of 30-day, 90-day, 180-day, and 365-day all-cause mortality in critically ill patients with AMI. And after adjusting for possible confounding variables, two different trends have emerged. Stratified by tertiles, high admission NPAR was independently associated with 180-day and 365-day all-cause mortality in critically ill patients with AMI (tertile 3 vs. tertile 1: adjusted HR, 95%CI: 1.71,1.10-2.66, p<0.05;1.66,1.10-2.51, p<0.05). In other hand, stratified by quartiles, highest admission NPAR levels were independently associated with 90-day, 180-day and 365-day all-cause mortality (quartile 4 vs. quartile 1: adjusted HR, 95% CI: 2.36,1.32-4.23, p<0.05; 2.58,1.49-4.47, p<0.05; 2.61,1.56-4.37, p<0.05). ROC test showed that admission NPAR had a moderate ability to predict all-cause mortality of critically ill patients with AMI. No obvious interaction was found by subgroup analysis in most subgroups.
Conclusions
admission NPAR was an independent predictor for 180-day and 365-day all-cause mortality in critically ill patients with AMI.
Mechanism and Modeling of Human Disease-associated Near-exon Intronic Variants That Perturb RNA Splicing
Authors: Lin Chien-Ling , Chiang Hung-Lun , Chen Yi-Ting , Su Jia-Ying , Lin Hsin-Nan , Yu Chen-Hsin , Hung Yu-Jen , Wang Yun-Lin , Huang Yen-Tsung
Published: October 2021

The authors have requested that this preprint be removed from Research Square.
Sex-Related Differences in Visuomotor Skill Recovery Following Concussion in Working-Aged Adults
Authors: Smeha Nicole , Kalkat Ravneet , Sergio Lauren E. , Hynes Loriann M.
Published: October 2021

Background: The ability to perform visually-guided motor tasks requires the transformation of visual information into programmed motor outputs. When the guiding visual information does not align spatially with the motor output, the brain processes rules to integrate somatosensory information into an appropriate motor response. Performance on such rule-based, “cognitive-motor integration” tasks is affected in concussion. Here, we investigate the relationship between visuomotor skill performance, concussion history, and sex during the course of a post-concussion management program. Methods: A total of 43 participants, divided into 3 groups based on their concussion history, completed a recovery program over the course of 4 weeks. Prior to, mid-way, and following the program, all participants were tested on their visuomotor skills. Results: We observed an overall change in visuomotor behaviour in all groups, as participants completed the tasks faster and more accurately. Specifically, we observed significant visuomotor skill improvement between the first and final sessions in participants with a concussion history compared to no-concussion-history controls. Notably, we observed a stronger recovery of these skills in females. Conclusions: Our findings indicate that (1) concussion impairs visuomotor skill performance, (2) the performance of complex, rule-based tasks can be improved over the course of a recovery program, and (3) stronger recovery in females suggests sex-related differences in the brain networks controlling skilled performance, and the effect of injury on these networks.
Effects of SiC On the Microstructure, Densification, Hardness and Wear Performance of TiB2 Ceramic Matrix Composite Consolidated Via Spark Plasma Sintering
Authors: Oguntuyi Samson Dare , Shongwe Mxolisi Brendon , Tshabalala Lerato , Johnson Oluwagbenga T. , Malatji Nicholus
Published: October 2021

Monolithic TiB2 are known to have a good combination of densification and hardness which are sometimes useful but limited in application. However, their usage in service at elevated temperatures such as in power thermal plants, cutting tools, tribological purposes (cutting tools, mechanical seals, blast nozzles, and wheel dressing tools), etc leads to catastrophic failure. Hence, the introduction of sintering additives in the TiB2 matrix has a high influence on the improvement of its sinterability, and properties (fracture toughness, wear resistance etc.,) of the resulting composite needed to meets the requirement for various industrial applications. In this study, the influence of SiC as sintering additives on the microstructure, densification, hardness and wear performance of TiB2 ceramic was observed. Hence, TiB2, TiB2-10wt%SiC and TiB2-20wt%SiC were sintered at 1850 oC for 10 minutes under 50 MPa. The impacts of SiC on the TiB2 were observed to improve the microstructure correspondingly improving densification and mechanical properties, most especially with the composites with 20wt% SiC. Combined excellent densification, hardness and fracture toughness of 99.5%, 25.5 GPa, 4.5 MPa.m1/2 were achieved respectively for TiB2-20wt%SiC. Diverse in-situ phase and microstructural alterations were detected in the sintered composites, and it was discovered that the in-situ phase of TiC serves as the contributing factor to the enhanced features of the composites. Moreover, the coefficient of friction and wear performance outcomes of the synthesized composites described a decrease in the coefficient with an enhanced wear resistance via the increasing SiC particulate, although the application of the load from 10 N-20 N increased the wear rates.
Comparison of the Effectiveness of High-Flow Nasal Oxygen vs. Standard Facemask Oxygenation for pre- and apneic oxygenation during Anesthesia Induction: A Systematic Review and Meta-analysis
Authors: Song Jian-li , Sun Yan , Shi Yu-bo , Liu Xiao-ying , Su Zhen-bo
Published: October 2021

BackgroundIn recent years, high flow nasal oxygen(HFNO) has been widely used in clinic, especially in perioperative period.Many studies have discussed the role of HFNO in pre- and apneic oxygenation, but their results are controversial.Our study aimed to examine the effectiveness of HFNO in pre- and apneic oxygenation by a meta-analysis ofRCTs.MethodsEMBASE, PUBMED, and COCHRANE LIBRARY databases were searched from inception to July 2021 for relevantrandomized controlled trails(RCTs) on the effectiveness of HFNO versus standard facemask ventilation(FMV) inpre- and apenic oxygenation. Studies involving one of the following six indicators: (1)Arterial oxygen partialpressure(PaO2), (2)End expiratory oxygen concentration(EtO2), (3)Safe apnoea time, (4)Minimum pulse oxygensaturation(SpO2min), (5)Oxygenation(O2) desaturation, (6)End expiratory carbon dioxide(EtCO2) or Arterial carbondioxide partial pressure(PaCO2) were included. We select random effect model or fixed effect model for analysisaccording to the heterogeneity of the article, and express it as the mean difference(MD) or risk ratio(RR) with aconfidence interval of 95%(95%CI). We conducted a risk assessment of bias for eligible studies and assessed theoverall quality of evidence for each outcome.Results14 RCTs and 1012 participants were finally included. We found the PaO2 was higher in HFNO group than FMVgroup with a MD(95% CI) of 57.38 mmHg(25.65 to 89.10; p=0.0004) after preoxygenation and the safe apnoeatime was significantly longer with a MD(95% CI) of 86.93 seconds(44.35 to 129.51; p<0.0001) during anesthesiainduction. There were no significant statistical difference in the minimum O2 saturation, CO2 accumulation, endexpiratory oxygen concentration and O2 desaturation rate during anesthesia induction between the two groups.ConclusionsThis systematic review and meta-analysis suggests that HFNO should be considered as an airway managementtool for patients with high-risk hypoxemia or difficult airway during anesthesia induction. Compared with FMV,continuous use of HFNO during anesthesia induction can significantly improve oxygenation and prolong safeapnoea time in surgical patients.
Nonlinear response of gear system based on a novel backlash model with coupling dynamic change and surface topography
Authors: Yu Xin , Sun Yunyun , Li Hongguang , Wu Shijing
Published: October 2021

Backlash is one of main nonlinear internal excitation factors in gear transmission system and therefore has been widely concerned. Most existing models of backlash are based on a random constant, which ignore the dynamic characteristics of backlash itself and the effects of surface topography. To model the backlash precisely, in this paper, the constant part of backlash is revised through average height of all asperities in contact region related to surface roughness by fractal method. Simultaneously, the dynamic part is modeled considering the displacement of gear center motion that comes from shaft deformation in coupling dynamic meshing. A complete backlash model consisting of the two parts is established subsequently and a corresponding close-loop algorithm is proposed to solve system dynamics by coupling mesh stiffness and time varying pressure angle. Through time history charts, phase portraits and Poincare mapping as well as frequency spectrograms, calculation results clearly demonstrate the comprehensive effects of dynamic backlash on the nonlinear dynamics involving vibration amplitude, frequency and chaotic characteristics of a spur gear pair. The effects of surface topography on backlash and system nonlinear response including vibration amplitude and chaotic features are also analyzed, therefore dynamic backlash and surface topography are important factors that cannot be ignored in gear issue. The comparison with experimental data as well as other previous models is conducted to verify the superiority of proposed model.
Differences in RNA polymerase II complexes and their interactions with surrounding chromatin on human and cytomegalovirus genomes
Authors: Spector Benjamin , Parida Mrutyunjaya , Ball Christopher , Li Ming , Meier Jeffrey , Luse Donal S. , Price David
Published: October 2021

Interactions of the RNA polymerase II (Pol II) preinitiation complex (PIC) and paused early elongation complexes with the first downstream (+1) nucleosome are thought to be functionally important. However, current methods are limited for investigating these relationships, both for cellular chromatin and the human cytomegalovirus (HCMV) genome. Digestion with human DNA fragmentation factor (DFF) before immunoprecipitation (DFF-ChIP) precisely revealed both similarities and major differences in PICs driven by TBP on the host genome in comparison with PICs driven by TBP or the viral-specific, late initiation factor UL87 on the viral genome. Host PICs and paused Pol II complexes are frequently found in contact with the +1 nucleosome and paused Pol II can also be found in a complex involved in the initial invasion of the +1 nucleosome. In contrast, viral transcription complexes have very limited nucleosomal interactions, reflecting a relative lack of chromatinization of transcriptionally active regions of HCMV genomes.
Metagenomics-informed soil biogeochemical models projected less carbon loss in tropical soils in response to climate warming
Authors: song Yang , Yao Qiuming , Yao Xiaojuan , Wright Joseph , Wang Gangsheng , Hazen Terry , Turner Benjamin , Tfaily Malak , Paša-Tolic Ljiljana , Johnston Eric , Kim Minjae , Konstantinos Konstantinos , Pan Chongle , Mayes Melanie
Published: October 2021

A major challenge of quantifying feedback between microbial communities and climate is the vast diversity of microbial communities and the intricacy of soil biogeochemical processes they mediate. We overcome this challenge by simplifying the representation of diverse enzyme functions from metagenomics data. We developed a dynamic allocation scheme for enzyme functional classes (EFCs) based on the premise that microbial communities act to maximize acquisition of limiting resources while minimizing energy expenditure for acquiring unlimited resources. We incorporated this scheme into a biogeochemical model to explicitly represent microbial functional diversity and simulate responses of microbially-mediated soil biogeochemical processes to varying environmental and nutrient conditions. Representing microbial functional diversity and environmental acclimation improved predictions of the stoichiometry of microbial biomass and mitigated the sensitivity of soil organic carbon to warming in nutrient-deficient regions. Our results indicate the importance of microbial functional diversity and environmental acclimation for projecting climate feedbacks of nutrient-limited soils.
Virtual Reality-based Vision Therapy Versus OBVAT in the Treatment of Convergence Insufficiency, Accommodative Dysfunction: A Randomized Controlled Trial
Authors: Li Shijin , Tang Angcang , Yang Bi , Wang Jianglan , Liu Longqian
Published: October 2021

Background: Virtual reality is being increasingly applied in vision therapy. However, the differences in effectiveness, optimal treatment cycle, and prognosis between virtual reality-based vision therapy and traditional therapies remain unknown. The purpose of this study was to compare the effectiveness of virtual reality-based vision therapy and office-based vergence/accommodative therapy in young adults with convergence insufficiency or accommodative dysfunction.Methods: The patients were randomly assigned to either the virtual reality-based vision therapy group or the office-based vergence/accommodative therapy group. The vision therapy lasted 12 weeks (1 h/week) in both groups. Binocular visual functions (vergence and accommodation) were measured and a subjective questionnaire-based assessment was performed at baseline and after 6 and 12 weeks of therapy.Results: In total, 33 patients with convergence insufficiency and 30 with accommodative dysfunction completed the study. After 12 weeks of treatment for convergence insufficiency, the Convergence Insufficiency Symptom Survey score (F2,31 = 13.704, P < 0.001), near point of convergence (F2,31 = 21.774, P < 0.001), positive fusional vergence (F2,31 = 71.766, P< 0.001), and near horizontal phoria (F2,31 = 16.482, P < 0.001) improved significantly in both groups. Moreover, the monocular accommodative amplitude (F2,25 = 22.154, P < 0.001) and monocular accommodative facility (F2,25 = 86.164, P < 0.001) improved significantly in both groups after 12 weeks of treatment. A statistically significant difference was observed in monocular accommodative facility (F1,25 = 8.140, P = 0.009) between the two groups, but not in other vergence and accommodative functions (0.098 < P < 0.687).Conclusion: Virtual reality-based vision therapy significantly improved binocular vision functions and symptoms in patients with convergence insufficiency and accommodative dysfunction, thereby suggesting its effectiveness as a new optional or additional treatment for young adults with these conditions.Trial registration: This study was registered at the Chinese Clinical Trials Registry on 16/04/2019 (identifier: ChiCTR1900022556).
Termination of Pregnancy for Fetal Anomaly: A Systematic Review of the Healthcare Experiences and Needs of Parents
Authors: Heaney Mrs Suzanne , Tomlinson Professor Mark , Aventin ine
Published: October 2021

BackgroundImproved technology and advances in clinical testing have resulted in increased detection rates of congenital anomalies during pregnancy, resulting in more parents being confronted with the possibility of terminating a pregnancy for this reason. There is a large body of research on the psychological experience and impact of terminating a pregnancy for fetal anomaly. However, there remains a lack of evidence on the holistic healthcare experience of parents in this situation. To develop a comprehensive understanding of the healthcare experience and needs of parents, this systematic review sought to summarise and appraise the literature on parents’ experiences following a termination of pregnancy for fetal anomaly.Review Question:What are the healthcare experiences and needs of parents who undergo a termination of pregnancy following an antenatal diagnosis of a fetal anomaly?MethodsA systematic review was undertaken with searches completed across six multi-disciplinary electronic databases (Medline, Embase, PsycINFO, CINAHL, Web of Science, and Cochrane). Eligible records were qualitative, quantitative or mixed methods studies, published between January 2010 and August 2021, reporting the results of primary data on the healthcare experiences or healthcare needs in relation to termination of pregnancy for fetal anomaly for either or both parents. Findings were synthesised using Thematic Analysis.ResultsA total of 30 records were selected for inclusion in this review of which 24 were qualitative, five quantitative and one mixed-methods. Five overarching themes emerged from the synthesis of findings: (1) Context of Care, (2) Person-centred Care, (3) Compassionate Care, (4) Co-ordinated Care, and (5) Inclusive Care.ConclusionCompassionate healthcare professionals who provide non-judgemental and sensitive care can impact positively on parents’ satisfaction with the care they receive. A well organised and co-ordinated healthcare system is needed to provide an effective and high-quality service.Registration:PROSPERO registration number: CRD42020175970
Ophthalmic and Genetics Profiles of Cystinosis in Tunisian Patients
Authors: Chkioua Latifa , Amri Yessine , Saheli Chayma , Mili Wassila , Mabrouk Sameh , Chabchoub Imen , Boudabous Hela , Azzouz Wissem Ben , Turkia Hadhami Ben , Ferchichi Salima , Tebib Neji , Massoud Taieb , Ghorbel Mohamed , Laradi Sandrine
Published: October 2021

Background: Ocular cystinosis is a rare autosomal recessive disorder characterized by intralysosomal cystine accumulation in renal, ophthalmic (cornea, conjunctiva), and other organ abnormalities. Patients with ocular cystinosis are mostly asymptomatic and typically experience mild photophobia due to cystine crystals in the cornea observed accidently during a routine ocular examination. The ocular cystinosis is associated with different mutations in CTNS gene. Cysteamine therapy mostly corrects the organ abnormalities. Methods: This study was performed in collaboration with the department of ophthalmology of Farhat Hached Hospital. The Optical Coherence Tomography (OCT) of the cornea and retinal photography were used to search cystine crystals within the corneas and conjunctiva in eight Tunisian patients. Screening for the common 57-kb deletion was performed by standard multiplex PCR, followed by direct sequencing of the entire CTNS gene. Results: The studied patients were found to have cystine crystal limited anterior corneal stroma and the conjunctiva associated with retinal crystals accumulation. CTNS gene sequencing disclosed 7 mutations: three missense mutations (G308R, p.Q88K, and p.S139Y); one duplication (C.829dup), one framshift mutation (p.G258f), one splice site mutation (c.681+7delC) and a large deletion (20327-bp deletion). Crystallographic structure analysis suggests that the novel mutation p.S139Y is buried in a first transmembrane helix closed to the lipid bilayer polar region, introducing a difference in hydrophobicity which could affect the hydrophobic interactions with the membrane lipids. The second novel mutation p.Q88K which is located in the lysosomal lumen close to the lipid membrane polar head region, introduced a basic amino acid in a region which tolerate only uncharged residue. The third missense mutation introduces a positive change in nonpolar tail region of the phospholipid bilayer membrane affecting the folding and stability of the protein in the lipid bilayer. Conclusion: Our data demonstrate that impaired transport of cystine out of lysosomes is the most common, which is obviously associated with the mutations of transmembrane domains of cystinosine resulting from a total loss of its activity.
RNA-seq Explores the Mechanism of Oxygen-Boosted Sonodynamic Therapy Based on All-in-One Nanobubbles to Enhance Ferroptosis for the Treatment of HCC
Authors: Chen Yichi , Shang Haitao , Wang Chunyue , Zeng Jiaqi , Zhang Shentao , Wu Bolin , Cheng Wen
Published: October 2021

Background
The combination of sonodynamic therapy and oxygenation strategy is widely used in cancer treatment. However, due to the complexity, heterogeneity and irreversible hypoxic environment produced by Hepatocellular carcinoma (HCC) tissues, oxygen-enhancing sonodynamic therapy (SDT) have failed to achieve the desired results. With the emergence of ferroptosis with reactive oxygen species (ROS) cytotoxicity, this novel cell death method has attracted widespread attention.
Methods
In this study, nanobubbles (NBs) were connected with the sonosensitizer Indocyanine green (ICG) to construct a 2-in-1 nanoplatform loaded with RAS-selective lethal (RSL3, ferroptosis promoter) (RSL3@O2-ICG NBs), combined with oxygen-enhanced SDT and potent ferroptosis. In addition, nanobubbles (NBs) combined with low-frequency ultrasound (LFUS) are called ultrasound-targeted nanobubble destruction (UTND) to ensure specific drug release and improve safety.
Results
MDA/GSH and other related experimental results show that RSL3@O2-ICG NBs can enhance SDT and ferroptosis. Through RNA sequencing (RNA-seq), the differential expression of LncRNA and mRNA before and after synergistic treatment was identified, and then GO and KEGG pathways were used to enrich and analyze target genes and pathways related ferroptosis sensitivity. Then we searched for the expression of differentially expressed genes in the TCGA Hepatocellular carcinoma cohort. At the same time, we evaluated the proportion of immune cell infiltration and the identification of co-expression network modules and related prognostic analysis. We found that it was significantly related to the tumor microenvironment of hepatocellular carcinoma. The prognostic risk genes "SLC37A2" and "ITGB7" may represent new hepatocellular carcinoma ferroptosis-inducing markers and have guiding significance for treating hepatocellular carcinoma.
Conclusions
The therapeutic effect of the in vitro synergistic treatment has been proven to be significant, revealing the prospect of 2-in-1 nanobubbles combined with SDT and ferroptosis in treating HCC.
Comparing NKp44+ and NKp44− ILC3s in Human Lung Cancer via Transcriptional Sequencing
Authors: Cheng Hang , Zhu Shan , Jin Chengyan , Wu Jing , Lv Xinping , Li Tete , Zang Guoxia , Gao Bao , Yang Zhiguang , Cui Jiuwei , Ueno Hideki , Liu Yong-Jun , Chen Jingtao
Published: October 2021

Purpose: Innate lymphoid cells (ILCs) play essential roles in mucosal innate immunity. The presence and function of ILCs in human lung cancer have not been extensively studied. This study aimed to identify and analyze the characteristics of the predominant subgroups in lung cancer. Methods: Single-cell suspensions were obtained from lung tissue diseased regions, non-diseased regions, and peripheral blood. The distribution of the ILC subgroups was analyzed by flow cytometry. The RNA of all samples was sequenced by BGI Group. Differentially expressed genes (DEGs) were assessed by functional and pathway enrichment analyses. Results: ILC3s were exclusively increased in the lung cancer diseased region. The NKp44 + ILC3 subgroup was found in the diseased and non-diseased regions, but not in the peripheral blood. RNA sequencing indicated similar basic transcripts in NKp44 − ILC3s and NKp44 + ILC3s, but more enrichment in the signal transduction pathway and signaling molecules and interaction pathway in NKp44 + ILC3s. Compared with in NKp44 − ILC3s, gene transcripts tended to be upregulated in NKp44 + ILC3s in the Ras, RAP1, Jak-STAT, Notch, NF-κB, and Toll-like receptor signaling pathways and downregulated in the TGF-β signaling pathway. In the signaling molecules and interaction pathway, levels of most key molecules were higher in NKp44 + ILC3s in the cell adhesion molecules and cytokine-cytokine receptor interaction pathways. Conclusion: ILC3s was the dominant group in lung cancer and NKp44 + ILC3s was significant in diseased region. By transcripts analysis, the upregulated pathways in NKp44 + ILC3s enable survival, proliferation, activation, interleukin production, and antigen presentation. Our results provide the transcript landscape of DEGs in NKp44 + and NKp44 − ILC3s in lung cancer, providing a theoretical basis for further study of potential therapies.
Willingness to Pay for a National Health Insurance (NHI) in Saudi Arabia: A Cross-sectional Study
Authors: Alharbi Abeer
Published: October 2021

Background Public health services in Saudi Arabia are provided free of charge to its citizens at the point of use. Recently, however, the government has realized that this model is unsustainable in the long run. Therefore, Saudi decision-makers are seeking to have a sustainable health system through the introduction of a contributory National Health Insurance that require making regular financial contributions from its members. Objective This study aims to explore the people’s willingness to pay for a National Health Insurance system in Saudi Arabia. The study also aims to understand the factors affecting their willingness or unwillingness to pay NHI, such as, their demographic and socio-economic characteristics, the type of their usual health care provider, and their satisfaction with the current healthcare services.Methods A cross-sectional study design with Contingent Valuation (CV) technique was used to measure the value of National Health Insurance based on an individual’s willingness to pay. The data were collected from 475 participants using an online survey via Google Forms between March 2021 and April 2021. Frequencies, logistic regression, and linear regression, were conducted to answer the research questions.Results The percentage of individuals who was willing to pay for NHI was higher than those who were not willing to pay (62.9%) vs (37.1%). There was a significant association between the type of usual healthcare provider and the likelihood of paying for NHI (OR CI = 0.20 to 0.51, p< 0.05=0.00). Also, there was a significant association between satisfaction with healthcare services and the likelihood of paying for NHI (OR CI = 0.02 to 0.31, p< 0.05=0.00). The median amount of money the people were willing to pay as a monthly contribution for NHI was 100 SAR (26.5 USD) with the average being 152 SAR (40 USD). There was a significant association between age and the maximum amount the participants were willing to pay (ß=-0.15,t=-2.55,p<0.05=0.01). In addition, the results show a significant relationship between income and the maximum amount of money people were willing to pay (ß=-0.25,t=3.81,p<0.05=0.001).Conclusion This study provided some evidence that most of the population of Saudi Arabia were willing to pay for NHI if implemented. The factors that appeared to influence the willingness to pay and the amount of monthly payment included the type of usual source of care, satisfaction with current public services, age, and income.
Experimental Study on the Structural Features and Corrosion Characteristics of Dolomite and Limestone in the Karst Stone Mountainous Areas in Northern Guangxi
Authors: Gu Zhanfei , Liu Zhikui
Published: October 2021

Taking dolomite and limestone in Guilin and Liuzhou regions in the north of Guangxi Province as research objects, this paper analyzed their mineral composition and chemical composition, and then carried out the chemical corrosion test, the corrosion test under the chemical-temperature actions, and the corrosion test under the action of vibration load, respectively. The results showed that: (i) the dolomite in northern Guangxi mainly has fine crystalline texture and massive structure with low content of acid insoluble matters, while limestone mainly has powder crystalline texture and massive structure with high content of acid insoluble matters, and the purity of both dolomite and limestone are very high; (ii) the difference of corrosion between dolomite and limestone mainly depends on the ratio of CaO/MgO in their chemical composition, and the content of silica and acid insoluble matters; (iii) the corrosion rates of the pure dolomite and the pure limestone are basically the same under the same external conditions; (iv) temperature and vibration load have relatively large influence on the corrosion rates of dolomite and limestone, and the corrosion rates of dolomite and limestone increase with the increase of temperature, but the influence of vibration load on the corrosion rate is more significant than temperature. This research can provide theoretical basis and technical support for large-scale engineering construction and prevention of karst geologic disasters in karst stone mountainous areas in the northern Guangxi.
Keywords: dolomite and limestone; structural features; corrosion characteristics; northern Guangxi
Privacy Preserving model for patient centric health record management using chaincode
Authors: mani vinodhini , M Prakash
Published: October 2021

Cloud computing poses a challenge to the healthcare infrastructure, as it affects privacy, confidentiality, and security rules concerning large binary objects such as x-rays and CT scan reports. However, health records are stored and accessed using an encryption hash which is stored in the interplanetary file system (IPFS), called a peer-to-peer system. But the patient’s data is sold, share for research purposes by their healthcare providers without their knowledge as it affects their privacy and security. In the healthcare industry today, customers face the issue of health record that lacks interoperability, resulting in difficulty aggregating and examining patient data. The objective of this research is to develop cybersecurity measurement approaches that ensure patient information security by protecting against cyber threats using blockchain technology based on healthcare IT. Consequently, this paper proposes an innovative solution to the problem, namely Patient-centric healthcare data management (PCHDM). It was built using IPFS, a permissioned distributed ledger system that uses Hyperledger Fabric, which stores health records, but only with the permission of the owner. A unique cryptographic public key encryption algorithm is used to encrypt IPFS data to build an electronic health record blockchain system. Our platform offers two types of solutions: (i) a solution that utilizes a database of hyper ledger fabric, which is an on-chain database, (ii) off-chain solutions which encrypt data and store it securely off-chain using IPFS. A robust blockchain solution for PCHDM will be created by encrypting the data stored in IPFS using appropriate public key cryptographic algorithms. To determine which blocks should be incorporated into the blockchain, the Byzantine Fault Tolerance is applied in the health chain architectural model. This system hosts smart contracts and application logic as well as smart contracts known as "chain code" via container technology. As part of this research, health record hashes were stored on the blockchain and the actual health data was stored off-chain in IPFS, which is the decentralized cloud storage system that achieves scalability. Due to the encryption of healthcare records with a hash, this model proves that unauthorized access is impossible because the records are more scalable, interoperable, and reliable. Stakeholders are more confident in collaborating and sharing their medical records with this model.
Adaptive treatment allocation and selection in multi-arm clinical trials: a Bayesian perspective
Authors: Arjas Elja , Gasbarra Dario
Published: October 2021

Background: Adaptive designs offer added flexibility in the execution of clinical trials, including the possibilities of allocating more patients to the treatments that turned out more successful, and early stopping due to either declared success or futility. Commonly applied adaptive designs, such as group sequential methods, are based on the frequentist paradigm and on ideas from statistical significance testing. Interim checks during the trial will have the effect of inflating the Type 1 error rate, or, if this rate is controlled and kept fixed, lowering the power. Results: The purpose of the paper is to demonstrate the usefulness of the Bayesian approach in the design and in the actual running of randomized clinical trials during Phase II and III. This approach is based on comparing the performance of the different treatment arm in terms of the respective joint posterior probabilities evaluated sequentially from the accruing outcome data, and then taking a control action if such posterior probabilities fall below a pre-specified critical threshold value. Two types of actions are considered: treatment allocation, putting on hold at least temporarily further accrual of patients to a treatment arm (Rule 1), and treatment selection, removing an arm from the trial permanently (Rule 2). The main development in the paper is in terms of binary outcomes, but extensions for handling time-to-event data, including data from vaccine trials, are also discussed. The performance of the proposed methodology is tested in extensive simulation experiments, with numerical results and graphical illustrations documented in a Supplement to the main text. As a companion to this paper, an implementation of the methods is provided in the form of a freely available R package. Conclusion: The proposed methods for trial design provide an attractive alternative to their frequentist counterparts.
Transcriptional Profiling of Macrophages Reveals Distinct Parasite Stage-driven Signatures During Early Infection by Leishmania Donovani
Authors: Chaparro Visnu , Graber Tyson E. , Alain Tommy , Jaramillo Maritza
Published: October 2021

Macrophages undergo swift changes in mRNA abundance upon pathogen invasion. Herein we describe early remodelling of the macrophage transcriptome during infection by amastigotes or promastigotes of Leishmania donovani. Approximately 10% - 16% of host mRNAs were differentially modulated in L. donovani-infected macrophages when compared to uninfected controls. This response was partially stage-specific as a third of changes in mRNA abundance were either exclusively driven by one of the parasite forms or significantly different between them. Gene ontology analyses identified categories associated with immune functions (e.g. antigen presentation and leukocyte activation) among significantly downregulated mRNAs while cytoprotective-related categories (e.g. DNA repair and apoptosis inhibition) were enriched in upregulated transcripts during amastigote infection. Interestingly a combination of upregulated (e.g. cellular response to IFNβ) and repressed (e.g. leukocyte activation, chemotaxis) immune-related transcripts were overrepresented in the promastigote-infected dataset. In addition, Ingenuity Pathway Analysis (IPA®) coupled specific mRNA subsets with a number of upstream transcriptional regulators predicted to be modulated in macrophages infected with L. donovani amastigotes (e.g. STAT1 inhibition) or promastigotes (e.g. NRF2, IRF3, and IRF7 activation). Overall, our results indicate that early parasite stage-driven transcriptional remodelling in macrophages contributes to orchestrate both protective and deleterious host cell responses during L. donovani infection.
Discovery, in-vitro and in-vivo efficacy of an anti-inflammatory small molecule inhibitor of C-reactive protein
Authors: Zeller Johannes , Shing Karen Cheung Tung , Nero Tracy , Krippner Guy , McFadyen James , Bogner Balazs , Kreuzaler Sheena , Kiefer Jurij , Horner Verena , Braig David , Kather Michel , Kammerer Bernd , Woollard Kevin , Sharma Prerna , Morton Craig , Pietersz Geoffrey , Parker Michael , Peter Karlheinz , Eisenhardt Steffen
Published: October 2021

C-reactive protein (CRP) is an acute phase protein. We recently identified a novel mechanism that leads to a conformational change from the native, pentameric structure (pCRP) to a pentameric intermediate (pCRP*) and ultimately to the monomeric form, mCRP, both being highly pro-inflammatory. This ‘CRP activation’ is mediated by binding of pCRP to activated/damaged cell membranes via exposed phosphocholine (PC) lipid head groups. We designed a low molecular weight pCRP – PC inhibitor, C10M. Binding assays and X-ray crystallography revealed direct, competitive binding of C10M to pCRP, blocking interaction with PC and thereby inhibiting formation of pCRP*/mCRP and their pro-inflammatory effects. The anti-inflammatory potential of C10M was confirmed in-vitro by various measures of leukocyte and endothelial cell activation and in-vivo in rat models of acute ischemia/reperfusion injury and hindlimb transplantation. In conclusion, inhibition of pCRP*/mCRP generation via the PC-mimicking compound C10M represents a promising, potentially broadly applicable anti-inflammatory therapy.
Microarray Analysis And Functional Prediction Of Differentially-Expressed Circular RNAs In Acquired Middle Ear Choleateatoma
Authors: Xie Shumin , Jin Li , Yin Tuanfang , Ren Jihao , Liu Wei
Published: October 2021

Background: Middle ear cholesteatoma is characterized by hyper-proliferation of keratinocytes. Circular RNA (circRNA) plays an essential role in the pathogenesis of many proliferative diseases. However, the role of circRNA in the etiopathogenesis of middle ear cholesteatoma is rarely investigated so far. Our aim was to investigate the differential expression profiling of circRNAs between acquired middle ear cholesteatoma and normal skin, and to indentify potential circRNAs contributing to the etiopathogenesis of middle ear cholesteatoma. Microarray analysis and functional prediction were performed to investigate the circRNA expression profiling between middle ear cholesteatoma and normal skin. Validation of differentially expressed circRNAs was conducted by qRT-PCR. Prediction of m6A modification was also carried out. Results: Microarray analysis displayed that totally 93 up-regulated and 85 down-regulated circRNAs were identified in middle ear cholesteatoma. Through validation, expressions of hsa_circRNA_104327 and hsa_circRNA_404655 were significantly higher, while hsa_circRNA_000319 was significantly down-regulated in cholesteatoma. GO classification, KEGG pathway, and ceRNA network analyses suggested that these differentially expressed circRNAs might play importantant roles in the etiopathogenesis of middle ear cholesteatoma. Prediction of m6A modification exhibited that hsa_circRNA_000319 possessed 4 m6A sites with very high confidence, and hsa_circRNA_404655 had 3 m6A sites with high confidence.Conclusions: Our study indicated possible roles of differentially expressed circRNAs in the etiopathogenesis of middle ear cholesteatoma. Targeting on these differentially expressed circRNAs may provide a new and effective treatment for middle ear cholesteatoma in the future.
PGM1 Suppresses Colorectal Cancer Cell Migration And Invasion by Regulating PI3K/ AKT Pathway
Authors: Zheng Zhewen , Zhang Xue , Bai Jian , Long Long , Liu Di , Zhou Yunfeng
Published: October 2021

BackgroundPhosphoglucomutase 1(PGM1) is known for its involvement in cancer pathogenesis. However, its biological role in colorectal cancer (CRC) is unknown. Here, we studied the functions and mechanisms of PGM1 in CRC.Methods We verified PGM-1 as a DEG by a comprehensive strategy of the TCGA-COAD dataset mining and computational biology. Relative levels of PGM-1 in CRC tumors and adjoining peritumoral tissue were identified by qRT-PCR, WB, and IHC staining in a tissue microarray. PGM1 functions were analyzed using CCK8, EdU, colony formation, cell cycle, apoptosis, and Transwell migration and invasion assays. The influence of PGM1 was further investigated using tumor formation in vivo.ResultsPGM1 mRNA and protein were both reduced in CRC and the reduction was related to CRC pathology and overall survival. PGM1 knockdown stimulated both proliferation and colony formation, promoting cell cycle arrest and apoptosis while overexpression has opposite effects in CRC cells both in vivo and in vitro. Furthermore, we lined the actions of PGM1 to the PI3K/ AKT pathway. ConclusionWe verified that PGM1 suppresses CRC through the PI3K/ AKT pathway. These results suggest the potential for targeting PGM1 in CRC therapies.
Mutation analysis of second primary tumors in head and neck cancer in Taiwanese patients through next-generation sequencing
Authors: Liu Ting-Yuan , Lee Chien-Chin , Chen Yu-Chia , Chang Ya-Sian , Huang Hsi-Yuan , Lee Ya-Ting , Yen Ju-Chen , Chao Dysan , Chang Jan-Gowth
Published: October 2021

Head and neck cancer has poor overall survival. Patients with head and neck cancer more frequently develop second primary tumors than do patients with other cancers, leading to a poor prognosis. In this study, we used next-generation sequencing to analyze and compare mutations between first tumors and second tumors in head and neck cancer. We retrieved tumor tissues collected from 15 patients who were diagnosed twice as having cancer. We used driver gene and trunk mutations to distinguish between recurrent cancer and primary cancer in oral cancer. We observed unique driver gene mutations in three patients with an initial clinical diagnosis of recurrent cancer; hence, we believe that the corresponding patients had primary cancer. Four patients with an initial clinical diagnosis of primary cancer were found to actually have recurrent cancer according to our results. Three (75%) patients with recurrent cancer demonstrated NUP98 mutations. NUP98 mutations may be a new biomarker for diagnosing recurrent oral cancer. Genetic testing can be used to enhance the accuracy of clinical diagnosis.
Improving Genetic Knowledge Among Physicians: A Necessity in the Era of Genomic Medicine
Authors: Hureaux Marguerite , Watson Sarah
Published: October 2021

Background: Genetic analyses have experienced rapid development over the past decades. This evolution is accompanied by a considerable increase in indications in clinical practice. As a result, physicians are exposed to prescribing and understanding genetics results in their daily practice. The objective was to assess the knowledge of young physicians on new genetic techniques and their expectations concerning molecular biology education. Methods: This study is based on the results of an anonymized questionnaire on genetics knowledge sent to young French physicians specialized in medical oncology, radiation therapy, and clinical hematology in France; and on a retrospective analysis of nonconformities to requirements of the ISO 15189 accreditation standard in genetics samples from a Parisian university hospital center. Results: Of the 87 young physicians (median age 29, 58.6% female) who responded to the survey, 60.3% did not differentiate several standard molecular biology techniques. Median Visual Analog Scale for theoretical knowledge of standard genetic technics was 35/100 (IQR 20-56). Median Visual Analogical Scale for genetics diagnostic and theragnostic indications knowledge were 50/100 (IQR 31.2-70) and 43/100 (IQR 19.2-65), respectively. Proficiency in genetics results interpretation was assessed with a Median Visual Analog Scale of 47/100 (IQR 23.25-69). Finally, 82.4% of young physicians believed that the current teaching of molecular biology was not suited to their current practice and 91.9% requested a specific training implementation. These results were supported by the high rate of nonconformities regarding the prescription (43%) among the different types of nonconformities of genetics samples.Conclusion: Medical education on new techniques of genetics by young French physicians appears to be insufficient, and a specific training should be considered. A better knowledge of this discipline is necessary in order to control the clinical, ethical and financial issues associated with the exponential use of molecular biology in medicine.
pKAI: a fast and interpretable deep learning approach for accurate electrostatics-driven pKa predictions
Authors: Reis Pedro , Bertolini Marco , Montanari Floriane , Rocchia Walter , Machuqueiro Miguel , Clevert Djork-Arné
Published: October 2021

The pKa values of ionizable residues influence protein folding, stability and biological function. The pKa in bulk water is known for all residues, however, in a protein environment, it can significantly be affected by confinement and electrostatics. Existing computational methods to estimate pKa shifts rely on theoretical approximations and lengthy computations. Furthermore, the amount of experimentally determined pKa values is still very limited, hindering the development of faster machine learning-based methods. In this work, we use a data set of 6 million pKa shifts — determined by PypKa, a continuum electrostatics method — to train deep learning models that are shown to rival the physics-based predictor. On ~750 experimentally determined data points, our model displays the best accuracy and it is the only one that breaks the 1 pK unit RMSE barrier of this considerably difficult test set. Although trained using a very simplified view of the surroundings of the titratable group (namely, atom types and distances to other titratable groups within a given radius), the models are shown to assign proper electrostatic charges to chemical groups, to keep the known correlation between solvent exposure and pKa shift magnitude, and to grasp the importance of close interactions, including hydrogen bonds. Inference times allow speedups of more than 1000 times faster than physics-based methods, especially for large proteins. By combining speed, accuracy and a reasonable understanding of the theoretical basis for pKa shifts, our models provide a game-changing solution for fast estimations of macroscopic pKa from ensembles of microscopic (pKhalf) values as well as for many downstream applications such as molecular docking and constant-pH molecular dynamics simulations.