bluuebunny/crossref_metadata_2025 huggingface dataset:
A simple and rapid diagnostic method for 13 types of High risk human papillomavirus (HR-HPVs) detection using CRISPR-Cas12a technology
Authors: Gong Jiaojiao , Zhang Guanghui , Wang Wangguo , Liang Liping , Li Qianyun , Liu Menghao , Xue Liang , Tang Guanghui
Published: April 2021

Cervical carcinoma is the second most common cancer in women worldwide with greater than 99% of the cases caused by human papillomaviruses (HPVs). Early detection of HPVs especially the high risk types (HR-HPVs) are essential to prevent the disease progression. The existing methods for HPV detection, such as qPCR are of high sensitivity and specificity, but the need for expensive machinery and well-trained personnel slow down the disease detection. The emerging Cas12a-based method presents a new technique for nucleic acid detection. However, it is time-consuming and labor-intensive when used for HPV detection, as several reactions are required in order to identify multiple HPV infections. We herein present a non-genotyping method for 13 types of HR-HPV detection in a single reaction by combining the isothermal recombinase polymerase amplification (RPA) method with CRISPR-Cas12a technology. The result could be achieved in 30 minutes with high sensitivity (500 copies per reaction). This assay reprsents great advances for the application of RPA-Cas12a system and holds a great potential to address the key challenges facing the HPV diagnostics.
NeosedumosideIII induced Apoptosis of Human Hepatocellular Carcinoma HepG2 cells and SMMC-7721 Cells and Related Mechanism
Authors: Li Xin-Yu , Zhou Xin , Liu Yu- , Qiu Feng , Zhao Qing-Qing
Published: April 2021

Purpose: NeosedumosideIII (Neo) is a megastigmanes and belongs to monocyclic sesquiterpenoids compound with antioxidant, anti-inflammatory and other pharmacological activities. In order to explore the anti-cancer effect and possible mechanism of Neo, the study examined the anti-proliferation and apoptosis effect of Neo against human hepatocellular carcinoma HepG2 cells and SMMC-772 cells and related mechanism in vitro. Methods ：The anti-proliferation effect of Neo was detected on HepG2 cells and SMMC-772 cells by MTT assay and IC50 with increasing dose and time. Cell cycle and apoptosis were detected by flow cytometer. The changes of Bcl-2, Bax, Caspase-3, Caspase-8 and Caspase-9 proteins were detected by western blotting.Results ：The results indicated that Neo could inhibited proliferation of HepG2 cells and SMMC-772 cells in vitro and promoted apoptosis, it significantly induced apoptosis of HepG2 cells and SMMC-772 cells arrested cell cycle at G0/G1 phase in a dose-dependent manner, reduce the expression of Bcl-2 protein, and increase the expression of Bax and Caspase-3, Caspase-8 and Caspase-9 proteins. Conclusion：Neo could inhibit proliferation and induce apoptosis of HepG2 cells and SMMC-7721 cells in vivo which suggested that it might be served as a promising candidate for the treatment of liver cancer.
Study of APOBEC3B focused breast cancer pathways and the clinical relevance
Authors: Choudhary Hani , Albukhari Ashwag , Mobashir Mohammad , Abdulaal Wesam
Published: April 2021

APOBEC3B is considered as an enzymatic source of mutation in case of breast cancer and Human T-Cell Leukemia Virus Type 1 and Bone Leiomyosarcoma are also associated with it. The major functions controlled or affected due to APOBEC3B are gene expression, mRNA editing such as C -> U conversion, and deoxycytidine deaminase activity. Here, the main goal of the study was to perform a systematic analysis of APOBEC3B associated genes and its functional impact in human breast cancer. For this purpose, the datasets have been utilized from the publicly available database such as GEO, OncoLnc, and TCGA. Based on the requirements for fetching the values, different bioinformatics approaches have been applied at different levels. Further, co-regulated genes obtained from co-expression network have been processed and the mutated genes with the pathways enrichment analysis, and the clinical relevance using survival curve analysis by using OncoLnc have been performed. In the results, we found that there are a number of critical pathways known to directly associated with breast cancer are altered because of the genes which are either overexpressed or top mutated and are associated with APOBEC3B and these pathways are cell cycle, p53 signaling, immune signaling pathways, progesterone-mediated oocyte maturation, apoptosis, critical metabolic pathways, and pathways in cancers. From the mutational and survival analysis data, we also observe that there are a number of well-known cancer associated signaling pathways (mainly cancer), immune signaling pathway, critical metabolic associated pathways, cell cycle, ubiquitin-proteasomal signaling pathways, and p53 signaling. Network-level study of pathways and their components CD40LG as the potential gene where CD40LG is directly affecting 10 pathways and most of them are the parts of immune system and known to control a number of leading human diseases including cancers.
Static Compliance and Driving Pressure are Associated with ICU Mortality in Intubated COVID-19 ARDS
Authors: Boscolo Annalisa , Sella Nicolò , Lorenzoni Giulia , Pettenuzzo Tommaso , Pasin Laura , Pretto Chiara , Tocco Martina , Tamburini Enrico , De Cassai Alessandro , Rosi Paolo , Polati Enrico , Donadello Katia , Gottin Leonardo , De Rosa Silvia , Baratto Fabio , Toffoletto Fabio , Ranieri V. Marco , Gregori Dario , Navalesi Paolo
Published: April 2021

Background: ascertaining whether respiratory system static compliance (Crs), driving pressure (DP), and tidal volume normalized for ideal body weight (VT/kg IBW) at the 1st day of controlled mechanical ventilation (CMV) are associated with intensive care unit (ICU) mortality in COVID-19 acute respiratory distress syndrome (ARDS).Methods: observational multicenter cohort study. All consecutive COVID-19 adult patients admitted to 25 ICUs belonging to the COVID-19 VENETO ICU network (February 28th-April 28th, 2020), who received CMV, were screened. Only patients fulfilling ARDS criteria and with complete records of Crs, DP and VT/kg IBW within the 1st day of CMV were included. Crs, DP and VT/kg IBW were collected in sedated, paralyzed and supine patients.Results: 704 COVID-19 patients were screened and 241 enrolled. Seventy-one patients (29%) died in ICU. The logistic regression analysis showed that: i) Crs was not linearly associated with ICU mortality (p-value for non-linearity=0.01), with a greater risk of death for values <48 ml/cmH2O; ii) the association between DP and ICU mortality was linear (p-value for non-linearity=0.68), and increasing DP from 10 to 14 cmH2O caused significant higher odds of in-ICU death (OR 1.45, 95%CI 1.06-1.99); iii) VT/kg IBW was not associated with a significant increase of the risk of death (OR 0.92, 95%CI 0.55-1.52). Multivariable analysis confirmed these findings.Conclusions: Crs <48 ml/cmH2O was associated with ICU mortality, while DP was linearly associated with mortality. DP should be kept as low as possible, even in the case of relatively preserved Crs, irrespective of VT/kg IBW, to reduce the risk of death.
The Effects of The COVID-19 Pandemic on Patients With Lysosomal Storage Disorders in Israel
Authors: Kristal Eyal , Pode-Shakked Ben , Hazan Guy , Banne Ehud , Ling Galina , David Odeya , Shany Eilon , Raas-Rothschild Annick , Anikster Yair , Kneller Katya , Hershkovitz Eli , Landau Yuval E. , Spiegel Ronen , Zehavi Yoav , Staretz-Chacham O
Published: April 2021

Background- Severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) is the causative agent of the current COVID-19 pandemic. Lysosomal storage disorders (LSD) comprise of 70 inherited inborn errors of metabolism. Affected individuals suffer from multi-systemic involvement with variable severity and rate of disease progression between different diseases. Some of the LSDs have established treatments whether parenteral, or oral therapies. The full impact of the COVID-19 pandemic together with the lockdown on the wellbeing and medical management of patients with rare diseases, such as LSDs, is widely unknown. Herein, we describe the effects of the COVID-19 pandemic and its associated mandatory home lockdown on patients with LSDs in Israel. Results- We present a prospective multi-center questionnaire study including 48 LSD patients from four medical centers in Israel. The study objective was to assess the impact of the COVID-19 pandemic restrictions on individuals with LSDs in Israel, as reported by their caregivers. Secondary objectives were to assess the morbidity from SARS CoV-2 in LSD patients and the impact of changes in mood and behavior on compliance to treatment and to assess the relationship between changes in mood to changes in cognition and behavior. Thirty one of 38 patients (82%) who received any kind of regular treatment did not miss treatments. Among patients receiving enzyme replacement therapy (ERT) in the in-hospital setting, 5 patients (20%) experienced treatment disruptions. Four patients had tested positive for SARS-Cov-2 virus infection by PCR. Seven out of the 48 patients (14%) described mood changes with cognitive and motor deterioration during the home quarantine. Conclusions- We observed high rates of treatment adherence and low morbidity through the COVID-19 pandemic in patients with LSDs in Israel. LSDs patients can be a model for patients with complex chronic diseases requiring routine treatments and surveillance during a pandemic or other disruption of daily routine.
Promise of Risk Stratification for Multicancer Screening with Liquid Biopsy Tests
Authors: Chatterjee Nilanjan , Kim Sungwon , Garcia-Closas Montserrat , Scharpf Rob , Visvanathan Kala , Velculescu Victor
Published: April 2021

Noninvasive multicancer liquid biopsy tests are rapidly emerging for early detection, but implementation will require risk stratification to enhance risk-benefit balance. Using data from the UK Biobank study, we trained and validated a model that allows estimation of absolute risk of developing at least one of the eight common cancers among women. We found that pan-cancer risk scores (PCRSs), defined by the combination of body mass index, smoking, family history of cancer, and cancer-specific polygenic risk scores, were strongly associated with the risk of developing at least one cancer (hazard ratio = 1.40 per sd unit, 95% CI: 1.35 - 1.46, 5-year AUC = 0.61). Projections using recently reported diagnostic accuracy for a multicancer screening test show that positive predictive values of it is expected to vary widely across strata defined by age and PCRS due to differences in underlying absolute risks. Our study suggests that risk-stratification, based on age, emerging polygenic risk scores, and other important cancer risk factors, have significant potential to increase risk-benefit balance of early detection through multicancer liquid biopsy tests.
Effects of Order on Memory of Event Times
Authors: Naim Michelangelo , Katkov Mikhail , Tsodyks Misha
Published: April 2021

Memorizing time of an event may employ two processes (i) encoding of the absolute time of events within an episode, (ii) encoding of its relative order. Here we study interaction between these two processes. We performed experiments in which one or several items were presented, after which participants were asked to report the time of occurrence of items. When a single item was presented, the distribution of reported times was quite wide. When two or three items were presented, the relative order among them strongly affected the reported time of each of them. Bayesian theory that takes into account the memory for the events order is compatible with the experimental data, in particular in terms of the effect of order on absolute time reports. Our results suggest that people do not deduce order from memorized time, instead people’s memory for absolute time of events relies critically on memorized order of the events.
Antioxidant Defense, Chlorophyll Fluorescence and VvCBF4-VvNAC1 Genes Expression in Grapevine Cultivars (Vitis Vinifera L.) in Response to Cold Stress
Authors: Aazami M. A. , Aruq M. Asghari , Hassanpouraghdam M. B.
Published: April 2021

Background: Cold stress is one of the limitative factors of different species of crops on the planet, causing significant damage to the Iranian agricultural industry every year. Grapes are the product of temperate warm zones and sensitive to early autumn cold and spring cold. The current study the effects of cold stress (+1 °C for 4, 8, and 16 hours) on three grapevine cultivars (Ghiziluzum, Khalili, and Perllete) were investigated. Results: The results showed that cold stress caused significant changes in the antioxidant and biochemicals content in the studied cultivars. Furthermore, examining the chlorophyll fluorescence indices, cold stress caused a significant increase in minimal fluorescence (F0), a decrease in maximal fluorescence (Fm), and the maximum photochemical quantum yield of photosystem II (Fv/Fm) in all cultivars. According to the obtained results, among the three studied cultivars, ‘Perllete’ with the highest increase in proline content and the activity of antioxidant enzymes and also, having the lowest accumulation of malondialdehyde, hydrogen peroxide, electrolyte leakage, and F0 as well as less decrease in Fm and Fv/Fm had the higher tolerance to the cold stress than ‘Ghiziluzum’ and ‘Khalili’ cultivars. VvCBF4 and VvNAC1 genes expression was increased in all three cultivars at +1 °C at 8 hours and then decreased. The increase in VvCBF4 and VvNAC1 genes expression in ‘Perllete’ cultivar was higher than the other two cultivars. Conclusion: ‘Perllete’ and ‘Ghiziluzum’ showed the highest tolerance to low temperature stress, respectively. ‘Khalili’ was sensitive to low temperature stress.
Current Approaches and Problems Faced by Orthopedic Surgeons in All-Inside Arthroscopic Meniscus Repairs
Authors: Turan Kaya , Muratoğlu Osman Görkem , Çabuk Haluk , Ertürer Ramazan Erden
Published: April 2021

The authors have requested that this preprint be removed from Research Square.
Why Do Animals Swirl and How Do They Group?
Authors: Nuzhin Egor E. , Panov Maxim E. , Brilliantov Nikolai V.
Published: April 2021

We report a possible solution for the long-standing problem of the biological function of swirling motion, when a group of animals orbits a common center of the group. We exploit the hypothesis that learning processes in the nervous system of animals may be modelled by reinforcement learning (RL) and apply it to explain the phenomenon. In contrast to hardly justified models of physical interactions between animals, we propose a small set of rules to be learned by the agents, which results in swirling. The rules are extremely simple and thus applicable to animals with very limited level of information processing. We demonstrate that swirling may be understood in terms of the escort behavior, when an individual animal tries to reside within a certain distance from the swarm center. Moreover, we reveal the biological function of swirling motion: a trained for swirling swarm is by orders of magnitude more resistant to external perturbations, than an untrained one. Using our approach we analyze another class of a coordinated motion of animals – a group locomotion in viscous fluid. On a model example we demonstrate that RL provides an optimal disposition of coherently moving animals with a minimal dissipation of energy.
HIFU for the treatment of gastric cancer with liver metastases with unsuitable indications for hepatectomy and radiofrequency ablation: a prospective and propensity score-matched study Running title: HIFU treatment for gastric cancer with liver metastases
Authors: Gu Lihu , He Ning , Hong Jiaze , Yang Tong , Ng Derry , Gao Xudong , Yan Kun , Fan Xiaoxiang , Zheng Zhi , Chen Ping , Zheng Jianjun , Zheng Qi
Published: April 2021

Background: The purpose of this study was to explore the efficacy and safety of high intensity focused ultrasound (HIFU) in gastric cancer with liver metastasis (GCLM) patients who were contraindicated for either hepatectomy or radiofrequency ablation (RFA).Methods: This is a prospective, observational study on GCLM patients with 1-3 liver metastases. The primary gastric lesions were thoroughly resected and any case that exhibited extra-hepatic metastasis was excluded. A 1:2:2 propensity score-matching analysis was performed using a logistic regression model on the HIFU group, best supportive care (BSC) group, and palliative chemotherapy (PC) group. The primary endpoints include progression-free survival (PFS) and overall survival (OS). Results: Forty patients were finally included, there were 8 cases in HIFU group, 16 cases in BSC group, and 16 cases in PC group. The median follow-up time for the entire cohort was 10 months. The median PFS was 16.5 months in HIFU group, 2 months in BSC group, and 5 months in PC group. The median OS was 27.5 months in the HIFU group, 7 months in the BSC group, and 11.5 months in the PC group. Additionally, no grade 3 or higher adverse events occurred in the HIFU group.Conclusion: The results of this study showed that HIFU treatment could improve the long-term prognosis of GCLM patients without a significant increase in the occurrence of adverse events. Compared with PC and BSC, HIFU is the preferred treatment option when GCLM patients without extra-hepatic metastasis are unable to undergo either surgery or RFA.
gene.iobio: an interactive web tool for versatile, clinically-driven variant interrogation and prioritization
Authors: DiSera Tonya , Velinder Matt , Ward Alistair , Qiao Yi , Georges Stephanie , Miller Chase , Pitman Anders , Richards Will , Ekawade Aditya , Viskochil David , Carey John C , Pace Laura , Bale Jim , Clardy Stacey L , Andrews Ashley , Botto Lorenzo , Marth Gabor
Published: April 2021

With increasing utilization of comprehensive genomic data to guide clinical care, anticipated to become the standard of care in many clinical settings, the practice of diagnostic medicine is undergoing a notable shift. However, the move from single-gene or panel-based genetic testing to exome and genome sequencing has not been matched by the development of tools to enable diagnosticians to interpret increasingly complex or uncertain genomic findings. Here, we present gene.iobio, a real-time, intuitive and interactive web application for clinically-driven variant interrogation and prioritization. We show gene.iobio is a novel and effective approach that significantly improves upon and reimagines existing methods. In a radical departure from existing methods that present variants and genomic data in text and table formats, gene.iobio provides an interactive, intuitive and visually-driven analysis environment. We demonstrate that adoption of gene.iobio in clinical and research settings empowers clinical care providers to interact directly with patient genomic data both for establishing clinical diagnoses and informing patient care, using sophisticated genomic analyses that previously were only accessible via complex command line tools.
Therapeutic Potential of Adipose-Derived Mesenchymal Stem Cells (Admscs) and/or Taurine in Aluminum Chloride-Induced Alzheimer's Disease Rat Model
Authors: Hosney Mohamed , Sakraan Alaa , Asaad Aman , El-Deftar Mervat , Elzayat Emad
Published: April 2021

Alzheimer's disease (AD) is the most prevalent type of dementia characterized by its progression, neurobehavioral and neuro-pathological characteristics, leading to a diverse neuronal loss. Adipose-derived mesenchymal stem cells (ADMSCs) have previously proved potential role in preventing the pathogenesis of several neurodegenerative disorders, so regarded as a promising new approach for AD regenerative therapy. Taurine was found to enhance stem cell activation and propagation yielding a higher concentration of neural progenitors and stem cells, and aid to lessen the number of activated microglia leading to down-regulated inflammation in vitro. The present study aimed to investigate the possible therapeutic potential of ADMSCs and/or taurine in treating AD rat model. It was planned to include three successive phases; induction, withdrawal, and therapeutic phases. Fifty male Wistar rats were divided into 2 main groups: control (C) group and AD model group. Behavioral changes, as manifested by the T-Maze experiment, had been recorded. β-amyloid levels had been measured in brain homogenate and serum by ELISA. Oxidative stress marker (MDA), and anti-oxidant enzymes activity (SOD, GSH, and CAT) in brain, as well as serum acetylcholine esterase activity were spectrophotometrically determined. Pro-apoptotic (p53 and Bax) and anti-apoptotic (Bcl2) gene expression in brain were evaluated using RT-qPCR. The histopathological alterations in brain tissues were also observed. The present study proved the potential therapeutic ability of ADMSCs and/or taurine in alleviating the adverse pathological changes induced by AlCl3 in AD rat model at both physiological and molecular levels.
Stability of "Support-Surrounding Rock" System for Fully Mechanized Longwall Mining in Steeply Dipping Coal Seams
Authors: Shenghu Luo , wang tong , Yongping Wu , Jingyu Huangfu , Huatao Zhao
Published: April 2021

The key to the safe and efficient longwall mining of steeply dipping seams lies in the stability control of the "support-surrounding rock" system. This paper analyzes the difficulty of controlling the stability of the support during the longwall mining process of steeply dipping coal seams in terms of the characteristics of the non-uniform filled-in gob using a combination of physical test, theoretical analysis and field measurements. Considering the floor as an elastic foundation, we built a "support-surrounding rock" mechanical model based on data obtained on "support-surrounding rock" systems in different regions and the laws of support motion under different load conditions. Our findings are summarized as follows. First, depending on the angle of the coal seam, the caving gangue will roll (slide) downward along the incline, resulting in the formation of a non-uniform filling zone in the deep gob in which the lower, middle, and upper sections are filled, half-filled, and empty, respectively. In addition, an inverted triangular hollow surface is formed on the floor of the gob in the middle and upper sections behind the support. Furthermore, as the angle of the coal seam, length of the working face, and mining height increase, the characteristics of the non-uniform filled-in gob are enhanced. Second, we found that, as a result of support by the gangue, the "support-surrounding rock" system is relatively stable in the lower part of the working face while, in the middle and upper sections of the working face, the contact method and loading characteristics of the support are more complicated, making stability control difficult. Third, the magnitude and direction of the load, action point, and mining height all affect the stability of the support to varying degrees, with the tangential load and action position of the roof load having the most significant impacts on the stability of the support. Under loading by the roof, rotation and subsidence of the support inevitably occur, with gradually increasing amplitude and effects on the inter-support and sliding forces. Finally, we found that it is advisable in the process of moving the support to adopt "sliding advance of support" measures and to apply a "down-up" removal order to ensure overall stability. These research results provide reference and guidance of significance to field practice production.
The expression and significance of AKR1B10 in laryngeal squamous cell carcinoma
Authors: Liu Jixuan , Ban Hongyan , Liu Yafang , Ni Jinsong
Published: April 2021

Aldosterone reductase family 1 member B10 (AKR1B10) is a nicotinamide adenine dinucleotide phosphate (NADPH) (reduced coenzyme II)-dependent oxidoreductase, and its biological functions include carbonyl detoxification, hormone metabolism, osmotic adjustment, and lipid synthesis. Studies suggested that AKR1B10 is a new biomarker for cancer based on its overexpression in epithelial tumors, such as breast cancer, cervical cancer, and lung cancer. At present, studies on the expression of AKR1B10 in laryngeal cancer have not been reported. However, we found that AKR1B10 is upregulated in laryngeal carcinoma, and its expression was negatively correlated with the degree of differentiation. In addition, AKR1B10 expression was positively correlated with tumor size; lymph node metastasis; long-term drinking; and Ki-67, mutant p53, and matrix metalloproteinase 2 expression. AKR1B10 was overexpressed in Hep-2 laryngeal carcinoma cells. Oleanolic acid inhibited AKR1B10 activity and expression in Hep-2 cells and suppressed Hep-2 cell proliferation, migration, and invasion. Therefore, AKR1B10 may be related to the development of laryngeal carcinoma, suggesting its use as a prognostic indicator for laryngeal cancer.
Successful Treatment of Recurrent Hyperpyrexia, Stroke, Intracardiac Thrombosis and Inflammatory Pseudotumor Secondary to Behçet’s Syndrome With Drug Therapy Alone
Authors: Wang Shuolin , Zhang Lei , Li Tian-fang , Liang Xu , Gao Yajing , Liu Shengyun
Published: April 2021

BackgroundBehçet’s syndrome (BS) is an inflammatory vessel disease characterized by recurrent oral and genital ulcers. It is a rare disorder that affects blood vessels throughout the body. It can affect any bodily system, including the skin, joints and cardiovascular, respiratory, central nervous and degestive systems. But cerebral infarction related to cerebral artery, intracardiac thrombosis (ICT) and inflammatory pseudotumor (IPT) are complications hard to see. And there is no effective therapy in clinic.Case presentationWe report the case of a 17-year-old patient with a two-month history of recurrent hyperpyrexia without obvious infection symptoms. He had a medical history of cerebral infarction ten months ago. Antinuclear antibody (ANA), antiphospholipid antibodies, parasite antibodies and antineutrophil cytoplasmic antibodies (ANCA) were all negative, consequently. Echocardiography demonstrates heterogeneous echoes in the right ventricle and apex. He was suspected to have cardiac myxomas and infective endocarditis and underwent thoracotomy afterwards. Histological examinations showed the specimen is inflammatory mass of vascular origin and intracardiac thrombus (ICT). However, the hyperpyrexia and intracardiac masses relapsed in two months. The antibiotic treatment failed to control the temperature and he was diagnosed as BS and treated with prednisone, aspirin and oral cyclophosphamide. Since then, the body temperature turned to normal and the size of intracardiac mass maintained stable. Conclusion﻿BS should be considered as a causative factor in young man with stroke, intracardiac masses and hyperpyrexia. Glucocorticoid and immunosuppressive agents may be effective for IPT and ICT in patient with BS.
Variation of Femoral Component Size by Reference Points and Target Alignments in Total Knee Arthroplasty
Authors: Ishibashi Shojiro , Mizu-uchi Hideki , Kawahara Shinya , Tsushima Hidetoshi , Akasaki Yukio , Nakashima Yasuharu
Published: April 2021

Selecting appropriately sized components is important in total knee arthroplasty because they can affect postoperative knee function and pain. This study investigated size differences of 19 different femoral component placements from the standard position by three-dimensional virtual surgery using three-dimensional bone models of 101 varus osteoarthritic knees. Distal femoral bone was cut perpendicular to the femoral mechanical axis (MA) in the coronal plane. Twenty different component placements consisting of five cutting directions (perpendicular to MA, 3° and 5° extension/flexion relative to MA in the sagittal plane), two rotational alignments (clinical and surgical epicondylar axes), and two rotational types of anterior reference guide (central and medial) were simulated. The mean anteroposterior dimension of the standard position was 55.5 mm which means that the difference compared to 19 different methods ranged from -1.2 ± 0.2 mm to 7.1 ± 1.3 mm. Multiple regression analysis revealed that flexion cutting direction, surgical epicondylar axis, and central were associated with smaller component size. In conclusion, the femoral component size can be affected easily by not only cutting direction but also the reference guide type and the target alignment. Our findings could provide surgeons with clinically useful information to fine-tune for unintended loose or tight joint gaps by adjusting the component size.
A signiﬁcant effect of the HUWE1 copy number on autistic spectrum disorder and the development of zebraﬁsh
Authors: Wu Haojuan , Liang Yan , Li Juan , Zhang Xueguang , Xu Baoshan , Wang Xiang , Cheng Juan , Dinnyes Andras , Xie Jiang , Xu wenming
Published: April 2021

Autistic spectrum disorder (ASD) is a complex neurodevelopmental disorder. The copy number variation (CNV) of genes in the X-chromosome is speculated to play a critical role in ASD. The HECT, UBA and WWE domain containing the E3 ubiquitin protein ligase 1 (HUWE1) gene is located on the X-chromosome and is associated with neurodevelopment. However, the CNV of HUWE1 has not been linked to ASD. In this study, we identified increased copy numbers of HUWE1 in ASD patients compared to the controls. Moreover, an elevated severity of ASD phenotype was observed in patients with more HUWE1 copy numbers. In vitro, overexpression HUWE1 could decrease the proliferation of nervous system derived cells and promote their apoptosis, declining the G2/M phase transition. The functional assay showed that HUWE1, an E3 ubiquitin protein ligase, regulated the ubiquitination degradation of key mediators in the Wnt/β-catenin signaling pathway, which is involved in neurodevelopment. Consistent with the ASD patients, overexpression of huwe1 in zebrafish embryos caused defective brain development, small eyes, cardiac edema and a curly spinal cord, supporting the pivotal role of the HUWE1 CNV in neurodevelopmental disorders. In this study, we demonstrated the role of the HUWE1 CNV for complement pathway factors in the origin of ASD for the first time. Genetic analysis of the HUWE1 copy number could inform the clinical counseling of ASD patients.
Vitamin D levels are associated with low-density lipoprotein cholesterol in Chinese children with type 1 diabetes
Authors: Shu Jianbo , Wang Xinhui , Zhang Mingying , Zhi Xiufang , Guan Jun , Gu Chunyu , Pu Linjie , Gao Long , Cai Chunquan , Yang Wei , Lv Ling
Published: April 2021

Objective There is an increased level of low-density lipoprotein cholesterol (LDL-C)in children with type 1 diabetes mellitus(T1DM). In addition, the Vitamin D level in T1DM patients is usually below the normal reference range. The aim of this study was to explore the relationship between Vitamin D levels and LDL-C in Chinese children with T1DM. Methods A retrospective cross-sectional study was conducted in the Endocrine inpatient wards of Tianjin Children’s Hospital, 143 children with T1DM were included. The related clinical and laboratory examinations, including anthropometric parameters, lipid profiles, and Vitamin D levels, were collected in all subjects. Results The univariate analysis results did not show a significant correlation between Vitamin D levels and LDL-C (P=0.634). Furthermore, a nonlinear relationship was observed between Vitamin D levels and LDL-C by smooth curve fitting after adjusting for potential confounders. A multivariate piecewise linear regression model revealed a significant negative association between LDL-C and Vitamin D levels when LDL-C was greater than 3.1 mmol/L(β -2.9, 95% CI -5.4,-0.5; P=0.022). However, we did not observe a significant relationship between LDL-C and Vitamin D levels when LDL-C was lower than 3.1 mmol/L(β 2.4, 95% CI -0.2,5.1; P=0.076).Conclusions This study identified a nonlinear relationship between Vitamin D levels and LDL-C independent of other potential confounding factors, suggesting that the deficiency or insufficiency of Vitamin D in T1DM children with high LDL-C levels should be considered, especially LDL-C is higher than 3.1 mmol/L, which provides evidence of the timing about Vitamin D supplementation in T1DM children.
The Effects of a Mitochondrial Targeted Peptide (Elamipretide/SS31) on BAX Recruitment and Activation During Apoptosis
Authors: Grosser Joshua , Fehrman Rachel , Keefe Dennis , Redmon Martin , Nickells Robert
Published: April 2021

Objective: Elamipretide (SS31) is a mitochondria-targeted peptide that has reported functions of stabilizing mitochondrial cristae structure and improving mitochondrial bioenergetics. Several studies have documented cell protective features of this peptide, including impairment of intrinsic apoptosis by inhibiting the recruitment and activation of the pro-apoptotic BAX protein. We used live-cell imaging of ARPE-19 cells expressing fluorescently labeled BAX, cytochrome c, and a mitochondrial marker to investigate the effect of elamipretide on the kinetics of BAX recruitment, mitochondrial outer membrane permeabilization (as a function of cytochrome c release), and mitochondrial fragmentation, respectively. Result: In nucleofected and plated ARPE-19 cells, elamipretide accelerated the formation of larger mitochondria. In the presence of the apoptotic stimulator, staurosporine, cells treated with elamipretide exhibited moderately slower rates of BAX recruitment. Peptide treatment, however, did not significantly delay the onset of BAX recruitment or the final total amount of BAX that was recruited. Additionally, elamipretide showed no impairment or delay of cytochrome c release or mitochondrial fragmentation, two events associated with normal BAX activation during cell death. These results indicate that the protective effect of elamipretide is not at the level of BAX activity to induce pro-apoptotic mitochondrial dysfunction after the initiation of staurosporine-induced apoptosis.
Quantitative analysis of membrane-mediated interactions and aggregation of flexible peripheral proteins orchestrating large-scale membrane remodeling
Authors: Sadeghi Mohsen , Noé Frank
Published: April 2021

Shaping and remodeling of biomembranes is essential for cellular trafficking, with membrane-binding peripheral proteins playing the key role in it. Significant membrane remodeling as in endo- and exocytosis is often due to clusters or aggregates of many proteins whose interactions may be direct or mediated via the membrane. While computer simulation could be an important tool to disentangle these interactions and understand what drives cooperative protein interactions in membrane remodeling, this has so far been extremely challenging: protein-membrane systems involve time- and lengthscales that make detailed atomistic simulations impractical, while most coarse-grained models lack the degree of detail needed to resolve the dynamics and physical effect of protein and membrane flexibility. Here, we develop a coarse-grained model of the bilayer membrane bestrewed with rotationally-symmetric flexible membrane-bound proteins. We show how this model can be parameterized based on local curvatures, protein flexibility, and the in-plane dynamics of proteins. We measure the effective interaction potential for the membrane-mediated interactions between peripheral proteins. Furthermore, we investigate the kinetics, equilibrium distributions, and the free energy landscape governing the formation and break-up of protein clusters on the surface of the membrane. We demonstrate how the flexibility of the protein plays a deciding role in highly selective macroscopic aggregation behavior. Finally, we present large-scale simulations of membrane tubulation, and discuss the sequence of events and the stability of intermediates.
Chronic Cadmium Exposure Impairs Macrophage Mitochondrial Homeostasis and Promotes Macrophage Polarization Contributing to Atherosclerosis via Regulating RIPK3 Signaling
Authors: Zhang Jiexin , Feng Weijing , Chen Peier , Ning Xiaodong , Ou Caiwen , Chen Minsheng
Published: April 2021

Background: Chronic cadmium (Cd) exposure can contribute to the progression of cardiovascular disease (CVD), especially atherosclerosis (AS), but the underlying mechanism is unclear. Since mitochondrial homeostasis is emerging as a core player in the development of CVD, it might serve as a potential mechanism linking Cd exposure and AS. Here, we aimed to investigate the Cd-induced AS through macrophage polarization and tried to find out the mechanism of mitochondrial dysfunction caused by Cd exposure. Methods and results: In vitro, flow cytometry showed that Cd exposure markedly promoted M1-type polarization of macrophages, manifesting as the increasing expression of NF-kB, NLRP3 and their downstream inflammatory factors, IL-1β and IL-6. Mitochondrial function test revealed that the decreasing mitochondrial membrane potential and increasing superoxide (mROS) and mitochondrial fission were involved in Cd-induced macrophage polarization. Transmission electron microscope observation and immunofluorescence both identified the decrease of mitophage after Cd exposure. And improving mitochondrial function above significantly restored the balance of macrophage polarization. In vivo, Cd exposure was positively correlated with blood Cd concentration, and oil red O staining showed higher blood Cd significantly increased the area of AS plaques. Besides, M1-type polarization of macrophages and mitochondrial dysfunction were observed in mouse aortic roots through immunofluorescence and western blot as the dosage of Cd increasing. And the administered NAC or Mdivi-1, which decreased mROS or mitochondrial fission, markedly attenuated AS plaques and macrophage M1-type polarization in Cd-treated group. Finally, the up-regulated expressions of RIPK3 and p-MLKL were observed both in vitro and in vivo. And knocking out RIPK3 with decreasing expression of p-MLKL followed did improve mitochondrial dysfunction caused by Cd which effectively reversed macrophage polarization. Conclusion: Cd exposure activated RIPK3 pathway and impaired mitochondrial homeostasis, resulting in macrophage polarization to a pro-inflammatory phenotype and subsequent AS. These findings suggest that improving mitochondrial homeostasis may provide a potential therapeutic target for AS induced by chronic Cd exposure.
Biofilm Growth By Listeria Monocytogenes On Stainless Steel and Expression of Biofilm-Related Genes Under Stressing Conditions
Authors: Silva Danilo Augusto Lopes da , Tavares Rafaela de Melo , Camargo Anderson Carlos , Yamatogi Ricardo Seiti , Martinis Elaine Cristina Pereira De , Nero Luis Augusto
Published: April 2021

This research was carried out to assess the ability of L. monocytogenes for adhesion and growth in biofilm on stainless steel coupons under different stressing conditions (NaCl, curing salts and quaternary ammonium compounds - QAC), besides determining the expression of different genes involved in biofilm formation and stress response. Results from crystal violet assay revealed that one isolate carrying a premature stop codon (PMSC) in agrC gene formed high-density biofilms in the presence of QAC or cure salts (7.5% and 10%). Reverse Transcriptase-qPCR results revealed that isolates of L. monocytogenes lineages I and II presented differences in transcriptional profile of genes related to biofilm formation and adaptation to environmental conditions. In conclusion, our results demonstrated how L. monocytogenes can survive, multiply and form biofilm under adverse conditions related to food processing environments. Differences in transcriptional expression were observed, highlighting the role of regulatory gene networks for particular serotypes under different stress responses.
Transcriptomic Assessment of Dietary Fish Meal Partial Replacement By Soybean Meal and Prebiotic Inclusion In The Liver of Juvenile Pacific Yellowtail (Seriola Lalandi)
Authors: Juárez Oscar E. , Delgado-Vega Rigoberto , Cruz Fabiola Lafarga De La , Lazo Juan Pablo , López-Landavery Edgar , Tovar Dariel , Galindo-Sánchez Clara E.
Published: April 2021

Seriola lalandi is an important species for aquaculture, due to its rapid growth, adaptation to captivity and formulated diets, and high commercial value. Due to the rise in fish meal (FM) price, efforts are made to replace it partially or entirely with vegetable meals in diets for carnivorous fish. The use of prebiotics when feeding vegetable meals has improved fish health. In this study, four experimental diets were assessed in juveniles, the control diet consisted of FM as the main protein source, the second diet included 2% GroBiotic®-A (FM-P), the third included FM with 25% replacement by soybean meal (SM25), and the fourth consisted in SM25 with 2% of GroBiotic®-A (SM25-P). RNA-seq of the liver tissue was performed, followed by differential expression analysis and functional annotation to identify genes affected by the diets. Growth was not affected by this level of FM replacement, but it was improved by the prebiotic. Annotation was achieved for 78,826 transcripts, of which 135 were up-regulated and 78 down-regulated among all treatments compared to the control. Transcriptomic profiles of control samples were clustered with those from fishes fed SM25 and SM25-P diets, and the most differentiated group was that one fed the FM-P diet. SM25-P showed the least amount of differentially expressed genes, maintaining general transcriptomic profiles of control diet in the liver, therefore this diet is a potential economic alternative to the FM diet, for S. lalandi juveniles. Assessment of the effects of this diet along the digestive tract is recommended.
Intermediate Field Directions Recorded in Pliocene Basalts in Styria (Austria): Evidence for Cryptochron C2r.2r-1
Authors: Schnepp Elisabeth , Arneitz Patrick , Ganerød Morgan , Scholger Robert , Fritz Ingomar , Egli Ramon , Leonhardt Roman
Published: April 2021

Pliocene volcanic rocks from South-East-Austria were paleomagnetically investigated. Samples were taken from 28 sites located on eight different volcanoes. Rock magnetic investigations revealed that magnetic carriers are Ti-rich or Ti-poor titanomagnetites with mainly pseudo-single-domain grain size. Characteristic remanent magnetization directions were obtained from alternating field as well as from thermal demagnetization. Four localities give reversed directions agreeing with the expected direction from secular variation. Another four localities of the Klöch-Königsberg volcanic complex (3) and the Neuhaus volcano (1) have reversed directions with shallow inclinations and declinations of about 240° while the locality Steinberg yields a positive inclination of about 30° and 200° declination. These aberrant directions cannot be explained by local or regional tectonic movements. All virtual geomagnetic pole positions are located on the southern hemisphere. Four virtual geomagnetic poles lie close to the geographic pole, while all others are concentrated in a narrow longitude sector offshore South America (310° to 355°) with low virtual geomagnetic pole latitudes ranging from − 15° to -70°. The hypothesis that a transitional geomagnetic field configuration was recorded during the short volcanic activity of these five localities is supported by 9 paleointensity results and 39Ar/40Ar dating. Virtual geomagnetic dipole moments range from 1.1 to 2.9·1022 Am2 for sites with low VGP latitudes about 60° and from 3.0 to 9.3·1022 Am2 for sites with higher virtual geomagnetic pole latitudes. The new 39Ar/40Ar ages of 2.51 ± 0.27 Ma for Klöch and 2.39 ± 0.03 Ma for Steinberg allow for the correlation of the Styrian transitional directions with cryptochron C2r.2r-1 of the geomagnetic polarity time scale.
Silencing of UBE2D1 Inhibited Cell Migration in Gastric Cancer, Decreasing Ubiquitination of SMAD4
Authors: Xie Honghu , He Yu , Wu Yugang , Lu Qicheng
Published: April 2021

Background: Gastric cancer (GC) is the second leading cause of cancer-related deaths. Because it is hard to diagnose at early stage, the overall 5 years survival rate is lower than 25%. High migration is the main hallmark of malignant cells at advanced stage of GC. Thus, it is urgent to find biomarkers for early diagnosis and more effective therapy of GC.Methods: In this study, silencing and overexpression lentiviruses targeting the ubiquitin-conjugating enzyme E2 D1 (UBE2D1), transwell, wound healing, and pulmonary metastasis mouse model were applied to analyze the function of UBE2D1 in vitro and in vivo. Real-time PCR and immunohistochemistry were used to elucidate the level of UBE2D1 in GC samples.Results: Silencing of UBE2D1 inhibited cell migration and the levels of Epithelial-mesenchymal transition (EMT) makers (MMP2 and MMP9) in AGS and MKN45 cells. Silencing of UBE2D1 inhibited cell metastasis in mouse model. On the contrary, UBE2D1 overexpression increased cell migration and the levels of MMP2 and MMP9 in MGC-803 cells. Further, silencing of UBE2D1 decreased the ubiquitination level of mothers against decapentaplegic homolog 4 (SMAD4), and the increase of cell migration induced by UBE2D1 overexpression could be reversed by SMAD4.Conclusion: Silencing of UBE2D1 inhibited cell migration through transforming growth factor β (TGF-β)/SMAD4 signaling pathway in GC.
Tracheal Intubation in Out-Of-Hospital Setting is Associated With A High Failure Rate of The First Attempt: A Multicenter Prospective Study
Authors: Galinski Michel , Wrobel Marion , Boyer Romain , Reuter Paul Georges , Ruscev Mirko , Debaty Guillaume , Gilles Bagou , Dehours Emilie , Bosc Juliane , Lorendeau Jean-Paul , Goddet Sybille , Marouf Kamelia , Catoire Pierre , Gil-Jardiné Cédric , Simonnet Bruno
Published: April 2021

BackgroundTracheal intubation in an out-of-hospital setting is a frequent and potentially difficult procedure. The risk of adverse events increases dramatically with the number of attempts. The failure rate of the first intubation attempt ranges from 5 to 32% and the risk factors are unclear. We evaluated the failure rate of the first intubation attempt in an out-of-hospital setting and identified variables potentially associated with such failure.MethodsThis was an observational prospective multicenter study performed over 17 months and involving 10 prehospital emergency medical units. Airway management for patients who needed tracheal intubation followed the national guidelines. Rapid sequence intubation with a sedative and myorelaxant drugs was systematically performed for spontaneously breathing patients. After each tracheal intubation, the operator was required to provide, by completing a data-collection form, information on operator and patient characteristics and the environmental conditions during the intubation. The primary endpoint was failure of the first intubation attempt.ResultsDuring the study period, 1546 patients were analyzed, of whom 59% had cardiac arrest, and 486 intubations failed on the first attempt (31.4% [95% confidence interval = 30.2–32.6]). A multivariate analysis revealed that the following 7 of 28 factors were associated with an increased risk of a failed first intubation attempt: operator with fewer than 50 prior intubations, small inter-incisor space, limited extension of the head, macroglossia, ear/nose/throat tumor, cardiac arrest, and vomiting. The frequency of adverse events was 13.4% and increased with each additional attempt.ConclusionsThe failure rate of the first attempt was high. Most risk factors could be identified only at the moment of occurrence and were not easily anticipated. Finally, the risk of complications increased with the number of attempts.