bluuebunny/crossref_metadata_2025 huggingface dataset:
Age-dependent Shift in the de Novo Proteome Accompanies Pathogenesis in an Alzheimer’s Disease Mouse Model
Authors: Elder Megan , Erdjument-Bromage Hediye , Oliveira Mauricio , Mamcarz Maggie , Neubert Thomas , Klann Eric
Published: September 2020

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder, however neuropathological changes begin years before memory impairment. Investigation of the early molecular abnormalities in AD might offer innovative opportunities to target memory impairment prior to onset. Decreased protein synthesis plays a fundamental role in AD, yet the consequences of this dysregulation for cellular function remain unknown. We hypothesize that alterations in the de novo proteome drive early metabolic alterations in the hippocampus that persist throughout AD progression. Using a combinatorial amino acid tagging approach to selectively label and enrich newly synthesized proteins, we found that the de novo proteome is disturbed in young APP/PS1 mice prior to symptom onset, affecting the synthesis of multiple components of the synaptic, lysosomal and mitochondrial pathways. Furthermore, the synthesis of large clusters of ribosomal subunits were affected throughout development. Our data suggest that large-scale changes in protein synthesis could underlie cellular dysfunction in AD.
Ginsenoside Rg3 Inhibits Pulmonary Fibrosis by Preventing HIF-1α Nuclear Localisation
Authors: Fu Zhuo , Xu Yong-sheng , Cai Chun-quan
Published: September 2020

Introduction: Excessive fibroblast proliferation during pulmonary fibrosis leads to structural abnormalities in lung tissue and causes hypoxia and cell injury. However, the mechanisms and effective treatment are still limited.Methods: In vivo, we used bleomycin to induce pulmonary fibrosis in mice. IHC and Masson staining were used to evaluate the inhibitory effect of ginsenoside Rg3. In vitro, scanning electron microscopy, transwell and wound healing were used to evaluate the cell phenotype of LL 29 cells. In addition, biacore was used to detect the binding of ginsenoside Rg3 and HIF-1α.Results: Here, we find that bleomycin induces the activation of the HIF-1α/TGFβ1 signalling pathway and further enhances the migration and proliferation of fibroblasts through the epithelial mesenchymal transition (EMT). Ginsenoside Rg3 can slow down the progression of pulmonary fibrosis by inhibiting the nuclear localisation of HIF-1α. In addition, molecular docking and biacore experiments indicated that ginsenoside Rg3 can bind HIF-1α and restrict the progression of pulmonary fibrosis in animals. Hypoxia can lead to excessive proliferation of lung fibroblasts and further accelerate lung fibrosis.Conclusions: This finding suggests that early targeted treatment of hypoxia may have potential value in the treatment of pulmonary fibrosis.
Prevalence, Burden of Disease, and Lost in Health State Utilities Attributable to Chronic Musculoskeletal Disorders and Pain in Chile
Authors: Zitko Pedro , Bilbeny Norberto , Balmaceda Carlos , Abbott Tomas , Carcamo Cesar , Espinoza Manuel
Published: September 2020

Background: Musculoskeletal disorders are a leading cause of disability adjusted life years (DALY) in the world. In addition to DALY, other approaches such as the attributable fraction have been proposed to estimate the burden of diseases. We aim to describe the prevalence and to compare the DALYs and loss of health state utilities (LHSU) attributable to common musculoskeletal disorders in Chile.Methods: We used data from the Chilean National Health Survey carried out in 2016-2017. Six musculoskeletal disorder were detected through the COPCOPRD questionnaire: chronic musculoskeletal pain, chronic low back pain, chronic shoulder pain, osteoarthritis of hip and knee, and fibromyalgia. We calculated the DALY for each disorder for 18 sex and age strata, and LHSU at individual and population level. We also calculated the fraction of LHSU attributable to pain.Results: Chronic musculoskeletal pain disorder affects a fifth of the adult population, with a significant difference between sexes. Among specific musculoskeletal disorders highlights chronic low back pain with the highest prevalence. Musculoskeletal disorders are a significant cause of LHSU at the individual level, especially in the case of fibromyalgia. Chronic musculoskeletal pain caused 503,919 [283,940 - 815,132] DALYs in 2017, and roughly two hundred thousand LSHU at population level, which represents 9.7% [8.8 - 10.6] of the total LSHU occurred in that year. Discrepancy in the burden of musculoskeletal disorders was observed according to DALY or LSHU estimation. The pain and discomfort domain of LHSU accounted for around half of total LHSU in people with musculoskeletal disorders. Conclusion: chronic musculoskeletal pain is a major source of burden and LHSU. Fibromyalgia should deserve more attention in future studies. Using the attributable fraction offers a straightforward and flexible way to explore the burden of musculoskeletal disorders.
Lung-Protective Ventilation Increases Cerebral Metabolism and Non-Inflammatory Brain Injury in Porcine Experimental Sepsis
Authors: Nyberg Axel , Gremo Erik , Blixt Jonas , Sperber Jesper , Larsson Anders , Lipcsey Miklós , Pikwer Andreas , Castegren Markus
Published: September 2020

Background: Protective ventilation with lower tidal volumes reduces systemic and organ-specific inflammation. In sepsis-induced encephalopathy or acute brain injury the use of protective ventilation has not been widely investigated (experimentally or clinically). We hypothesized that protective ventilation would attenuate cerebral inflammation in a porcine endotoxemic sepsis model. The aim of the study was to study the effect of tidal volume on cerebral inflammatory response, cerebral metabolism and brain injury. Nine animals received protective mechanical ventilation with a tidal volume of 6 mL x kg-1 and nine animals were ventilated with a tidal volume of 10 mL x kg-1. During a 6-hour experiment, the pigs received an endotoxin intravenous infusion of 0.25 µg x kg-1 x h-1. Systemic, superior sagittal sinus and jugular vein blood samples were analysed for inflammatory cytokines and S100B. Intracranial pressure, brain tissue oxygenation and brain microdialysis were sampled every hour. Results: No differences in systemic or sagittal sinus levels of TNF-α or IL-6 were seen between the groups. The low tidal volume group had increased cerebral blood flow (p<0.001) and cerebral oxygen delivery (p<0.001), lower cerebral vascular resistance (p<0.05), higher cerebral metabolic rate (p<0.05) along with higher cerebral glucose consumption (p<0.05) and lactate production (p<0.05). Moreover, low tidal volume ventilation increased the levels of glutamate (p<0.01), glycerol (p<0.08) and showed a trend towards higher lactate to pyruvate ratio (p=0.08) in cerebral microdialysate as well as higher levels of S-100B (p<0.05) in jugular venous plasma compared with medium-high tidal volume ventilation.Conclusions: Contrary to the hypothesis, protective ventilation did not affect inflammatory cytokines. The low tidal volume group had increased cerebral blood flow, cerebral oxygen delivery and cerebral metabolism together with increased levels of markers of brain injury compared with medium-high tidal volume ventilation.
Identification, Systematic Evolution and Expression Analyses of The AAAP Gene Family in Capsicum Annuum
Authors: Pan Xiaoxue , Hu Mingyu , Wang Zhongwei , Guan Ling , Jiang Xiaoying , Bai Wenqin , Wu Hong , Lei Kairong
Published: September 2020

Background: The amino acid/auxin permease (AAAP) family represents a class of proteins that transport amino acids across cell membranes. Members of this family are widely distributed in different organisms and participate in processes such as growth and development and the stress response in plants. However, a systematic comprehensive analysis of AAAP genes of the pepper (Capsicum annuum) genome has not been reported. Results: In this study, we performed systematic bioinformatics analyses to identify AAAP family genes in the C. annuum ‘Zunla-1’ genome to determine gene number, distribution, structure, duplications and expression patterns in different tissues and stress. A total of 53 CaAAAP genes were identified in the ‘Zunla-1’ pepper genome and could be divided into eight subgroups. Significant differences in gene structure and protein conserved domains were observed among the subgroups. In addition to CaGAT1, CaATL4, and CaVAAT1, the remaining CaAAAP genes were unevenly distributed on 11 of 12 chromosomes. In total, 33.96% (18/53) of the CaAAAP genes were a result of duplication events, including three pairs of genes due to segmental duplication and 12 tandem duplication events. Analyses of evolutionary patterns showed that segmental duplication of AAAPs in pepper occurred before tandem duplication. The expression profiling of the CaAAAP by transcriptomic data analysis showed distinct expression patterns in various tissues and response to different stress treatment, which further suggest that the function of CaAAAP genes has been differentiated. Conclusions: This study of CaAAAP genes provides a theoretical basis for exploring the roles of AAAP family members in C. annuum.
Dynamic Modeling and Optimal Control of Cystic Echinococcosis
Authors: Rong Xinmiao , Fan Meng , Zhu Huaiping
Published: September 2020

Background: Cystic echinococcosis is one of the most severe helminth zoonosis with a drastic impact on human health and livestock industry. Investigating optimal control strategy and assessing the crucial factors are essential for developing countermeasures to mitigate this disease. Methods: Two compartment models were formulated to study the dynamics of cystic echinococcosis transmission, to evaluate the effectiveness of various control measures, and to find the optimal control strategy. Sensitive analyses were conducted by obtaining PRCCs and contour plot were used to evaluate the effect of key parameters on the basic reproduction number. Based on forward-backward sweep method, numerical simulations were employed to investigate effects of key factors on the transmission of cystic echinococcosis and to obtain the optimal control strategy. Results: The food resources of stray dog and invalid sheep vaccination rate, which are always neglected, were significant to the transmission and control of cystic echinococcosis. Numerical simulations suggest that, the implementation of optimal control strategy can significantly reduce the infections. Improving the cost of health education and domestic dog deworming could not decrease human infections. Conclusions: Our study showed that only a long-term use of the optimal control measures can eliminate the disease. Meanwhile, during the intervention, sheep vaccination and stray dogs disposing should be emphasized ahead of domestic dogs deworming to minimize the control cost. Simultaneously reducing other wild intermediate hosts and strengthening the sheep vaccination as well as disposing the stray dogs would be most effective.
The structure, function, and evolution of a complete human chromosome 8
Authors: Eichler Evan , Logsdon Glennis , Vollger Mitchell , Hsieh PingHsun , Mao Yafei , Liskovykh Mikhail , Koren Sergey , Nurk Sergey , Mercuri Ludovica , Dishuck Philip , Rhie Arang , de Lima Leonardo , Dvorkina Tatiana , Porubsky David , Mikheenko Alla , Bzikadze Andrey , Kremitzki Milinn , Lindsay Tina , Jain Chirag , Hoekzema Kendra , Murali Shwetha , Munson Katherine , Baker Carl , Sorensen Melanie , Lewis Alexandra , Surti Urvashi , Gerton Jennifer , Larionov Vladimir , Ventura Mario , Miga Karen , Phillippy Adam
Published: September 2020

The complete assembly of each human chromosome is essential for understanding human biology and evolution. Using complementary long-read sequencing technologies, we complete the first linear assembly of a human autosome, chromosome 8. Our assembly resolves the sequence of five previously long-standing gaps, including a 2.08 Mbp centromeric α-satellite array, a 644 kbp defensin copy number polymorphism important for disease risk, and an 863 kbp variable number tandem repeat at chromosome 8q21.2 that can function as a neocentromere. We show that the centromeric α-satellite array is generally methylated except for a 73 kbp hypomethylated region of diverse higher-order α-satellite enriched with CENP-A nucleosomes, consistent with the location of the kinetochore. Using a dual long-read sequencing approach, we complete the assembly of the orthologous chromosome 8 centromeric regions in chimpanzee, orangutan, and macaque for the first time to reconstruct its evolutionary history. Comparative and phylogenetic analyses show that the higher-order α-satellite structure evolved specifically in the great ape ancestor, and the centromeric region evolved with a layered symmetry, with more ancient higher-order repeats located at the periphery adjacent to monomeric α-satellites. We estimate that the mutation rate of centromeric satellite DNA is accelerated at least 2.2-fold, and this acceleration extends beyond the higher-order α-satellite into the flanking sequence.
Dyspnea is associated with overall symptom burden in patients with chronic respiratory insufficiency
Authors: Rantala Heidi Anniina , Leivo-Korpela Sirpa , Lehto Juho T. , Lehtimäki Lauri
Published: September 2020

Objective
Patients with chronic respiratory insufficiency suffer from many symptoms together with dyspnea. We evaluated the association of dyspnea with other symptoms in patients with chronic respiratory insufficiency due to chronic obstructive pulmonary disease or interstitial lung disease.
Results
This retrospective study included 101 patients. Dyspnea was assessed with modified Medical Research Council dyspnea questionnaire (mMRC) and other symptoms with Edmonton Symptom Assessment System (ESAS) and Depression Scale (DEPS). Patients with mMRC 4 (most severe dyspnea) compared to those with mMRC 0–3 reported higher median (IQR) symptom scores on ESAS in e.g. dry mouth (7.0 (4.0–8.0) vs. 3.0 (1.0–6.0), P < 0.001), tiredness (6.0 (3.0–7.0) vs. 3.0 (1.0–5.0), P < 0.001) and anxiety (3.0 (0.0-5.5) vs. 1.0 (0.0–3.0), P = 0.007). Patients with mMRC 4 were more likely to reach the DEPS threshold for depression compared to those with mMRC 0–3 (42.1% vs. 20.8%, P = 0.028). In conclusion, patients with chronic respiratory insufficiency need comprehensive symptom screening with relevant treatment, as they suffer from many severe symptoms worsening with increased dyspnea.
Silencing of MEG3 attenuated the role of lipopolysaccharides by modulating the miR-93-5p/PTEN pathway in Leydig cells
Authors: Zhou Xu , He Jingliang , Chen Jinbo , Cui Yu , Ou Zhenyu , Zu Xiongbing , Liu Nenghui
Published: September 2020

BackgroundLeydig cells reflect the activation of inflammation, decrease of androgen production, inhibition of cell growth and promotion of cell apoptosis under orchitis. Maternally expressed gene 3 (MEG3) exerts a crucial role in various human diseases, but under orchitis, the role and underlying molecular mechanism of MEG3 in Leydig cells remain unclear.MethodsLipofectamine 2000 was used for the cell transfections. qPCR and western blots assay were applied to assess the gene expression. ELISA assay was used to measure the TNFα, IL6 and testosterone secretion. CCK8 and EdU assay was employ to test the cell viability and proliferation respectively. Luciferase reporter and RIP assay were introduced to detect the binding of miR-93-5p with MEG3 and PTEN.ResultsLipopolysaccharides (LPS) induced TNFα and IL6 secretion, lowered testosterone production, inhibited cell viability and proliferation, and induced cell apoptosis in Leydig cells. MEG3 was upregulated in Leydig cells treated with LPS and that knockdown of MEG3 inhibited the role of LPS in Leydig cells. MEG3 absorbed miR-93-5p and that suppression of miR-93-5p restored the role of silenced MEG3 in Leydig cells under LPS treatment. miR-93-5p inhibited PTEN expression and that over-expressed PTEN alleviated the effect of miR-93-5p in Leydig cells treated with LPS. LPS activated the MEG3/miR-93-5p/PTEN signalling pathway in Leydig cells. ConclusionsThis study revealed that MEG3 serves as a molecular sponge to absorb miR-93-5p, thus leading to elevation of PTEN expression in Leydig cells under LPS treatment, offering a theoretical basis on which to establish potential new treatment strategies for orchitis.
Identiﬁcation, characterization and functional analysis of grape (Vitis vinifera L.) Mitochondrial Transcription Termination Factor (mTERF) genes in responding to biotic stress and exogenous phytohormone
Authors: Yin Xiangjing , Gao Yu , Song Shiren , Lu Jiang
Published: September 2020

Mitochondrial transcription termination factor (mTERF) is a large gene family which plays a significant role during plant growth against various environmental stresses. However, knowledge of mTERF genes in grapevine (Vitis L.) is limited. In this research, a comprehensive analysis of grape mTERF genes, including chromosome locations, phylogeny, protein motifs, gene structures, gene duplications, synteny analysis and expression profiles, was conducted. As a result, a total of 25 mTERF genes were identified from the grape genome, which are distributed on 13 chromosomes with diverse densities and segmental duplication events. The grape mTERF gene family is classified into nine clades based on phylogenetic analysis and structural characteristics. These VvmTERF genes showed differential expression patterns in response to multiple phytohormone treatments and biotic stresses, including treatments with abscisic acid and methyl jasmonate,and inoculation of Plasmopara viticola and Erysiphe necator These research findings, as the first of its kind in grapevine, will provide useful information for future development of new stress tolerant grape cultivars through genetic manipulation of VvmTERF genes.
Is the Correct Anatomical Placement of the Electrocardiogram (ECG) Electrodes Essential to Diagnosis in the Clinical Setting A Systematic Review
Authors: Hadjiantoni Alexandros Stavros
Published: September 2020

Background: Anatomical misplacement of the Electrocardiogram (ECG) electrode(s) is common, with significant impact on clinical diagnosis. Reasons are multi-faceted, with this review examining the consequential effects of misplacement to ECG morphology, diagnosis, prognosis, patient outcomes, and potential impact to patient care pathway. Objectives: This review examined the significance of misplacement, its’ commonality and ensuing effect on patient safety, accurate ECG acquisition and diagnosis, with evaluation of reasons for such misplacement.Methodology: Review of available literature was conducted using electronic databases. In-line with the Preferred Reporting Items for Systematic reviews and Meta – analysis protocols (PRISMA) 2015 checklist, this review was conducted with search criteria, search terms, eligibility for inclusion/ exclusion criteria, extraction and data analysis predetermined by the authors. Keywords were arranged according to grouping of terms surrounding ECG, anatomical placement, and diagnosis. The search strategy was conducted during September/October 2019. Scoping searches were conducted alongside reference lists of included studies hand searched (Snowballing) for further relevant studies. The Critical Appraisal Skills Programme (CASP) was used to methodically appraise papers (CASP, 2019). Screening of titles and abstracts of identified citations was performed by a single reviewer. Eligible articles then full text screened independently by two reviewers. Disagreements were discussed and resolved by a third reviewer. In instances of unclear reporting, authors were contacted to provide further information and clarity. Assessment of relevant literature and critical appraisal of primary research, pertaining to the clinical diagnosis and effects of anatomical misplacement of ECG electrodes, formulate the thematic discussion drawn by this review. Results: This review identified a plethora of causes, ranging from: operator error; lack of anatomical awareness; inaccurate assessment of anatomical landmarks; obesity; differences in anatomy/gender; levels of undress and lack of appreciation of consequences of misplacement, both modifiable and non-modifiable attributable to electrode misplacement. Clinical diagnosis can be altered owing to erroneous placement of electrodes. ECG morphology is altered due to incorrect anatomical misplacement, culminating substandard practice, a missed diagnosis or misdiagnosis and potential harm. Conclusion: Correct anatomical placement of ECG electrodes is essential to diagnosis in the clinical setting. Peer-led educational intervention with mandatory training is essential to improve practice. PROSPERO Registration Number: CRD42019152461
Necroptosis Triggered by ROS Accumulation and Ca2+ Overload, Partly Explains the Inflammatory Responses and Anti-Cancer Effects Associated With 1Hz, 100 mT ELF-MF in vivo
Authors: Barati Mojdeh , Javidi Mohammad Amin , Darvishi Behrad , Shariatpanahi Seyed Peyman , Moosavi Zahra S. Mesbah , Ghadirian Reyhane , Khani Tahereh , Sanati Hassan , Simaee Hossein , Barough Mahdieh Shokrollahi , Farahmand Leila , Ansari Alireza Madjid
Published: September 2020

Background: Focus on application of non-ionizing, extremely low frequency magnetic fields (ELF-EMF) as an alternative approach for treating cancer is rapidly rising nowadays. Nevertheless, little is known about the underlying anti-tumoral mechanism of action of them. Methods: In the present study, for the first time, we reported that along with apoptosis, 2 h/day exposure to 100 Hz, 1 mT ELF-EMF for a 5-day period, can induce necroptosis, a specific type of programed necrotic cell death, by promoting RIPK1/RIPK3/MLKL pathway which may also be responsible for observed pro-inflammatory responses in vivo, evident from an increase in plasma levels of pro-inflammatory cytokines including TNF-α, IL-1β, IL-2, IL-6, IL-17A and IFN-γ. Alongside, 30-day exposure to this system could also significantly suppress tumor growth and expression of markers of tumor cell proliferation, angiogenesis, and metastasis, namely Ki-67, CD31, VEGFR2 and MMP-9. Results: The number of tumor infiltrating lymphocytes (TILs), especially CD8+ Th cells were significantly increased following exposure to ELF-EMF. Interestingly, pretreating cancer cells with N-acetyl cysteine, a free-radical scavenger, or verapamil, an L-type calcium channel blocker in vitro, could diminish observed necroptotic and apoptotic responses while pretreating with calcium chloride, could aggravate responses.Conclusions: Overall, results of present study demonstrated that along with apoptosis, necroptosis is also a prominent form of cell death induced by exposure to ELF-EMF which is also dependent on elevated intracellular levels of ROS and calcium.
A Resting-State Functional MRI Study in Patients with Vestibular Migraine During Interictal Period
Authors: Wang Shuqing , Wang Haiping , Liu Xuejun , Yan Wenjing , Wang Minghui , Zhao Renliang
Published: September 2020

AimTo evaluate the spontaneous neuronal activities and the changes of brain functional network in patients with vestibular migraine (VM) using resting-state functional MRI (fMRI) during the interictal period.MethodsThree groups included 18 patients with VM, 21 patients with MWoA and 21 HCs underwent the scanning of the resting-state fMRI. First, brain regions with significant differentia of amplitude of low frequency fluctuation (ALFF) values were obtained. Secondly, functional connectivity (FC) analysis was performed in the brain region(s) with the most significant differentia of ALFF values which was defined as region of interest (ROI).Results(1) Compared with healthy volunteers, patients with VM and patients with MWoA showed significant ALFF decrease in the right putamen (P<0.05), and significant ALFF increase in the right lingual gyrus (P<0.05). What’s more, compared with patients with MWoA, patients with VM showed significant ALFF increase in the right lingual gyrus (P<0.05). In addition, we found that ALFF values in the right putamen of patients with VM were negatively correlated with the duration of migraine and the frequency of migraine attacks (P<0.05). (2) Compared with HCs, patients with VM showed significant FC increase among the cerebellum, the left dorsolateral superior frontal gyrus and the right putamen (P<0.05) but significant decrease among the left median cingulate, paracingulate gyri and the right putamen (P<0.05). Compared with patients with MWoA, patients with VM showed significant FC increase between the cerebellum and the right putamen (P<0.05) but significant FC decrease among the left median cingulate, paracingulate gyri and the right putamen (P<0.05).ConclusionThere are functional abnormalities in nociceptive, vestibular and visual cortex regions in patients with VM during the interictal period.
Inversion of Love Waves in Earthquake Ground Motion Records for Two-dimensional S-wave Velocity Model of Deep Sedimentary Layers
Authors: Kasamatsu Kentaro , Yamanaka Hiroaki , Sakai Shin’ichi
Published: September 2020

We have proposed a new waveform inversion method to estimate a 2D S-wave velocity structure of deep sedimentary layers using broadband Love waves. As a preprocessing operation in our inversion scheme, we decompose earthquake observation records into velocity waveforms at periods of 1 s interval. Then, we verify an assumption of 2D propagations of Love waves with polarization features based on a principal component analysis to select the segments applied for the inversion. A linearized iterative inversion analysis for the selected Love wave segments filtered at period of every 1 s allows a detailed estimation of boundary shapes of interfaces over the seismic bedrock with an S-wave velocity of approximately 3 km/s. We demonstrate the technique’s effectiveness with applications to observed seismograms in the Kanto plain, Japan. Differences between the estimated and existing structural models are remarkable at basin edges. A regional variation of the near-surface S-wave velocities in our model is similar to a distribution of surface geological classifications. Since a subsurface structure at a basin edge strongly affects earthquake ground motions in a basin with generations of surface waves, our method can provide a detail model of a complex S-wave velocity structure at an edge part for a strong ground motion prediction.
Understanding insulin and nutrition administration in glycemic control with the right side of the brain
Authors: Chase J. Geoffrey , Knopp Jennifer Launa
Published: September 2020

Background

Critically ill patients frequently experience stress-induced hyperglycaemia, leading to increased morbidity and mortality. Glycaemic control (GC) with insulin therapy alone has proven difficult, due to significant inter- and intra- patient variability in response to insulin therapy. This study reviews the problem and analyses the impact of physiological dynamics and patient variability on outcome glycemia.
Methods

A graphical model of metabolic dynamics is used to analyse the impact of fundamental glucose flux dynamics on insulin and nutrition administration in the context of maintaining a glycemic goal. It is used to delineate the limits of ability in controlling insulin and/or nutrition administration to achieve safe, effective glycemic control in critical illness in the presence of low insulin sensitivity and high insulin sensitivity variability.
Results

Insulin saturation limits insulin-mediated glucose uptake. At low insulin sensitivity, maintaining a glycemic target level requires reduced nutrition administration due to saturated insulin-mediated glucose uptake. Metabolic insulin sensitivity variability leads to insulin-mediated glucose uptake variability, requiring reduced nutrition administration at low insulin sensitivity and higher insulin doses to mitigate the risk of hypo- and hyper- glycemia.
Conclusions

This work reviews the clinical glycemic control problem using a graphically-based physiological analysis to show the need to control nutrition administration, along with insulin, to achieve safe, effective control. These reductions are necessary for highly insulin resistant patients, a condition typically occurring early in ICU stay. Glycemic control should directly control nutrition in addition to insulin to optimise all avenues of glucose flux and thus ensure safe, effective glycemic control.
In silico analysis of bacterial translation factors reveal distinct translation event specific pI values
Authors: JANA SOMA , Datta Partha Pratim
Published: September 2020

Background
Protein synthesis is a cellular process that takes place through the successive translation events within the ribosome with the help of the event-specific protein factors, namely, initiation, elongation, release, and recycling factors. The translation process is fundamental to all organisms living in the wide variety of environments. In this regard, we asked the questions about how similar are those translation factors to each other from a wide variety of bacteria? Hence, we did a thorough in silico study of the translation factors from 495 bacterial sp., and 4262 amino acid sequences, wherein we theoretically measured their pI and MW values that are the two determining factors for distinguishing individual proteins in 2D gel electrophoresis. Then we analyzed the output from various angles.
Results
Our study revealed that, not all the pI values are same or random, but there is a distinct order, such that the pI values of translation factors are translation event specific. We found that the translation initiation factors are mainly basic, whereas, elongation and release factors that interact with the inter-subunit space of the intact 70S ribosome during translation are strictly acidic. Further analysis revealed that the acidic property of those factors is due to the higher frequencies of glutamic acids. However, two translation factors, the translation initiation factor 2 (IF2) and the ribosome recycling factor (RRF) showed variable pI values. Remarkably, the variability of the pI values of these two factors showed distinct lineage with the order of phylogeny.
Conclusion
From our results we conclude that, among all the bacterial translation factors, elongation and release factors are more conserved in terms of their pI values in comparison to initiation and recycling factors. Acidic properties of these factors are independent of habitat, nature, or the phylogeny of the bacterial species. Furthermore; irrespective of the different shapes, sizes, and functions of the elongation and release factors, possession of their strictly acidic pI values indicate that the acidic nature of these factors is a necessary criterion, perhaps to interact into the partially enclosed rRNA rich inter-subunit space of the translating 70S ribosome.
Risk Factors for Venous Thromboembolism in Patients With Diabetes Undergoing Joint Arthroplasty
Authors: Deng Wei , Huo Lili , Yuan Qiang , Huang Deyong , Li Quan , Tian Wei
Published: September 2020

Background: Venous thromboembolism (VTE) is a significant complication after joint arthroplasty. Diabetes is related to a few changes in coagulation and fibrinolysis that may lead to thrombophilia. We aimed to investigate the incidence of and risk factors for VTEs in patients with diabetes undergoing total hip (THA) or total knee anthroplasty (TKA) in a single centre in China. Methods: Patients with diabetes who underwent THA or TKA from January 2016 to December 2018 (n=400) at Beijing Jishuitan hospital were recruited in this study. Lower limb venous Doppler ultrasound was performed before and after surgery to confirm deep venous thrombosis (DVT). Computer tomography pulmonary angiography was done to confirm pulmonary embolism (PE) for those with new postoperative DVT and typical symptoms of PE. A multivariate logistic regression model was conducted to examine factors associated with the development of postoperative VTE.Results: The overall incidence of postoperative VTE in patients with diabetes after THA or TKA was 46.8% (187 out of 400). Among the 187 VTE patients, 7.5% (14 out of 187) had proximal vein thrombosis and 92.5% (173 out of 187) had distal vein thrombosis. No PE occurred. Female patients and patients undergoing TKA had higher incidence of postoperative VTE. Patients who developed postoperative VTE were older, and had higher levels of preoperative D-Dimer level and Caprini score. Increased VTE risks were associated with high level of preoperative D-Dimer (OR=2.11, 95%CI=1.35-3.30) and TKA (OR=2.29, 95%CI=1.29-4.01). Postoperative initiation of concomitant mechanical prophylaxis and low molecular weight heparin (LMWH) was protective for postoperative VTE (OR=0.56, 95%CI=0.37-0.86). Conclusions: VTE is common in patients with diabetes undergoing joint arthroplasty. Patients undergoing TKA or with a high level of preoperative D-Dimer are at a considerable risk of developing postoperative VTE. There may be a protective role of postoperative initiation of concomitant mechanical prophylaxis and LMWH for VTE.
Relationship Between Leukocyte Counts and Large Vessel Occlusion in Acute Ischemic Stroke
Authors: Tárkányi Gábor , Karádi Zsófia Nozomi , Szabó Zsófia , Szegedi István , Csiba László , Szapáry László
Published: September 2020

Background: Neuroinflammation plays an important role in the pathogenesis of acute ischemic stroke (AIS) and peripheral leukocyte counts have proved to be independent predictors of stroke severity and outcomes. Clinical significance of large vessel occlusion (LVO) in AIS is increasing, as these patients are potential candidates for endovascular thrombectomy and likely to have worse outcomes if not treated urgently. The aim of our study was to assess the relationship between on admission leukocyte counts and the presence of LVO in the early phase of AIS.Methods: We have conducted a cross-sectional, observational study based on a registry of consecutive AIS patients admitted up to 4.5 hours after stroke onset. Blood samples were taken at admission and leukocyte counts were measured immediately. The presence of LVO was verified based on the computed tomography angiography scan on admission.Results: Total white blood cell (WBC) and neutrophil counts were significantly higher in patients with LVO than those without LVO (P<0.001 respectively). After adjustment for potential confounders total WBC counts (adjusted OR: 1.405 per 1x109/L increase, 95% CI: 1.209 to 1.632) and neutrophil counts (adjusted OR: 1.344 per 1x109/L increase, 95% CI: 1.155 to 1.564) were found to have the strongest associations with the presence of LVO. Total WBC and neutrophil counts had moderate ability to discriminate an LVO in AIS (AUC: 0.667 and 0.655 respectively). No differences were recorded in leukocyte counts according to the size of the occluded vessel and the status of collateral circulation in the anterior vascular territory. However, total WBC and neutrophil counts tended to be higher in patients with LVO in the posterior circulation (p= 0.005 and 0.010 respectively).Conclusion: Higher admission total WBC and neutrophil counts are strongly associated with the presence of LVO and has moderate ability to discriminate an LVO in AIS. Detailed evaluation of stroke-evoked inflammatory mechanisms and changes according to the presence of LVO demands further investigation.
Prevalence of Post Intensive Care Syndrome Among Japanese Intensive Care Unit Patients: A Prospective, Multicenter, Observational J-PICS Study
Authors: Kawakami Daisuke , Fujitani Shigeki , Morimoto Takeshi , Dote Hisashi , Takita Mumon , Takaba Akihiro , Hino Masaaki , Nakamura Michitaka , Irie Hiromasa , Adachi Tomohiro , Shibata Mami , Kataoka Jun , Korenaga Akira , Yamashita Tomoya , Okazaki Tomoya , Okumura Masatoshi , Tsunemitsu Takefumi
Published: September 2020

BackgroundMany studies have compared quality of life of post-intensive care syndrome (PICS) patients with age-matched population-based controls, instead of baseline quality of life. Furthermore, many studies on PICS used the 36-item Short Form (SF-36) health survey questionnaire version 2 but lack the data for SF-36 values before and after intensive care unit (ICU) admission. Thus, the clinically important changes in the parameters of SF-36 are unknown. Therefore, we determined the frequency of co-occurrence of PICS impairments at 6 months after ICU admission. We also evaluated the changes in SF-36 health survey questionnaire subscales and interpreted the patients’ subjective significance of impairment.MethodsA prospective, multicenter, observational cohort study was conducted in 16 ICUs across 14 Japanese hospitals. Adult ICU patients expected to receive mechanical ventilation for > 48 hours were enrolled and their 6-month outcome was assessed using the questionnaires. PICS definition was based on the physical status, change in SF-36 physical component score (PCS) ≥ 10 points; mental status, change in SF-36 mental component score ≥ 10 points; cognitive function, Short-Memory Questionnaire (SMQ) score worsened and SMQ score at 6 months < 40. Multivariate logistic regression model was used to identify the factors associated with PICS occurrence. The patients’ subjective significance of physical and mental symptoms was assessed using the 7-scale Global Assessment Rating.ResultsAmong 192 patients, 48 (29.6%) died at 6 months. Among the survivors at 6 months, 96 patients responded to the questionnaire; ≥1 PICS impairment occurred in 61 (63.5%) patients, and ≥ 2 occurred in 19 (19.9%) patients. Physical, mental, and cognitive impairments occurred in 33.3%, 14.6%, and 37.5% patients, respectively. Low education level was associated with PICS occurrence (Odds ratio: 3.8, 95% confidence interval: 1.1–17.9, P=0.036). Based on the patients’ subjective assessment, a 10-point change in PCS indicated moderate negative change.ConclusionsAmong the survivors who received mechanical ventilation, 64% had PICS at 6 months; co-occurrence of PICS impairments occurred in 20%. PICS occurrence was associated with low educational level. Future studies elucidating the minimal clinically important difference of SF-36 scores among the ICU patients and standardizing the PICS definition are required.Trial registrationUMIN000034072
Postoperative Radiotherapy Improved Survival in pT1-2N1 Oral and Oropharyngeal Cancer Without Adequate Neck Dissection ​
Authors: Yang Ching-Chieh , Kang Bor-Hwang , Liu Wen-Shan , Yin Chun-Hao , Lee Ching-Chih
Published: September 2020

Background: To assess the benefit of postoperative radiotherapy in patients with pT1-2N1M0 oral and oropharyngeal cancer by the quality of neck dissection.Methods: In the Surveillance, Epidemiology, and End Results database, pT1-2N1M0 oral and oropharyngeal cancer patients treated by primary tumor resection and neck dissection with or without radiotherapy were enrolled between 2004 and 2015. Univariate and multivariate analysis were used to explore the effect of adjuvant radiotherapy on 5-year overall survival (OS) and disease-specific survival(DSS).Results: Of the 1,765 patients identified, 1,108 (62.8%) had oral cancer, 1,141 (64.6%) were men, and 1,067 (60.5%) underwent adjuvant radiotherapy. After adjusting for confounding factors, postoperative radiotherapy reduced the adjusted hazard ratio (aHR) of 5-year OS to 0.64 (95% confidence interval[CI], 0.49-0.84) in those with <18 lymph nodes removed, but not in those with 19-24 lymph nodes removed (aHR, 0.78 ; 95% CI, 0.73-1.13), and in those with >25 lymph nodes removed (aHR, 0.96; 95% CI, 0.75-1.24). For 5-year DSS, similar effect was observed. The adjusted hazard ratio was 0.66 (95% confidence interval, 0.45-0.97) in those with <18 lymph nodes. The protective effect was not seen in those with 18-24 lymph nodes (aHR, 1.07; 95% CI 0.59-1.96), and in those with >25 lymph nodes (aHR, 1.12; 95% CI, 0.81-1.56). Sensitivity testing also showed a robust protective effect of postoperative radiotherapy in patients with <18 lymph nodes removed.Conclusion: Radiotherapy significantly improved survival in patients with pT1-2N1M0 oral and oropharyngeal cancer without adequate neck dissection.
Identification of Novel Alternative Splicing Events Associated with Tumorigenesis, Protein Modification, and Immune Microenvironment in Early-Onset Gastric Cancer
Authors: Zhang Jian , Goel Ajay , Zhu Lin
Published: September 2020

Background: Alternative splicing (AS), e.g. tandem alternative polyadenylation (TAPA), has emerged as major post-transcriptional modification events in human disease. However, the roles of AS and TAPA in early-onset gastric cancer (EOGC) have not been revealed.Methods: The global AS profiles of 80 EOGC patients were analyzed. The EOGC-specific AS events (ESASs) were identified in both EOGC and adjacent non-tumor tissues. Functional enrichment analysis, Splicing network, Alternative Polyadenylation (APA) core factor network, and cell abundancy analysis were performed. Furthermore, the landscapes of AS events in the varied subtypes of EOGC patients were evaluated. Results: Overall, 66,075 AS events and 267 ESASs were identified in EOGC. Furthermore, 4809 genes and 6152 gene isoforms were found to be aberrantly expressed in EOGC. The Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analyses showed that significant pathway alterations might exist in these AS events, genes, and gene isoforms. Moreover, the Protein-protein interaction (PPI) network analysis revealed that UBC, NEK2, EPHB2, and DCTN1 genes were the hub genes in the AS events in EOGC. The immune cell infiltration analysis indicated a correlation between the AS events and the cancer immune microenvironment. The distribution of AS events in varied EOGC subtypes, protein phosphorylation and glycosylation was uneven. Conclusion: The study highlighted the vital roles of AS in EOGC, including modulating the specific protein modification and reshaping the cancer immune microenvironment, and yielded new insights into the diagnosis of EOGC as well as cancer treatment.
Synthesis of DOTA-Pyridine Chelates for 64Cu Coordination and Radiolabeling of αMSH Peptide
Authors: Yang Hua , Gao Feng , McNeil Brooke , Zhang Chengcheng , Zeisler Stefan , Kumlin Joel , Zeisler Jutta , Bénard François , Ramogida Caterina , Schaffer Paul , Yuan Zheliang
Published: September 2020

Background : 64Cu is one of the few radioisotopes that can be used for both imaging and therapy, enabling theranostics with identical chemical composition. Development of stable chelators is essential to harness the potential of this isotope, challenged by the presence of endogenous copper chelators. Pyridyl type chelators show good coordination ability with copper, prompting the present study of a series of chelates DOTA-xPy (x=1-4) that sequentially substitute carboxyl moieties with pyridyl moieties on a DOTA backbone. Results: We found that the presence of pyridyl groups significantly increases 64 Cu labeling yield, with DOTA-2Py, -3Py and -4Py quantitatively complexing 64 Cu at room temperature within 5 min (10 -4 M). [ 64 Cu]Cu-DOTA-xPy (x=2-4) exhibited good stability in human serum up to 24 hours. When challenged with 1000 eq. of NOTA, no transmetallation was observed for all three 64 Cu complexes. DOTA-xPy (x=1-3) were conjugated to a cyclized α-melanocyte-stimulating hormone (αMSH) peptide by using one of the pendant carboxyl groups as a bifunctional handle. [ 64 Cu]Cu-DOTA-xPy-αMSH retained good serum stability (>96% in 24 hours) and showed high binding affinity (Ki=2.1-3.7 nM) towards the melanocortin 1 receptor. Conclusion : DOTA-xPy (x=1-3) are promising chelators for 64 Cu. Further in vivo evaluation is necessary to assess the full potential of these chelators as a tool to enable further theranostic radiopharmaceutical development.
A Solitary Giant Neurofibroma of Inguinal Region——A Case Report
Authors: Zhou Haiying , Lu Hui
Published: September 2020

BackgroundNeurofibroma is a rare nerve sheath tumor of neuroectodermal origin, especially the huge and isolated neurofibroma located in the inguinal region. To our knowledge, no such case has previously been reported.Case presentationWe report a case of 34-year-old male patient with a 4-year history of progressive enlargement of the medial root mass in his left thigh with sitting and standing disorders along with pain. The tumor was completely removed by operation, and pathological diagnosis showed neurofibroma. There was no obvious neurologic defect after surgery, and no recurrence tendency was found in the follow-up of 2 years.ConclusionsFor a large solitary mass with slow growth and no malignant clinical manifestations for a long time, clinicians can not rule out the hypothetical diagnosis of neurofibroma, even though its growth site is very rare, such as this case of a huge tumor located in the groin. For neurogenic tumors, early operation should be performed, and the prognosis of patients after tumor resection is excellent.
Identification of MEG8-miR378d-SOBP Axis as a Novel Regulatory Network and Associated With Immune Infiltrates in Ovarian Carcinoma by Integrated Bioinformatics Analysis
Authors: Lei Jian , He Zhen-Yu , Wang Jun , Hu Min , Zhou Ping , Lian Chen-Lu , Hua Li , Wu San-Gang , Zhou Juan
Published: September 2020

BackgroundTo investigate the potential molecular mechanism of ovarian cancer (OC) evolution and immunological correlation using the integrated bioinformatics analysis.MethodsData from the Gene Expression Omnibus (GEO) was used to gain differentially expressed genes (DEGs). Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analysis were completed by utilizing the Database for Annotation, Visualization, and Integrated Discovery (DAVID). After multiple validation via The Cancer Genome Atlas (TCGA), Gene Expression Profiling Interactive Analysis 2 (GEPIA 2), the Human Protein Atlas (HPA) and Kaplan-Meier (KM) plotter, immune logical relationships of the key gene SOBP were evaluated based on Tumor Immune Estimation Resource (TIMER), and Gene Set Enrichment Analysis (GSEA) software. Finally, the lncRNAs-miRNAs-mRNAs sub-network was predicted by starBase, Targetscan, miRBD, and LncBase, individually. Correlation of expression and prognosis for mRNAs, miRNAs and lncRNAs were confirmed by TCGA, GEPIA 2, starBase, and KM.ResultsA total of 192 shared DEGs were discovered from the four data sets, including 125 upregulated and 67 downregulated genes. Functional enrichment analysis presented that they were mainly enriched in cartilage development, pathway in PI3K-Akt signaling pathway. Lower expression of SOBP was the independent prognostic factor for inferior prognosis in OC patients. Intriguingly, downregulated SOBP enhanced the infiltration levels of B cells, CD8+ T cells, Macrophage, Neutrophil and Dendritic cells. GSEA also disclosed low SOBP showed significantly association with the activation of various immune-related pathways. Finally, we firstly reported that MEG8-miR378d-SOBP axis was linked to development and prognosis of ovarian cancer through regulating cytokines pathway.Conclusions Our study establishes a novel MEG8-miR378d-SOBP axis in the development and prognosis of OC, and the triple sub-network probably affects the progression of ovarian tumor by regulating cytokines pathway.