bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigating Causal Relations Between Circulating Metabolites and Alzheimer’s Diseases: A Mendelian Randomization Study
Authors: Huang Shu-Yi , Yang Yu-Xiang , Zhang Ya-Ru , Kuo Kevin , Li Hong-Qi , Shen Xue-Ning , Chen Shi-Dong , Chen Ke-Liang , Dong Qiang , Tan Lan , Yu Jin-Tai
Published: July 2021

BackgroundMetabolomics is a promising approach that can be used to understand pathophysiological pathways of Alzheimer disease (AD). However, the relationships between metabolism and AD are poorly understood. The aim of this study is to investigate the causal association between circulating metabolites and risk of AD by combining metabolomics with genomics through two-sample Mendelian randomization (MR) approach.MethodsGenetic associations with 123 circulating metabolic traits were utilized as exposures. A large summary statistics data from International Genomics of Alzheimer’s Project was used in primary analysis, including 21,982 AD cases and 41,944 controls. Validation was further performed using family history of AD data from UK Biobank (27,696 cases of maternal AD, 14,338 cases of paternal AD and 272,244 controls). We utilized the inverse-variance weighted method as primary analysis and four additional MR methods (MR-Egger, weighted median, weighted mode, and MR pleiotropy residual sum and outlier) for sensitivity analyses.ResultsWe found one-fold increased risk of developing AD per standard deviation increase in the levels of circulating ApoB (odd ratio (OR)=3.18; 95% confidence interval (CI): 1.52–6.66, P=0.0022) and glycoprotein acetyls (OR=1.21; 95% CI: 1.05–1.39, P=0.0093), serum total cholesterol (OR=2.73; 95% CI: 1.41-5.30, P=0.0030), and low-density lipoprotein (LDL) cholesterol (OR=2.34; 95% CI: 1.53-3.57, P=0.0001). Whereas glutamine (OR=0.81; 95% CI: 0.71-0.92, P=0.0011) were significantly associated with lower risk of AD. We also detected causal effects of several different composition of LDL fractions on increased AD risk, which has been verified in validation. However, we found no association between circulating high-density lipoprotein cholesterol and AD.ConclusionsOur findings provided robust evidence supporting causal effects of circulating glycoprotein acetyls, ApoB, LDL cholesterol, and serum total cholesterol on higher risk of AD, whereas glutamine showed the protective effect. Further research is required to decipher the biological pathways underpinning associations.
Retroperitoneal Mass: Lymphoma as Differential Diagnosis To Retroperitoneal Fibrosis. Case Report.
Authors: Nussberger Madalina , Kim Olaf , Cogliatti Sergio , Neumann Thomas
Published: July 2021

Background The nature of a solid retroperitoneal mass can either be autoimmune or neoplastic and should be investigated by imaging and histology. The spectrum of differential diagnoses includes primarily retroperitoneal fibrosis and retroperitoneal tumors. Because treatments of retroperitoneal fibrosis and retroperitoneal tumors vary substantially, accurate and early diagnosis is highly relevant. Case presentation We present a case of a fifty-four-year old woman that was admitted to our hospital with stroke like symptoms. Suspecting a vasculitis, magnet resonance imaging of the head and abdomen were done, which revealed a circular enhancement of a cranial vessel as well as retroperitoneal and peri-aortic masses. Concerning this specific radiographic patterns, an autoimmune process like retroperitoneal fibrosis was hypothesized. Steroid treatment did not lead to significant remission though. On re-evaluation of the mass because of refractory disease, fine needle aspiration did not show malignant cells while surgery and histologic assessment revealed neoplastic lymphoproliferation. The final diagnosis was a non- Hodgkin B- Cell Lymphoma. Chemo- and Immunotherapy was initiated. A control abdominal computer tomography was performed which revealed a significant remission of the retroperitoneal mass. Conclusion Initially, the retroperitoneal mass was highly suspicious for RF. The results of imaging can be useful, however, histology should always be taken into consideration when there is an uncertain clinical presentation. Without histology we would have missed a non-Hodgkin B-Cell Lymphoma in this case. Minimal invasive techniques like fine needle aspiration may be practical but can demonstrate false negative results.
The diversity of unique 1,4,5,6-Tetrahydro-2-methyl-4-pyrimidinecarboxylic acid coding common genes and novel Universal stress protein in Ectoine TRAP cluster (UspA) in 32 Halomonas species
Authors: Rekadwad Bhagwan , Li Wen-Jun , PD Rekha
Published: July 2021

ObjectivesTo decipher the diversity of unique ectoine-coding housekeeping genes in the genus Halomonas.ResultsIn Halomonas, 1,4,5,6-Tetrahydro-2-methyl-4-pyrimidinecarboxylic acid has a crucial role as a stress-tolerant chaperone, a compatible solute, a cell membrane stabilizer, and a reduction in cell damage under stressful conditions. Apart from the current 16S rRNA biomarker, it serves as a blueprint for identifying Halomonas species. Halomonas elongate 1H9 was found to have 11 ectoine-coding genes. The presence of a superfamily of conserved ectoine-coding among members of the genus Halomonas was discovered after genome annotations of 93 Halomonas spp. As a result of the inclusion of 11 single copy ectoine coding genes in 32 Halomonas spp., genome-wide evaluations of ectoine coding genes indicate that 32 Halomonas spp. have a very strong association with Halomonas elongata 1H9, which has been proven evidence-based approach to elucidate phylogenetic relatedness of ectoine-coding child taxa in the genus Halomonas. Total 32 Halomonas species have a single copy number of 11 distinct ectoine-coding genes that help Halomonas spp., that produce ectoine under stressful conditions. Furthermore, the existence of the Universal stress protein (UspA) gene suggests that Halomonas species developed directly from primitive bacteria, highlighting the role of Halomonas species in evolutionary terms.
Comparison of Single and Repeated Dosing of Anti-Inflammatory Human Umbilical Cord Mesenchymal Stromal Cells in a Mouse Model of Polymicrobial Sepsis
Authors: Fazekas Barbara , Alagesan Senthilkumar , Watson Luke , Ng Olivia , Conroy Callum M. , Català Cristina , Andres Maria Velascode , Negi Neema , Gerlach Jared Q. , Lozano Francisco , Elliman Stephen J. , Griffin Matthew D.
Published: July 2021

Mesenchymal stromal cells (MSCs) ameliorate pre-clinical sepsis and sepsis-associated acute kidney injury (SA-AKI) but clinical trials of single-dose MSCs have not indicated robust efficacy. This study investigated immunomodulatory effects of a novel MSC product (CD362-selected human umbilical cord-derived MSCs [hUC-MSCs]) in mouse endotoxemia and polymicrobial sepsis models.Initially, mice received intra-peritoneal (i.p.) lipopolysaccharide (LPS) followed by single i.p. doses of hUC-MSCs or vehicle. Next, mice underwent cecal ligation and puncture (CLP) followed by intravenous (i.v.) doses of hUC-MSCs at 4 hours or 4 and 28 hours. Analyses included serum/plasma assays of biochemical indices, inflammatory mediators and the AKI biomarker NGAL; multi-color flow cytometry of peritoneal macrophages (LPS) and intra-renal immune cell subpopulations (CLP) and histology/immunohistochemistry of kidney (CLP).At 72 hours post-LPS injections, hUC-MSCs reduced serum inflammatory mediators and peritoneal macrophage M1/M2 ratio. Repeated, but not single, hUC-MSC doses administered at 48 hours post-CLP resulted in increased survival, lower serum concentrations of inflammatory mediators, lower plasma NGAL and reversal of sepsis-associated depletion of intra-renal T-cell and myeloid cell subpopulations. Hierarchical clustering analysis of all 48-hour serum/plasma analytes demonstrated partial co-clustering of repeated-dose hUC-MSC CLP animals with a Sham group but did not reveal a distinct signature of response to therapy. It was concluded that repeated doses of CD362-selected hUC-MSCs are required to modulate systemic and local immune/inflammatory events in polymicrobial sepsis and SA-AKI. Inter-individual variability and lack of effect of single dose MSC administration in the CLP model are consistent with observations to date from early-phase clinical trials.
A Spatial Model of a Vibrating Conveyor Taking Into Consideration The Self-Synchronisation Process of Inertial Vibrators. Analysis of The Effect of The Layout of The vibrators On The Operation of The Conveyor
Authors: Cieplok Grzegorz , Sieńko Rafał
Published: July 2021

This article presents a spatial model of a vibrating conveyor supported on steel-elastomer vibration isolators and vibrated by two inertial vibrators as well as the results of analyses of the effect of the layout of vibrators on the operation of the conveyor. The displacement of the line of action of the resultant of the forces of the vibrators beyond the centre of mass of the machine body manifests itself in the departure of the machine body from the desirable rectilinear motion and problems associated with the unevenness of material movement. The model presented in this article takes into account an extremely important coupling between vibrators and the body of the machine, which is responsible for the process of self-synchronisation of the vibrators and the correctness of machine operation. The results of theoretical analyses presented in this paper were verified by laboratory tests and reference to observations based on the authors’ industrial experience.
Dynamic heterogeneity in active glass-forming liquids is qualitatively different compared to its equilibrium behaviour
Authors: Paul Kallol , Nandi Saroj Kumar , Karmakar Smarajit
Published: July 2021

Activity driven glassy dynamics is ubiquitous in collective cell migration,intracellular transport, dynamics in bacterial and ants colonies as well as artificially driven synthetic systems such as vibrated granular materials, etc. Active glasses are hitherto assumed to be qualitatively similar to their equilibrium counterparts at a suitably defined effective temperature, ff. Combining large-scale simulations with analytical mode-coupling theory for such systems, we show that, in fact, an active glass is qualitatively different from an equilibrium glassy system. Although the relaxation dynamics can be similar to an equilibrium system at a ff, effects of activity on the dynamic heterogeneity (DH), which has emerged as a cornerstone of glassy dynamics, is quite nontrivial and complex. In particular, active glasses show dramatic growth of DH, and systems with similar relaxation time and ff can have widely varying DH. Comparison of our non-equilibrium extended mode-coupling theory for such systems with simulation results show that the theory captures the basic characteristics of such systems. Our study raises fundamental questions on the supposedly central role of DH in controlling the relaxation dynamics in a glassy system and can have important implications even for the equilibrium glassy dynamics.
P38α Deficiency in Macrophages Ameliorates Murine Experimental Colitis by Regulating Inflammation and Immune Process
Authors: Chen Wei , Liang Rui , Yi Youcai , Chen Xiaoyu , Fan Huining , Zhu Jin-Shui , Zhang Jing
Published: July 2021

Introduction: P38α is a mitogen-activated protein kinase (MAPK) that mediates inflammatory responses. P38α alterations have been associated with the inflammation-related diseases. However, the role of macrophages-derived p38α in dextran sulfate sodium (DSS)-induced murine experimental colitis remains unclear.Objectives: We characterized the role of macrophages-derived p38α in DSS-induced colitis.Methods: The expression of macrophage-derived p38α in human colitis and normal tissues was measured by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analysis. Macrophage-specific p38α knockout (p38αΔMφ) and wild type (WT) mice administrated by 3% DSS were used to establish experimental colitis. The alterations in inflammatory cytokines, intestinal epithelial barrier, cell proliferation and cell apoptosis between p38αΔMφ and WT groups were determined by IHC, immunofluorescence (IF), TdT-mediated dUTP Nick-End Labeling (TUNEL) and Western blot analyses. The enriched pathways between p38αΔMφ and WT groups were identified by RNA-seq and KEGG analysis. SB203580 and BIRB796 as the p38 MAPK inhibitors were used to treat DSS-induced colitis. Results: p38α was co-localized with CD68 in the cytoplasm and their co-expression indicated an increased level in colitis tissues as compared with the normal tissues. P38α deficiency in macrophages was sufficient to suppress the exacerbated clinical symptoms and inflammation responses in experimental colitis, followed by reducing cytokine release, increasing MUC-2 and Claudin-2 secretion and promoting colonic mucosa repair. Further investigations validated that the immune process-related factors such as Lgals9, Rtp4, Ddx60, Nlrp1b, Hsh2d, Oas2 and Oas3 were upregulated in colon tissues from p38αΔMφ group as compared with the WT group. Inhibition of p38 MAPK attenuated DSS-induced colitis. Conclusion: Our findings demonstrated that p38α deficiency in macrophages ameliorated murine experimental colitis by regulating inflammation and immune process.
Supratotal Resection of Glioblastoma Allows Better Survival Outcomes than Gross Total Resection
Authors: Baik Seung Hyun , Kim So Yeon , Na Young Chul , Cho Jin Mo
Published: July 2021

Objective: Supra-total resection (SupTR) of glioblastoma allows superior long-term disease control and increases overall survival. On the other hand, aggressive conventional approaches, including gross total resections (GTR), are limited by the impairment risk of adjacent eloquent areas, which may cause severe postoperative functional morbidity. This study aimed to analyze institutional cases with respect to the potential survival benefits of additional resection, including lobectomy, as a paradigm for SupTR in patients of glioblastoma.Methods: Between 2014 and 2018, 15 patients with glioblastoma underwent GTR and additional lobectomy at our institution. The postoperative Karnofsky performance score (KPS), progression-free survival (PFS), and overall survival (OS) were analyzed for the patients.Results: Patients with SupTR showed significantly prolonged PFS and OS. The median PFS and OS values for the entire study group were 33.5 months (95% confidence intervals [CI]: 18.5–57.3 months) and 49.1 months (95% CI: 24.7–86.6 months), respectively. Multivariate analysis revealed that O6-DNA-methylguanine methyltransferase (MGMT) promoter methylation status was the only predictor for both superior PFS (p = 0.03, OR 5.7, 95% CI 1.0–49.8) and OS (p = 0.04, OR 6.5, 95% CI 1.1–40.2). There was no significant difference between the pre- and post-operative KPS scores. Conclusions: Our results strongly suggest that SupTR with lobectomy allows superior PFS and OS without negatively affecting the patient performance.
Investigation of Jervol Water Types Properties Effects on Underwater Optical Wireless OCDMA System Performances for Different Modulation Techniques
Authors: Kandouci Chahinaz
Published: July 2021

In this paper, an analytical evaluation of direct detection OCDMA system using zero cross correlation codes is presented in an underwater wireless optical channel (UWOC). Performances were evaluated by varying the main simulation parameters (range,transmitted power,number of users and inclination angle) considering different modulation techniques for different water types (categorized according to Jerlov classification).
A dual mechanism of action of AT-527 against SARS-CoV-2 polymerase
Authors: Canard Bruno , Shannon Ashleigh , Fattorini Veronique , Sama Bhawna , Selisko Barbara , Feracci Mikael , Falcou Camille , Gauffre Pierre , El-Kazzi Priscila , Decroly Etienne , Alvarez Karine , Eydoux Cecilia , Guillemot Jean-Claude , Moussa Adel , Good Steven , Colla Paolo La , Lin Kai , Sommadossi Jean-Pierre , Zhu Yingxao , Yan Xiaodong , Shi Hui , Ferron Francois , Delpal Adrien
Published: July 2021

A worldwide effort is ongoing to discover drugs against the Severe Acute Respiratory Syndrome coronavirus type 2 (SARS-CoV-2), which has so far caused >3.5 million fatalities (https://covid19.who.int/). The virus essential RNA-dependent RNA polymerase complex is targeted by several nucleoside/tide analogues whose mechanisms of action and clinical potential are currently evaluated. The guanosine analogue AT-527, a double prodrug of its 5'-triphosphate AT-9010, is currently in phase III clinical trials as a COVID19 treatment. Here we report the cryo-EM structure at 2.98 Å resolution of the SARS-CoV-2 nsp12-nsp7-(nsp8)2 complex with RNA showing AT-9010 bound at three sites of nsp12. At the RdRp active-site, one AT-9010 is incorporated into the RNA product. Its 2'-methyl group prevents correct alignment of a second AT-9010 occupying the incoming NTP pocket. The 2'-F, 2'-methyl 3'-OH ribose scaffold explains the non-obligate RNA chain-termination potency of this NA series for both HCV NS5 and SARS-CoV RTCs. A third AT-9010 molecule 5'-diphosphate binds to a coronavirus-specific pocket in the nsp12 N-terminus NiRAN domain, a SelO pseudo-kinase structural and functional homologue. This unique binding mode impedes NiRAN-mediated UMPylation of SARS-CoV-2 nsp8 and nsp9 proteins. Our results suggest a mechanism of action for AT-527 in line with a therapeutic use for COVID19.
Characteristics and Spatial Influencing Factors of Natural Regeneration within Aquaculture ponds in a Mangrove Forest
Authors: xin kun , Sheng Nong , Liao Baowen , Xiong Yanmei , Jiang Zhongmao , Zhang Yun
Published: July 2021

Regeneration is an important component of community succession and understanding regeneration dynamics is essential for forest protection and recovery management. Mangroves are distributed along coastlines and this unique habitat has resulted in very different regeneration process. This study took Dongzhaigang mangrove forest in Hainan, China as the study area, considered the 10 years regeneration process in 8 abandoned aquaculture ponds, and the spatial factors that influence the regeneration process are analyzed. The objectives were to: a) investigate the natural dynamics of the mangrove regeneration process in abandoned ponds, b) determine the main spatial factors affecting the natural regeneration process. The results showed that the number of species and individuals showed a tendency to initially rise and then decline, with the maximum occurring at 6–8 years. The results of a diversity index showed an initial rise, with stabilization then occurring over a 8 year period. Aegiceras corniculatum and Sonneratia apetala were typical pioneer mangrove species in the study area, while Bruguiera sexangula and Kandelia obovata were representative species of late regeneration period. Spatial factors, including pond area and shape, relative elevation, distance to a tidal creek and surrounding trees area played important roles in the regeneration of mangrove in ponds. Finally, the study considered the current situation regarding mangrove restoration in China and suggested that natural regeneration of mangroves is a good management option.
A High-Frequency Sound based PGC Demodulation Scheme for Fiber Optics Hydrophone
Authors: Shi Yunjie , Yin Mengke , Zhu Zijue , Wang Shun , Niu Panting , Dong Yuming , Zhang Liang
Published: July 2021

In the research field of fiber-optic hydrophone, the performance of demodulation scheme is crucial. In this work, a phase-generated-carrier (PGC) demodulation scheme based on high-frequency sound source is proposed. Highfrequency acoustic signal from the external sound source is applied to the fiber-optic hydrophone to achieve phase modulation of the interference signal instead of the piezo-electrical transducer (PZT) or frequency-modulated laser. It possesses the merits of low system complexity and low cost. Through the acoustic detection experiment, we achieve demodulation of acoustic signal at frequency varying from 300 Hz to 800 Hz, and the signal-to-noise ratio (SNR) is higher than 45 dB. Furthermore, the proposed scheme is successfully applied to time division multiplexing (TDM) experiment.
Bacterial and Fungal Profile, Drug Resistance Pattern and Associated Factors of Isolates Recovered From Blood Samples of Patients Referred to Ethiopian Public Health Institute: Cross-Sectional Study
Authors: Tsegaye Etsehiwot Adamu , Teklu Dejenie Shiferaw , Bonger Zelalem Tazu , Negeri Abebe Assefa , Bedada Tesfaye Legesse , Bitew Adane
Published: July 2021

Background
Blood stream infections are serious infections that usually induce prolongation of hospital stay, morbidity and mortality in several countries including Ethiopia. The aim of this study was to determine bacterial and fungal profile, their drug resistance patterns, and risk factors associated with blood stream infections.
Methods
A cross sectional study design was conducted from February 23 to June 23, 2020 at Ethiopian public health. A structured questionnaire was used to collect data on socio-demographic factors and clinical conditions. Blood specimens were analyzed using standard microbiological techniques. Antimicrobial susceptibility tests were performed using Kirby-Bauer disc diffusion technique and Vitek compact 2. Simple and multiple logistic regressions were used to assess the potential risk factors.
Results
A total of 175 pathogens isolated from 346 blood specimens. Of these, 60% Gram-negative bacteria, 30.86% Gram-positive bacteria and 9.14% fungal isolates were identified. Burkholderia cepacia and Coagulase negative staphylococcus were the predominant pathogen among Gram-negative and Gram-positive bacteria respectively. Among fungus, Candidia krusei (56.25%) was the most predominant isolate. The highest proportions of antibacterial resistance were observed among 3rd generation cephalosporin and penicillin. Most fungal isolates expressed resistance to fluconazole. Sex (p = 0.007), age (p < 0.001) and use of invasive medical devices (p = 0.003) were identified as risk factors for bacterial blood stream infections.
Conclusion
The study showed high prevalence of blood stream infection was due to Burkholderia cepacia and non-Candidia albicans spp. This finding alarming ongoing investigation of blood stream infection is important for recognizing future potential preventive strategies including environmental hygiene and management of comorbid medical diseases to reduce the problem.
Unconventional reconciliation path for quantum mechanics and general relativity
Authors: Yuguru Samuel
Published: July 2021

Physics in general is successfully governed by quantum mechanics at the microscale and principles of relativity at the macroscale. Any attempts to unify them using conventional methods have somewhat remained elusive for nearly a century up to the present stage. Here in this study, a classical gedanken experiment of electron-wave diffraction of a single slit is intuitively examined for its quantized states. A unidirectional monopole pair (MP) field as quanta of the electric field is pictorially conceptualized into 4D space-time. Its application towards quantum mechanics and general relativity appears consistent with existing knowledge in physics. This considers a multiverse of MP models at a hierarchy of scales. Einstein’s gravity is then defined to be of circular acceleration in time reversal mode to an overarching MP field precessing into forward time. Such descriptions provide a credible intuitive tool for physics applications in general. It can be further assessed using conventional methods, perhaps in incremental steps and this warrants further investigations.
A DTMEs-Based Digital Twin System Construction Method For Smart Factory
Authors: Xia Luyao , Jianfeng Lu , Zhang Hao , Xu Mengying , Li Zhaojia , Wang Sheng
Published: July 2021

Many enterprises have built their own digital twin factory model for physical factory planning, simulation optimization and real-time monitoring. However, the digital twin system, which has a single field, a short time cycle and unsinkable service, cannot fully reflect the interaction and integration of the physical and information world required by intelligent manufacturing. Therefore, the research on the construction method of the smart factory digital twin system with cross-domain and multi-model has an important influence on the application of smart manufacturing. In view of the above problems, this paper proposes the concept and composition of digital twin manufacturing ecosystem (DTMEs) based on the requirements and characteristics of product lifecycle, and analyzes the construction requirements of DTMEs for factory digital twin system, product digital twin system and supply chain digital twin system from the perspective of lifecycle. Finally, the smart factory digital twin system architecture is applied to the digital and intelligent upgrading of the hydraulic cylinder factory. The experimental results show that the intelligent improvement of the hydraulic factory, the reduction of Work-in-process inventory and the advance of delivery time, and prove the feasibility and effectiveness of the smart factory digital twin system.
A multi-factor trafficking site on the spliceosomal remodeling enzyme, BRR2, recruits C9ORF78 to regulate alternative splicing
Authors: Bergfort Alexandra , Preussner Marco , Kuropka Benno , Ilik İbrahim , Hilal Tarek , Weber Gert , Freund Christian , Aktas Tugce , Heyd Florian , Wahl Markus
Published: July 2021

The complete inventory of regulatory factors in human spliceosomes remains unknown, and many flexibly bound components are not revealed in present spliceosome structures. The intrinsically unstructured C9ORF78 protein was detected in C complex spliceosomes but is not contained in present spliceosome structures. We found a tight interaction between C9ORF78 and the key spliceosome remodeling factor, BRR2, in a large-scale yeast two-hybrid screen, validated by targeted in vitro assays. Affinity purification/mass spectrometry and RNA UV-crosslinking analyses identified several additional C9ORF78 interactors in spliceosomes. High-resolution cryogenic electron microscopy structures revealed how C9ORF78 and the spliceosomal B complex protein FBP21 wrap around the C-terminal helicase cassette of BRR2 in a mutually exclusive manner. Knock-down of C9ORF78 led to global alternative splicing changes, including a substantial usage of alternative NAGNAG 3’-splice sites, at least in part dependent on BRR2. Comparison of our structure to C* complex spliceosomes shows that C9ORF78 could contact several detected interactors from its BRR2 “home base”, in particular the RNA helicase PRPF22, a suggested 3’-splice site regulator. Together our data firmly establish C9ORF78 as a novel, late-stage splicing regulatory protein that takes advantage of a multi-factor trafficking site on BRR2, providing one explanation for the suggested, but puzzling, roles of BRR2 during splicing catalysis and alternative splicing.
Intracellular Responses of Glial Cells To Monomeric Tau Protein Are Closely Mediated By Heparan Sulfate Proteoglycans (HSPGs)
Authors: Song Liqing , Oseid Daniel E. , Wells Evan A. , Coaston Troy , Robinson Anne S
Published: July 2021

The conversion of soluble tau protein to insoluble, hyperphosphorylated neurofibrillary tangles is a major hallmark leading to neuronal death observed in neurodegenerative tauopathies. Recent work suggests that extracellular, soluble tau binds to negatively charged heparan sulfate proteoglycans (HSPGs) available on the cell surface. In addition, LRP1 has recently been recognized as a major tau receptor, mediating tau uptake and spread. We hypothesized based on this data that monomeric tau would be endocytosed in both an HSPG- and LRP-dependent manner, activating intracellular signaling pathways that would regulate cellular phenotypes. Using live-cell confocal microscopy and flow cytometry, we show that soluble 0N4R monomers were rapidly endocytosed by SH-SY5Y and C6 glioma cells, via actin-dependent macropinocytosis. We also demonstrated the crucial role of HSPGs and LRP1 in cellular endocytosis of monomeric tau by observing reduced tau uptake in C6 glial cells with genetic knockouts of xylosyltransferase-1 – a key enzyme in HSPG synthesis – and LRP1. An ERK1/2 inhibition experiment showed that inhibiting the MEK-ERK1/2 signaling pathway attenuated IL-6 and IL-1β gene expression but not TNF-α . An LRP1 knockdown experiment led to an attenuated propensity for tau uptake and further elevated IL-6 gene expression. Collectively, our data suggest that tau has multiple extracellular binding partners that mediate its internalization through distinct mechanisms. Additionally, this study demonstrates the important role of both HSPG and LRP1 in regulating cellular immune responses to tau protein monomer, which provides a novel target for alleviating the neuroinflammatory environment before the formation of neurofibrillary tangles.
Comparison of two end-to-end continuous sutures for intestinal anastomoses in dogs.
Authors: IGNA CORNEL , DASCALU ROXANA , SICOE BOGDAN , ZAHA CRISTIAN , BRUDIU ILEANA , SCHUSZLER LARISA
Published: July 2021

Background: Single-layer appositional closures are preferred to inverting or everting patterns, as submucosal apposition has been shown to promote primary healing of the intestinal wall, whereas inverted or everted closures require second-intention healing and can increase the risk of luminal stenosis or anastomosis site leakage. There are different suture patterns available, but relatively few studies comparing these aspects have been published.The aim of this study was to compare two suture techniques for end-to-end anastomosis of the canine intestine (jejunum and colon): handsewn intestinal anastomosis by appositional simple continuous suture and inverting Cushing suture. The objectives of this study were to investigate 1.) whether the type of suture influences the specific effort to which the anastomosis site is submitted to, 2.) whether the anastomosis technique influences the diameter of the intestinal lumen and 3.) survival and complication rates in canine clinical cases undergoing end-to-end anastomoses. Results: The equilibrium angle for implanting the sutures in an anastomosis is 35°, aspect completely fulfilled by the simple continuous suture. The efforts to which sutures are submitted to in anastomoses are minimal for the Cushing suture. The difference in size of the anastomoses’ lumen between simple continuous suture and the Cushing suture are minimal, without being statistically relevant. The differences between the lumen of the anastomoses performed using PDS and those performed using PGA are not statistically relevant. The retrospective analysis of the outcome for 676 dogs (clinical cases) that underwent intestinal resection and anastomosis reveals that the dehiscence rate was 1.48%, out of which 1.18% following simple continuous anastomoses, and 0.3% following Cushing anastomoses. Narrowing of the intestinal lumen due to anastomotic healing was not registered.Conclusions: Use of the Cushing suture should be considered for performing an end-to-end intestinal anastomosis, although more studies are required to determine if there are any clinically significant differences between the sutures investigated in this study.
A Molecular View of Amyotrophic Lateral Sclerosis Through the Lens of Interaction Network Modules
Authors: Jensen Klaus Højgaard , Stalder Anna Katharina , Wernersson Rasmus , Roloff-Handschin Tim-Christoph , Hansen Daniel Hvidberg , Groenen Peter MA
Published: July 2021

Background: Despite the discovery of familial cases with mutations in Cu/Zn-superoxide dismutase (SOD1), Guanine nucleotide exchange C9orf72, TAR DNA-binding protein 43 (TARDBP) and RNA-binding protein FUS as well as a number of other genes linked to Amyotrophic Lateral Sclerosis (ALS), the etiology and molecular pathogenesis of this devastating disease is still not understood. As proteins do not act alone but rather in networks, conducting an analysis of ALS at the system level may provide new insights into the molecular biology of ALS around these potential ALS-associated genes and put it into relationship to other neurological diseases.Methods: A set of ALS-associated genes/proteins were collected from publicly available databases and text mining of scientific literature. We used these as seed proteins to build protein-protein interaction (PPI) networks serving as a scaffold for further analyses. From the collection of networks, a set of core modules enriched in seed proteins were identified. The core modules were investigated for overrepresentation of Gene Ontology categories and association to other diseases. To assess the core modules’ ability to describe unknown or less well-studied ALS biology, they were queried for proteins more recently associated to ALS and not involved in the primary analysis.Results: We describe a set of 26 ALS core modules enriched in ALS-associated proteins. Our workflow is robust against individual highly connected proteins often dominating this type of analysis due to study bias or experimental artefacts. We show that these ALS core modules not only capture most of the current knowledge about ALS, but they also allow us to suggest biological interdependencies. In addition, new associations of ALS networks with other neurodegenerative diseases, e.g. Alzheimer’s, Huntington’s and Parkinson’s disease were found. A follow-up analysis of 140 ALS-associated proteins identified since 2014 reveals a significant overrepresentation of new ALS proteins in these 26 disease modules.Conclusions: Using protein-protein interaction networks offers a relevant approach for broadening the understanding of the biological context of known ALS-associated genes. Using a bottom-up approach for the analysis of protein-protein interaction networks is a useful method to avoid bias caused by over-connected proteins. Our ALS-enriched modules cover most known biological functions associated with ALS. The presence of recently identified ALS-associated proteins in the top network highlights the potential for using the ALS-associated networks as a scaffold for identification of novel ALS disease mechanisms, investigation of complex networks and hypothesis generation.
Drivers of the evolution and amplitude of African Humid Periods
Authors: Menviel Laurie , Govin Aline , Avenas Arthur , Meissner Katrin , Grant Katharine , Tzedakis Polychronis
Published: July 2021

During orbital precession minima, the Sahara was humid and hosted tropical plant species thus providing a corridor for Hominins migration. Uncertainties remain over the climatic processes controlling the initiation, demise and amplitude of these African Humid Periods (AHPs). Here we present transient simulations of the penultimate deglaciation and Last Interglacial period (LIG), and compare them to transient simulations of the last deglaciation and Holocene. We find that the strengthening of the Atlantic Meridional Overturning Circulation (AMOC) at the end of the deglacial millennial-scale events exerts a dominant control on the abrupt initiation of AHPs, as the AMOC modulates the position of the Intertropical Convergence Zone (ITCZ). In addition, residual Northern Hemispheric (NH) ice-sheets can delay the AHP peak.
Through its impact on NH ice-sheets disintegration and thus AMOC variations, the larger rate of insolation increase during the penultimate compared to the last deglaciation can explain the earlier and more abrupt LIG AHP onset.
Finally, we show that the background climate state modulates precipitation variability with higher variability under wetter background conditions.
WITHDRAWN: LP-cs Ameliorated CCl 4 -Induced Acute Liver Injury by Suppression of Cellular Stress
Authors: Xu Zeping , Li Xiaofeng , Li Yuying , Wang Ping , Wu Junnan , Yang Shizhuo , Zhang Xie , Ma Yanyan , Xie Longteng , Jiang Yongsheng , Chen Li , Liu Yanlong , Wang Fan , Li Hong
Published: July 2021

Background: Acute liver injury (ALI) involves excessive oxidative stress(OS) and inflammatory responses, leading to a high mortality rate due to lack of effective therapy. Carbon tetrachloride (CCl4) is widely used to induce ALI by induction of reactive oxygen species. Probiotics, including Lactobacillus plantarum ST-III, have been shown to produce antibacterial and antioxidant substances such as organic acids or bacteriocins that reduce liver damage. Nevertheless, the effect of Lactobacillus plantarum ST-III culture supernatant (L-P-cs) on CCl4-induced liver injury remains unclear.Methods: Mice were pretreated with L-P-cs or medium for 14days before one dose of 0.2% CCl4 at 10ml/kg body weight delivered by intraperitoneal injection. CCl4-induced liver injury was examined by measuring serum levels of liver transaminases and high mobility-group box 1 protein (HMGB1) and liver histological staining. Inflammation and apoptosis in liver were evaluated by real-time PCR, enzyme-linked immunosorbent assay (ELISA), and TUNEL staining. Apoptosis in NCTC 1469 cells was detected using CCK8 and western blotting (WB). In liver, OS and endoplasmic reticulum stress(ERS)-related proteins were measured using kits and WB.Results: L-P-cs significantly ameliorated CCl4-induced liver injury and reduced CCl4- induced inflammatory response and apoptosis, consistent with NCTC 1469 cells' results. L-P-cs also restored CCl4-induced increases in cell OS and ERS to normalize liver function. Specifically, L-P-cs pretreatment decreased CCl4-induced increases in nuclear factor (erythroid-2 related) factor 2, HO-1, superoxide dismutase, glucose regulatory protein, and activating transcription factor 6.Conclusion: L-P-cs synergistically improves liver lobule necrosis, hepatocyte inflammation, and apoptosis by reducing liver OS and ERS.
Antibiotic-Loaded Bone Cement Combined With Vacuum Sealing Drainage To Treat Deep Sternal Wound Infection Following Cardiac Surgery: The First Case Report
Authors: Jiang Xia , Bu Fanyu , Xu Yong , Jing Zhaohui , Jiao GUOqing , Li Mingqiu , Rong Xiaosong
Published: July 2021

Background: Deep sternal wound infection (DSWI) is a rare but serious complication after median sternotomy, and treatment success depends mainly on surgical experience. Here we first present a case of a patient successfully treated for antibiotic-loaded bone cement(ALBC) combined with vacuum sealing drainage(VSD) of DSWI.Case presentation: This case report presented a patient who underwent open heart surgery, and suffered postoperatively from a DSWI associated with enterococcus cloacae. Focus debridement combined with ALBC filling and VSD was conducted in stage I. Appropriate antibiotics were started according to sensitivity to be continued for two weeks until the inflammatory markers decreased to normal. One month after the surgery, patient’s wound was almost healed and was discharged from hospital with a drainage tube. Two months after the stage I surgery procedure, the major step was removing the previous ALBC, and extensive debridement in stage II. The patient fully recovered without further surgical treatment.Conclusions: The results of this case suggest that ALBC combined with VSD may be a viable and safe option for deep sternal wound reconstruction.
Cross neutralization of emerging SARS-CoV-2 variants of concern by antibodies targeting distinct epitopes on spike
Authors: Wilson Patrick , Changrob Siriruk , Fu Yanbin , Guthmiller Jenna , Halfmann Peter , Li Lei , Stamper Christopher , Dugan Haley , Accola Molly , Rehrauer William , Zheng Nai-Ying , Huang Min , Wang Jiaolong , Erickson Steven , Utset Henry , Graves Hortencia , Amanat Fatima , Sather D. Noah , Krammer Florian , Kawaoka Yoshihiro
Published: July 2021

Several severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have arisen that exhibit increased viral transmissibility and partial evasion of immunity induced by natural infection and vaccination. To address the specific antibody targets that were affected by recent viral variants, we generated 43 monoclonal antibodies (mAbs) from 10 convalescent donors that bound three distinct domains of the SARS-CoV-2 spike. Viral variants harboring mutations at K417, E484 and N501 could escape most of the highly potent antibodies against the receptor binding domain (RBD). Despite this, we identified 12 neutralizing mAbs against three distinct regions of the spike protein that neutralize SARS-CoV-2 and the variants of concern, including B.1.1.7 (alpha), P.1 (gamma) and B.1.617.2 (delta). Notably, antibodies targeting distinct epitopes could neutralize discrete variants, suggesting different variants may have evolved to disrupt the binding of particular neutralizing antibody classes. These results underscore that humans exposed to wildtype (WT) SARS-CoV-2 do possess neutralizing antibodies against current variants and that it is critical to induce antibodies targeting multiple distinct epitopes of the spike that can neutralize emerging variants of concern.
Prognostic significance of mean platelet volume in lung cancer patients: A meta-analysis
Authors: Kharel Sanjeev , Shrestha Suraj , Shakya Prafulla , Rawat Rohit , Shilpakar Ramila
Published: July 2021

Background Lung cancer is the most prevalent cancer globally with a grim prognosis alongside a very high number of cancer-related deaths. Mean platelet volume (MPV) is the measure of platelet size and is considered a surrogate marker of platelet activation. Low MPV indicates exhausted platelets causing worse outcomes in cancer patients. As the correlation between platelet count/platelet size and lung cancer prognosis still remains a topic of debate, this meta-analysis was done to comprehensively evaluate the prognostic significance of MPV among lung cancer patients.Methods A systematic search of electronic databases PubMed, Embase, and Google scholar and additional sources for relevant studies were done with no language restrictions from inception to 7th May 2021. Overall Survival (OS) and Disease-Free Survival (DFS)/Progression-Free Survival (PFS) and hazard ratio (HR) with 95% Confidence Interval (CI) were pooled to evaluate the relation of MPV with OS/DFS. Subgroup analysis based on cancer type, clinical stage, sample size, median age, cut-off value, and study region was done to identify the cause of significant heterogeneity.Results Eleven studies with 2421 lung cancer patients were included in our analysis. Our analysis showed no significant association between MPV levels with OS (H.R.:1.07, 95%C.I.:0.84–1.35, p = 0.60) and DFS/PFS (HR:1.04, 95%C.I.:0.68–1.60, p = 0.84). Under subgroup analysis, studies conducted in countries other than China (HR:1.53, 95% C.I.=1.14–2.03, p < 0.001, I2 = 42.11%) and studies with advanced-stage lung cancer patients (HR: 1.84, 95% C.I.=1.19–2.82, p-value = 0.01, I2 = 0%) showed significant association between MPV levels and worse DFS/PFS.Conclusion Pretreatment MPV levels did not show prognostic significance except in advanced lung cancer cases. Large multicentric studies with large samples and long follow-up times are necessary.
Vaginal Bleeding As The Presenting Manifestation of Post-Hepatectomy/-Splenectomy Portal-Mesenteric Venous Thrombosis
Authors: Yeh Che-Ming , Sun Jen-Tang , Fan Chieh-Min , Tsai Kuang-Chau , Chang Chih-Jung
Published: July 2021

Background: Portal-mesenteric venous thrombosis is not uncommon after hepatectomy or splenectomy but is under-recognized because of non-specific symptoms and lack of awareness of the clinicians. However, misdiagnosis or delayed treatment may have fatal consequences. Case Presentation: A 57-year-old menopausal woman with the medical history of hepatocellular carcinoma, stage I, underwent laparoscopic partial hepatectomy (S4) and splenectomy 2 months before the presentation of progressive vaginal spotting and vague abdominal pain. Dysfunctional uterine bleeding was suspected initially, but subsequent contrast-enhanced computed tomography due to concern for post-procedure complications revealed thrombosis in the portal vein and superior mesenteric vein. The patient received anticoagulant therapy, and her symptoms gradually resolved. Conclusions: To the best of our knowledge, vaginal variceal bleeding secondary to portal-mesenteric venous thrombosis has never been reported, but it can be the presenting manifestation for this condition. It should be considered in the differential diagnosis of patients who present with vague abdominal symptoms after hepatectomy or splenectomy.
Pre-Operative Modified Glasgow Prognostic Score 2 For The Prediction of Poor Post-Operative Performance Status Following Palliative Surgery For Pathological Spinal Fracture: A Retrospective Cohort Study
Authors: Ushiku Chikara , Akiyama Shoshi , Ikegami Taku , Inoue Takeshi , Shinohara Akira , Kajiwara Takayoshi , Arimura Daigo , Katsumi Shunsuke , Obata Shintaro , Soshi Shigeru , Saito Mitsuru
Published: July 2021

Background: Skeletal-related events due to spinal metastasis in cancer significantly impair patients’ activities of daily living and quality of life. Most of these events occur suddenly. To reduce their impairment occurred suddenly, and to allow them to return to their normal life immediately, many patients undergo palliative surgery; however, some patients do not improve their performance status (PS) as expected. There is little evidence regarding the factors influencing a patient’s PS after palliative surgery. We aimed to investigate the pre-operative predictors of poor PS 1 month after surgery.Methods: The study included a consecutive series of 71 patients with pathological spinal fracture who underwent palliative surgery. Pre-operative predictors of poor post-operative PS were investigated. The participants were categorized into two groups according to PS; the Good group (PS 0, 1, or 2) and the Poor group (PS 3 or 4). We performed univariate and multivariable logistic regression analyses on demographic information, unidentified primary site, AIS grade, poor PS, spinal instability neoplastic score, revised Tokuhashi score, New Katagiri score, modified Glasgow Prognostic Score (mGPS), neutrophil-lymphocyte ratio(NLR), and prognostic nutrition index (PNI). Results: Post-operatively, the Poor group included 38.0% of the patients. Univariate analysis revealed that the following pre-operative factors were related to poor outcomes (p<0.05): BMI<18.5; AIS grade C; poor PS; revised Tokuhashi score 0−8; New Katagiri score 7−10; mGPS 2; and PNI. In the multivariate analysis, mGPS 2 (OR = 22.8, 95% CI = 2.59−202.00, p<0.01) was a significant pre-operative predictor of poor post-operative PS. Conclusion: mGPS 2 was a predictive clinical factor that influenced PS 1 month after surgery. Patients with mGPS 2 should be carefully evaluated to determine their treatment, especially whether they should undergo palliative surgery.
Recombinant Production of IL-1Ra in Fusion to Albumin Binding Domain for Its Extended Half-Life
Authors: Shafiee Fatemeh , Yazdani Ali
Published: July 2021

Background: Anakinra, a FDA approved biological drug for Rheumatoid Arthritis, must be injected daily due to its short Half-life, leads to the lower patient compliance. So, the aim of this study was to produce IL-1Ra in fusing to albumin binding domain to extend its half-life and evaluate its biological effects.Methods and Results: The expression of IL-1Ra-ABD was performed in E. coli in fusing to intein1 of pTWIN1 in soluble and purified. The affinity of IL-1Ra-ABD to HSA was determined on Native-PAGE and its release percent toward time was determined. Finally, MTT assay was used to determine the antagonizing properties of recombinant IL-1Ra-ABD against IL-1β, on A375 cells. the expression induction of intein1-IL-1Ra-ABD using 0.1mM of IPTG at 15°C, and its cleavage represented a band approximately in 50 and 23 kDa respectively. Native-PAGE results showed that about 78% of IL-1Ra-ABD attached to the HSA after 2 hours of incubation, and MTT assay results showed no significant differences between the effects of our recombinant protein and native IL-1Ra.Conclusion: the production of soluble IL-1Ra-ABD with similar antagonizing effects to IL-1Ra was successfully performed. IL-1Ra-ABD showed suitable interaction with HSA and release over the time. However, pharmacokinetics and furthur biological evaluations are required.