bluuebunny/crossref_metadata_2025 huggingface dataset:
FX5, a non-steroidal glucocorticoid receptor antagonist, ameliorates diabetic cognitive impairment in mice
Authors: Zhu Dan-yang , Lu Jian , Xu Rui , Yang Juan-zhen , Meng Xiang-rui , Ou-Yang Xing-nan , Yan Qiu-ying , Nie Rui-fang , Zhao Tong , Chen Yi-di , Lu Yin , Zhang Yi-nan , Li Wen-jun , Shen Xu
Published: March 2022

Diabetic cognitive impairment (DCI) is a common diabetic complication characterized by learning and memory deficits. In diabetic patients, hyperactivated hypothalamic-pituitary-adrenal (HPA) axis leads to abnormal increase of glucocorticoids (GCs), which causes the damage of hippocampal neurons and cognitive impairment. In this study we investigated the cognition-improving effects of a non-steroidal glucocorticoid receptor (GR) antagonist 5-chloro-N-[4-chloro-3-(trifluoromethyl) phenyl]thiophene-2-sulfonamide (FX5) in diabetic mice. Four weeks after T1DM or T2DM was induced, the mice were administered FX5 (20, 40 mg·kg−1·d−1,i.g.) for 8 weeks. Cognitive impairment was assessed in open field test, novel object recognition test, Y-maze test, and Morris water maze test. We showed that FX5 administration significantly ameliorated the cognitive impairments in both type 1 and 2 diabetic mice. Similar cognitive improvement was observed in diabetic mice following brain GR-specific knockdown by injecting AAV-si-GR. Moreover, AAV-si-GRinjection occluded the cognition-improving effects of FX5, suggesting that FX5 functioning as a non-steroidal GR antagonist. In PA-treated primary neurons (as DCI model in vitro), we demonstrated that FX5 (2, 5, 10 μM) dose-dependently ameliorated synaptic impairment via upregulating GR/BDNF/TrkB/CREB pathway, protected against neuronal apoptosis through repressing GR/PI3K/AKT/GSK3β-mediated tauopathy and subsequent endoplasmic reticulum stress. In LPS-treated primary microglia, FX5 dose-dependently inhibited inflammation through GR/NF-κB/NLRP3/ASC/Caspase-1 pathway. These beneficial effects were also observed in the hippocampus of diabetic mice following FX5 administration. Collectively, we have elucidated the mechanisms underlying the beneficial effects of non-steroidal GR antagonist FX5 on DCI and highlighted the potential of FX5 in the treatment of the disease.
Dissection of artifactual and confounding glial signatures by single-cell sequencing of mouse and human brain
Authors: Marsh Samuel E. , Walker Alec J. , Kamath Tushar , Dissing-Olesen Lasse , Hammond Timothy R. , de Soysa T. Yvanka , Young Adam M. H. , Murphy Sarah , Abdulraouf Abdulraouf , Nadaf Naeem , Dufort Connor , Walker Alicia C. , Lucca Liliana E. , Kozareva Velina , Vanderburg Charles , Hong Soyon , Bulstrode Harry , Hutchinson Peter J. , Gaffney Daniel J. , Hafler David A. , Franklin Robin J. M. , Macosko Evan Z. , Stevens Beth
Published: March 2022

A key aspect of nearly all single-cell sequencing experiments is dissociation of intact tissues into single-cell suspensions. While many protocols have been optimized for optimal cell yield, they have often overlooked the effects that dissociation can have on ex vivo gene expression. Here, we demonstrate that use of enzymatic dissociation on brain tissue induces an aberrant ex vivo gene expression signature, most prominently in microglia, which is prevalent in published literature and can substantially confound downstream analyses. To address this issue, we present a rigorously validated protocol that preserves both in vivo transcriptional profiles and cell-type diversity and yield across tissue types and species. We also identify a similar signature in postmortem human brain single-nucleus RNA-sequencing datasets, and show that this signature is induced in freshly isolated human tissue by exposure to elevated temperatures ex vivo. Together, our results provide a methodological solution for preventing artifactual gene expression changes during fresh tissue digestion and a reference for future deeper analysis of the potential confounding states present in postmortem human samples.
BCL2A1 regulates Canady Helios Cold Plasma-induced cell death in triple-negative breast cancer
Authors: Murthy Saravana R. K. , Cheng Xiaoqian , Zhuang Taisen , Ly Lawan , Jones Olivia , Basadonna Giacomo , Keidar Michael , Canady Jerome
Published: March 2022

Breast cancer is the leading cause of cancer death among women. Triple-negative breast cancer (TNBC) has a poor prognosis and frequently relapses early compared with other subtypes. The Cold Atmospheric Plasma (CAP) is a promising therapy for prognostically poor breast cancer such as TNBC. The Canady Helios Cold Plasma (CHCP) induces cell death in the TNBC cell line without thermal damage, however, the mechanism of cell death by CAP treatment is ambiguous and the mechanism of resistance to cell death in some subset of cells has not been addressed. We investigate the expression profile of 48 apoptotic and 35 oxidative gene markers after CHCP treatment in six different types of breast cancer cell lines including luminal A (ER+ PR+/−HER2−), luminal B (ER+PR+/−HER2+), (ER−PR−HER2+), basal-like: ER−PR−HER2− cells were tested with CHCP at different power settings and at 4 different incubation time. The expression levels of the gene markers were determined at 4 different intervals after the treatment. The protein expression of BCL2A1 was only induced after CHCP treatment in TNBC cell lines (p < 0.01), whereas the HER2-positive and ER, PR positive cell lines showed little or no expression of BCL2A1. The BCL2A1 and TNF-alpha expression levels showed a significant correlation within TNBC cell lines (p < 0.01). Silencing BCL2A1 mRNA by siRNA increased the potency of the CHCP treatment. A Combination of CHCP and CPI203, a BET bromodomain inhibitor, and a BCL2A1 antagonist increased the CHCP-induced cell death (p < 0.05). Our results revealed that BCL2A1 is a key gene for resistance during CHCP induced cell death. This resistance in TNBCs could be reversed with a combination of siRNA or BCL2A1 antagonist-CHCP therapy.
B-cell-depletion reverses dysbiosis of the microbiome in multiple sclerosis patients
Authors: Troci Alba , Zimmermann Olga , Esser Daniela , Krampitz Paula , May Sandra , Franke Andre , Berg Daniela , Leypoldt Frank , Stürner Klarissa Hanja , Bang Corinna
Published: March 2022

To elucidate cross-sectional patterns and longitudinal changes of oral and stool microbiota in multiple sclerosis (MS) patients and the effect of B-cell depletion. We conducted an observational, longitudinal clinical cohort study analysing four timepoints over 12 months in 36 MS patients, of whom 22 initiated B-cell depleting therapy with ocrelizumab and a healthy control group. For microbiota analysis of the oral cavity and the gut, provided stool and oral swab samples underwent 16S rDNA sequencing and subsequent bioinformatic analyses. Oral microbiota-patterns exhibited a reduced alpha-diversity and unique differential microbiota changes compared to stool such as increased levels of Proteobacteria and decreased abundance of Actinobacteria. Following B-cell depletion, we observed increased alpha-diversity in the gut and the oral cavity as well as a long-term sustained reduction of pro-inflammatory Gram-negative bacteria (e.g., Escherichia/Shigella). MS patients have altered stool and oral microbiota diversity patterns compared to healthy controls, which are most pronounced in patients with higher disease activity and disability. Therapeutic B-cell depletion is associated with persisting regression of these changes. Whether these microbial changes are unspecific side-effects of B-cell depletion or indirectly modulate MS disease activity and progression is currently unknown and necessitates further investigations.
Rhythm control without catheter ablation may have benefits beyond stroke prevention in rivaroxaban-treated non-permanent atrial fibrillation
Authors: Chiou Wei-Ru , Lin Po-Lin , Huang Chun-Che , Chuang Jen-Yu , Liu Lawrence Yu-Min , Su Min-I , Liao Feng-Ching , Kuo Jen-Yuan , Tsai Cheng-Ting , Wu Yih-Jer , Wang Kuang-Te , Lee Ying-Hsiang
Published: March 2022

The current treatment paradigm for atrial fibrillation (AF) prioritizes rate control over rhythm control; however, rhythm control has shown benefits over other AF strategies. This study compares the outcomes of rivaroxaban with and without concomitant antiarrhythmic drugs (AADs), using propensity score matching to correct for statistical effects of baseline discrepancies. This multi-center retrospective study included 1,477 patients with non-permanent AF who took rivaroxaban for at least one month between 2011 and 2016 and had not received catheter ablation. Concomitant AAD use was compared against clinical outcome endpoints for effectiveness, safety, and major adverse cardiac events (MACE). Associations with concomitant AAD use were evaluated using multivariate Cox proportional hazard analyses. Patients were divided into two matched groups: rivaroxaban alone (n = 739) and with concomitant AADs (n = 738). The cumulative incidences of safety (p = 0.308), effectiveness (p = 0.583), and MACE (p = 0.754) were similar between the two groups, and multivariate analysis showed no significant differences. The new thromboembolism and all-cause death rates were higher in rivaroxaban alone (2.7% vs 0.8%, p = 0.005; and 10% vs. 6.9%, p = 0.032, respectively). The heart failure readmission rate was higher in the concomitant-AAD group (8.4% vs. 13.3%, p = 0.003). The concomitant use of rivaroxaban with AADs appears to be well-tolerated, with lower rates of thromboembolism and all-cause death, but is associated with more occurrences of congestive heart failure.
CRF07_BC is associated with slow HIV disease progression in Chinese patients
Authors: Ye Jingrong , Chen Jing , Wang Juan , Wang Yuncong , Xing Hui , Yu Fengting , Liu Lifeng , Han Yang , Huang Huihuang , Feng Yi , Ruan Yuhua , Zheng Minna , Lu Xinli , Guo Xiaoli , Yang Hong , Guo Qi , Lin Yi , Wu Jianjun , Wu Shouli , Tang Yilong , Sun Xiaoguang , Zou Xiaobai , Yu Guolong , Li Jianjun , Zhou Quanhua , Su Ling , Zhang Lincai , Gao Zhan , Xin Ruolei , He Shufang , Xu Conghui , Hao Mingqiang , Hao Yinxiao , Ren Xianlong , Li Jie , Bai Lishi , Jiang Tianjun , Zhang Tong , Shao Yiming , Lu Hongyan
Published: March 2022

HIV subtypes convey important epidemiological information and possibly influence the rate of disease progression. In this study, HIV disease progression in patients infected with CRF01_AE, CRF07_BC, and subtype B was compared in the largest HIV molecular epidemiology study ever done in China. A national data set of HIV pol sequences was assembled by pooling sequences from public databases and the Beijing HIV laboratory network. Logistic regression was used to assess factors associated with the risk of AIDS at diagnosis ([AIDSAD], defined as a CD4 count < 200 cells/µL) in patients with HIV subtype B, CRF01_AE, and CRF07_BC. Of the 20,663 sequences, 9,156 (44.3%) were CRF01_AE. CRF07_BC was responsible for 28.3% of infections, followed by B (13.9%). In multivariable analysis, the risk of AIDSAD differed significantly according to HIV subtype (OR for CRF07_BC vs. B: 0.46, 95% CI 0.39─0.53), age (OR for ≥ 65 years vs. < 18 years: 4.3 95% CI 1.81─11.8), and transmission risk groups (OR for men who have sex with men vs. heterosexuals: 0.67 95% CI 0.6─0.75). These findings suggest that HIV diversity in China is constantly evolving and gaining in complexity. CRF07_BC is less pathogenic than subtype B, while CRF01_AE is as pathogenic as B.
Impact of deleterious missense PRKCI variants on structural and functional dynamics of protein
Authors: Shah Hania , Khan Khushbukhat , Khan Naila , Badshah Yasmin , Ashraf Naeem Mahmood , Shabbir Maria
Published: March 2022

Protein kinase C iota (PKCɩ) is a novel protein containing 596 amino acids and is also a member of atypical kinase family. The role of PKCɩ has been explored in neurodegenerative diseases, neuroblastoma, ovarian and pancreatic cancers. Single nucleotide polymorphisms (SNPs) have not been studied in PKCɩ till date. The purpose of the current study is to scrutinize the deleterious missense variants in PKCɩ and determine the effect of these variants on stability and dynamics of the protein. The structure of protein PKCɩ was predicted for the first time and post translational modifications were determined. Genetic variants of PKCɩ were retrieved from ENSEMBL and only missense variants were further analyzed because of its linkage with diseases. The pathogenicity of missense variants, effect on structure and function of protein, association with cancer and conservancy of the protein residues were determined through computational approaches. It is observed that C1 and the pseudo substrate region has the highest number of pathogenic SNPs. Variations in the kinase domain of the protein are predicted to alter overall phosphorylation of the protein. Molecular dynamic simulations predicted noteworthy change in structural and functional dynamics of the protein because of these variants. The study revealed that nine deleterious variants can possibly contribute to malfunctioning of the protein and can be associated with diseases. This can be useful in diagnostics and developing therapeutics for diseases related to these polymorphisms.
Transient CFD analysis of fuel siphoning under a sudden inertial load
Authors: Bae Kang-Sik , Blosch Edwin L.
Published: March 2022

This paper presents the results of CFD investigations of siphoning between tanks of an aircraft fuel system under high-g conditions typical of an extreme pull-up maneuver. Negative gauge pressures in the siphon tank can occur, potentially breaking the siphon and decreasing the available fuel flow to the engine. A representative configuration of a system has been modeled, consisting of two fuel tanks plus a vent tank, fuel transfer lines, and gas lines for venting and supply of inert gas to the fuel tank ullage spaces. The fuel pressures and dynamics are simulated using a time-dependent Volume-of-Fluid modeling with normal force increasing rapidly from 1 to 9 g corresponding to an extended period of rapid pull-up during which the main supply tank becomes empty. Realistic values for engine fuel flow rate and fuel properties (JP-8) are used. This work is part of a broad effort to investigate fuel system performance issues that are difficult to test. Four simulations were performed in total, comparing 1 g flight and a 9 g pull-up both with and without a low-capacity pump assisting the siphon transfer. We find that the pump influences the siphon flow rate, the siphon break characteristics as the supply tank empties, and the magnitude of negative gauge pressures that occur in the siphon tank.
Improved remediation of co-contaminated soils by heavy metals and PAHs with biosurfactant-enhanced soil washing
Authors: Zhang Xu , Zhang Xiaodong , Wang Shuguang , Zhao Shan
Published: March 2022

Due to the huge toxicity of co-contaminated soil with PAHs and heavy metals and the complexity of their remediation, it is thus critical to take effective remediation actions to remove heavy metals and PAHs simultaneously from the co-contaminated soil. Biosurfactant-enhanced soil washing (BESW) were investigated in this study for remediation of soil co-contaminated with phenanthrene (PHE) and cadmium (Cd). The co-existence of PHE and Cd caused the change of the structure of soil and rhamnolipid micelle, which lead to different removal rate of PHE and Cd from co-contaminated soil compared with single contaminated soil. The results of FT-IR and NMR showed that PHE entered micelles of rhamnolipid and Cd formed the complexation with the external carboxyl groups of rhamnolipid micelle. We also found that pH, concentration of rhamnolipid solution, temperature and ionic strength had influence on co-contaminated soil remediation. The effects of above mentioned four factors on co-contaminated soil remediation in BESW processes were analyzed by using Taguchi design of experiment method. Taguchi based Grey Relational Analysis was conducted to identify the optimal remediation conditions, which included pH = 9, concentration of rhamnolipid = 5 g/L, temperature = 15 °C and ionic strength = 0.01 M. Under the optimal conditions for BESW, removal rates of cadmium and phenanthrene reached 72.4% and 87.8%, respectively in co-contaminated soil.
Biomechanical and structural responses of the aorta to intermittent hypobaric hypoxia in a rat model
Authors: Utrera Andrés , Navarrete Álvaro , González-Candia Alejandro , García-Herrera Claudio , Herrera Emilio A.
Published: March 2022

High altitude hypoxia is a condition experienced by diverse populations worldwide. In addition, several jobs require working shifts where workers are exposed to repetitive cycles of hypobaric hypoxia and normobaric normoxia. Currently, few is known about the biomechanical cardiovascular responses of this condition. In the present study, we investigate the cycle-dependent biomechanical effects of intermittent hypobaric hypoxia (IHH) on the thoracic aorta artery, in terms of both structure and function. To determine the vascular effects of IHH, functional, mechanical and histological approaches were carried out in the thoracic aorta artery, using uniaxial, pre-stretch, ring opening, myography, and histological tests. Three groups of rats were established: control (normobaric normoxia, NN), 4-cycles of intermittent hypoxia (short-term intermittent hypobaric hypoxia, STH), and 10-cycles of intermittent hypoxia (long-term intermittent hypobaric hypoxia, LTH). The pre-stretch and ring opening tests, aimed at quantifying residual strains of the tissues in longitudinal and circumferential directions, showed that the hypoxia condition leads to an increase in the longitudinal stretch and a marked decrease of the circumferential residual strain. The uniaxial mechanical tests were used to determine the elastic properties of the tissues, showing that a general stiffening process occurs during the early stages of the IH (STH group), specially leading to a significative increase in the high strain elastic modulus ($$E_{2}$$

E
2

) and an increasing trend of low strain elastic modulus ($$E_{1}$$

E
1

). In contrast, the LTH group showed a more control-like mechanical behavior. Myography test, used to assess the vasoactive function, revealed that IH induces a high sensitivity to vasoconstrictor agents as a function of hypoxic cycles. In addition, the aorta showed an increased muscle-dependent vasorelaxation on the LTH group. Histological tests, used to quantify the elastic fiber, nuclei, and geometrical properties, showed that the STH group presents a state of vascular fibrosis, with a significant increase in elastin content, and a tendency towards an increase in collagen fibers. In addition, advanced stages of IH (LTH), showed a vascular remodeling effect with a significant increase of internal and external diameters. Considering all the multidimensional vascular effects, we propose the existence of a long-term passive adaptation mechanism and vascular dysfunction as cycle-dependent effects of intermittent exposures to hypobaric hypoxia.
Computing microRNA-gene interaction networks in pan-cancer using miRDriver
Authors: Bose Banabithi , Moravec Matthew , Bozdag Serdar
Published: March 2022

DNA copy number aberrated regions in cancer are known to harbor cancer driver genes and the short non-coding RNA molecules, i.e., microRNAs. In this study, we integrated the multi-omics datasets such as copy number aberration, DNA methylation, gene and microRNA expression to identify the signature microRNA-gene associations from frequently aberrated DNA regions across pan-cancer utilizing a LASSO-based regression approach. We studied 7294 patient samples associated with eighteen different cancer types from The Cancer Genome Atlas (TCGA) database and identified several cancer-specific and common microRNA-gene interactions enriched in experimentally validated microRNA-target interactions. We highlighted several oncogenic and tumor suppressor microRNAs that were cancer-specific and common in several cancer types. Our method substantially outperformed the five state-of-art methods in selecting significantly known microRNA-gene interactions in multiple cancer types. Several microRNAs and genes were found to be associated with tumor survival and progression. Selected target genes were found to be significantly enriched in cancer-related pathways, cancer hallmark and Gene Ontology (GO) terms. Furthermore, subtype-specific potential gene signatures were discovered in multiple cancer types.
Transiently expressed CRISPR/Cas9 induces wild-type dystrophin in vitro in DMD patient myoblasts carrying duplications
Authors: Pini Veronica , Mariot Virginie , Dumonceaux Julie , Counsell John , O’Neill Helen C. , Farmer Sarah , Conti Francesco , Muntoni Francesco
Published: March 2022

Among the mutations arising in the DMD gene and causing Duchenne Muscular Dystrophy (DMD), 10–15% are multi-exon duplications. There are no current therapeutic approaches with the ability to excise large multi-exon duplications, leaving this patient cohort without mutation-specific treatment. Using CRISPR/Cas9 could provide a valid alternative to achieve targeted excision of genomic duplications of any size. Here we show that the expression of a single CRISPR/Cas9 nuclease targeting a genomic region within a DMD duplication can restore the production of wild-type dystrophin in vitro. We assessed the extent of dystrophin repair following both constitutive and transient nuclease expression by either transducing DMD patient-derived myoblasts with integrating lentiviral vectors or electroporating them with CRISPR/Cas9 expressing plasmids. Comparing genomic, transcript and protein data, we observed that both continuous and transient nuclease expression resulted in approximately 50% dystrophin protein restoration in treated myoblasts. Our data demonstrate that a high transient expression profile of Cas9 circumvents its requirement of continuous expression within the cell for targeting DMD duplications. This proof-of-concept study therefore helps progress towards a clinically relevant gene editing strategy for in vivo dystrophin restoration, by highlighting important considerations for optimizing future therapeutic approaches.
Seasonal and temporal patterns of rainfall shape arthropod community composition and multi-trophic interactions in an arid environment
Authors: Fischer Christina , Gerstmeier Roland , Wagner Thomas C.
Published: March 2022

In arid and semi-arid ecosystems, rainfall and rainfall temporal distribution shape species communities and multi-trophic interactions. Whereas the relationship between climate change-induced decline of precipitation and plants is well know, there is little knowledge of these relationships with consumers, such as arthropods of different trophic levels. In a 6-year period we studied precipitation effects and microhabitat conditions on multi-trophic interactions of ground-dwelling arthropods in an arid savannah. We analysed the effects of seasonal rainfall, plant cover and soil texture on community composition and activity density of arthropods of different trophic levels and investigated the critical window of vegetation and occurrence arthropods in relation to rainfall. Our result show, that arthropod community composition was determined by seasonal rainfall and plant cover. Soil texture did not explain arthropod response sufficiently. Especially detritivorous arthropods were strongly affected by precipitation and can therefore serve as indicators of droughts. Further, multi-trophic interactions can better be explained by short-term rainfall pulses, rather than by seasonal patterns, with a window of seven days being most suitable to explain the influence of rainfall. Plant cover responded immediately after the rainfall, followed by herbivorous and predatory arthropods, and with a lag of 23 days omnivorous arthropods. This highlights the importance of short-term rain pulses for multi-trophic interactions among arthropods and emphasized the relevance of studying detailed precipitation effects for the arthropod diversity and ecosystem stability in arid ecosystems.
Multiple asters organize the yolk microtubule network during dclk2-GFP zebrafish epiboly
Authors: Marsal Maria , Bernardello Matteo , Gualda Emilio J. , Loza-Alvarez Pablo
Published: March 2022

It is known that the organization of microtubule (MT) networks in cells is orchestrated by subcellular structures named MT organizing centers (MTOCs). In this work, we use Light Sheet Fluorescence and Confocal Microscopy to investigate how the MT network surrounding the spherical yolk is arranged in the dclk2-GFP zebrafish transgenic line. We found that during epiboly the MT network is organized by multiple aster-like MTOCS. These structures form rings around the yolk sphere. Importantly, in wt embryos, aster-like MTOCs are only found upon pharmacological or genetic induction. Using our microscopy approach, we underscore the variability in the number of such asters in the transgenic line and report on the variety of global configurations of the yolk MT network. The asters’ morphology, dynamics, and their distribution in the yolk sphere are also analyzed. We propose that these features are tightly linked to epiboly timing and geometry. Key molecules are identified which support this asters role as MTOCs, where MT nucleation and growth take place. We conclude that the yolk MT network of dclk2-GFP transgenic embryos can be used as a model to organize microtubules in a spherical geometry by means of multiple MTOCs.
Prediction of treatment outcome in clinical trials under a personalized medicine perspective
Authors: Berchialla Paola , Lanera Corrado , Sciannameo Veronica , Gregori Dario , Baldi Ileana
Published: March 2022

A central problem in most data-driven personalized medicine scenarios is the estimation of heterogeneous treatment effects to stratify individuals into subpopulations that differ in their susceptibility to a particular disease or response to a specific treatment. In this work, with an illustrative example on type 2 diabetes we showed how the increasing ability to access and analyzed open data from randomized clinical trials (RCTs) allows to build Machine Learning applications in a framework of personalized medicine. An ensemble machine learning predictive model is first developed and then applied to estimate the expected treatment response according to the medication that would be prescribed. Machine learning is quickly becoming indispensable to bridge science and clinical practice, but it is not sufficient on its own. A collaborative effort is requested to clinicians, statisticians, and computer scientists to strengthen tools built on machine learning to take advantage of this evidence flow.
Identification of the potential mechanism of Radix pueraria in colon cancer based on network pharmacology
Authors: Li Yi , Zhang Chunli , Ma Xiaohan , Yang Liuqing , Ren Huijun
Published: March 2022

Radix Puerariae(RP), a dry root ofPueraria lobata(Willd.) Ohwi, is used to treat a variety of diseases, including cancer. Several in vitro and in vivo studies have demonstrated the efficacy of RP in the treatment of colon cancer (CC). However, the biological mechanism of RP in the treatment of colon cancer remains unclear. In this study, the active component of RP and its potential molecular mechanism against CC were studied by network pharmacology and enrichment analysis. The methods adopted included screening active ingredients of Chinese medicine, predicting target genes of Chinese medicine and disease, constructing of a protein interaction network, and conducting GO and KEGG enrichment analysis. Finally, the results of network pharmacology were further validated by molecular docking experiments and cell experiments. Eight active constituents and 14 potential protein targets were screened from RP, including EGFR, JAK2 and SRC. The biological mechanism of RP against CC was analysed by studying the relationship between active components, targets, and enrichment pathways. These findings provide a basis for understanding the clinical application of RP in CC.
Change in knee cartilage components in stroke patients with genu recurvatum analysed by zero TE MR imaging
Authors: Li Wenshan , Li Youwei , Gao Qiang , Liu Jingxin , Wen Qiping , Jia Shiqi , Tang Fen , Mo Linhong , Zhang Yuanfang , Zhai Mingchun , Chen Yukun , Guo Yue , Gong Weijun
Published: March 2022

Genu recurvatum in stroke patients with hemiplegia causes readily cumulative damage and degenerative changes in the knee cartilage. It is important to detect early cartilage lesions for appropriate treatment and rehabilitation. The purpose of this cross-sectional study was to provide a theoretical basis for the early rehabilitation of hemiplegia patients. We used a zero TE double-echo imaging sequence to analyse the water content in knee joint cartilage at 12 different sites of 39 stroke patients with genu recurvatum and 9 healthy volunteers using a metric similar to the porosity index. When comparing the hemiplegic limb vs. the nonhemiplegic limb in patients, the ratios of the deep/shallow free water content of the femur cartilages at the anterior horn (1.16 vs. 1.06) and posterior horn (1.13 vs. 1.25) of the lateral meniscus were significantly different. Genu recurvatum in stroke patients with hemiplegia can cause changes in the moisture content of knee cartilage, and the changes in knee cartilage are more obvious as the genu recurvatum increases. The "healthy limb" can no longer be considered truly healthy and should be considered simultaneously with the affected limb in the development of a rehabilitation treatment plan.
Efficient prediction of temperature-dependent elastic and mechanical properties of 2D materials
Authors: Kastuar S. M. , Ekuma C. E. , Liu Z. -L.
Published: March 2022

An efficient automated toolkit for predicting the mechanical properties of materials can accelerate new materials design and discovery; this process often involves screening large configurational space in high-throughput calculations. Herein, we present the ElasTool toolkit for these applications. In particular, we use the ElasTool to study diversity of 2D materials and heterostructures including their temperature-dependent mechanical properties, and developed a machine learning algorithm for exploring predicted properties.
An intra-cytoplasmic route for SARS-CoV-2 transmission unveiled by Helium-ion microscopy
Authors: Merolli Antonio , Kasaei Leila , Ramasamy Santhamani , Kolloli Afsal , Kumar Ranjeet , Subbian Selvakumar , Feldman Leonard C.
Published: March 2022

SARS-CoV-2 virions enter the host cells by docking their spike glycoproteins to the membrane-bound Angiotensin Converting Enzyme 2. After intracellular assembly, the newly formed virions are released from the infected cells to propagate the infection, using the extra-cytoplasmic ACE2 docking mechanism. However, the molecular events underpinning SARS-CoV-2 transmission between host cells are not fully understood. Here, we report the findings of a scanning Helium-ion microscopy study performed on Vero E6 cells infected with mNeonGreen-expressing SARS-CoV-2. Our data reveal, with unprecedented resolution, the presence of: (1) long tunneling nanotubes that connect two or more host cells over submillimeter distances; (2) large scale multiple cell fusion events (syncytia); and (3) abundant extracellular vesicles of various sizes. Taken together, these ultrastructural features describe a novel intra-cytoplasmic connection among SARS-CoV-2 infected cells that may act as an alternative route of viral transmission, disengaged from the well-known extra-cytoplasmic ACE2 docking mechanism. Such route may explain the elusiveness of SARS-CoV-2 to survive from the immune surveillance of the infected host.
Prevalence, awareness, treatment, and control of hypertension based on ACC/AHA versus JNC7 guidelines in the PERSIAN cohort study
Authors: Sepanlou Sadaf , Najafi Farid , Poustchi Hossein , Parsaeian Mahboubeh , Ahmadi Ali , Somi Mohammadhossein , Moradpour Farhad , Alizadeh-Navaei Reza , Gohari Ali , Zamani Bijan , Esmaeilinadimi Ali , Rezaianzadeh Abbas , Mansour-Ghanaei Fariborz , Bahramali Ehsan , Ansari-Moghaddam Alireza , Hamzeh Behrooz , Zanganeh Yousefabadi Elham , Zare Sakhvidi Mohammad Javad , Mohebbi Iraj , Fattahi Mohammad Reza , Nejatizadeh Azim , Marioryad Hossein , Motamed-Gorji Nazgol , Roozafzai Farzin , Eghtesad Sareh , Mohammadi Zahra , Shayanrad Amaneh , Sharafkhah Maryam , Etemadi Arash , Kamangar Farin , Juraschek Stephen P. , Malekzadeh Reza
Published: March 2022

In this cross-sectional population-based study, we used the baseline data of the Prospective Epidemiologic Research Studies in IrAN cohort study collected in Iran from 2014 to 2020. The main outcomes were the prevalence of hypertension and proportion of awareness, treatment, and control based on the 2017 ACC/AHA guideline compared to the seventh report of the Joint National Committee (JNC7). Of the total of 163,770 participants, aged 35–70 years, 55.2% were female. The sex-age standardized prevalence of hypertension was 22.3% (95% CI 20.6, 24.1) based on the JNC7 guideline and 36.5% (31.1, 41.8) based on the ACC/AHA guideline. A total of 24,312 participants [14.1% (10.1, 18.1)] were newly diagnosed based on the ACC/AHA guideline. Compared to adults diagnosed with hypertension based on the JNC7 guideline, the newly diagnosed participants were mainly young literate males who had low levels of risk factors and were free from conventional comorbidities of hypertension. About 30.7% (25.9, 35.4) of them (4.3% of the entire population) were eligible for pharmacologic intervention based on the ACC/AHA guideline. Implementation of the new guideline may impose additional burden on health systems. However, early detection and management of elevated blood pressure may reduce the ultimate burden of hypertension in Iran.
The effect of age-related macular degeneration on cognitive test performance
Authors: Macnamara Anne , Schinazi Victor R. , Chen Celia , Coussens Scott , Loetscher Tobias
Published: March 2022

The reliable assessment of cognitive functioning is critical to the study of brain-behaviour relationships. Yet conditions that are synchronous which ageing, including visual decline, are easily overlooked when interpreting cognitive test scores. The purpose of this study was to demonstrate the negative consequences of visual impairments on cognitive tests performance. Moderate to severe levels of age-related macular degeneration were simulated, with a set of goggles, in a sample of twenty-four normally sighted participants while they completed two cognitive tasks: a vision-dependent reaction time task and a vision-independent verbal fluency test. Performance on the reaction time task significantly decreased (p < 0.001) in the simulated age-related macular degeneration condition, by as much as 25 percentile ranks. In contrast, performance on the verbal fluency test were not statistically different between the simulated and normal vision conditions (p = 0.78). The findings highlight the importance of considering visual functioning when assessing cognitive function. When vision is not accounted for, low test scores may inaccurately indicate poor cognition. Such false attributions may have significant ramification for diagnosis and research on cognitive functioning.
The connectivity network underlying the German’s Twittersphere: a testbed for investigating information spreading phenomena
Authors: Schroeder Daniel Thilo , Langguth Johannes , Burchard Luk , Pogorelov Konstantin , Lind Pedro G.
Published: March 2022

Online social networks are ubiquitous, have billions of users, and produce large amounts of data. While platforms like Reddit are based on a forum-like organization where users gather around topics, Facebook and Twitter implement a concept in which individuals represent the primary entity of interest. This makes them natural testbeds for exploring individual behavior in large social networks. Underlying these individual-based platforms is a network whose “friend” or “follower” edges are of binary nature only and therefore do not necessarily reflect the level of acquaintance between pairs of users. In this paper,we present the network of acquaintance “strengths” underlying the German Twittersphere. To that end, we make use of the full non-verbal information contained in tweet–retweet actions to uncover the graph of social acquaintances among users, beyond pure binary edges. The social connectivity between pairs of users is weighted by keeping track of the frequency of shared content and the time elapsed between publication and sharing. Moreover, we also present a preliminary topological analysis of the German Twitter network. Finally, making the data describing the weighted German Twitter network of acquaintances, we discuss how to apply this framework as a ground basis for investigating spreading phenomena of particular contents.
The image-based preoperative fistula risk score (preFRS) predicts postoperative pancreatic fistula in patients undergoing pancreatic head resection
Authors: Kolbinger Fiona R. , Lambrecht Julia , Leger Stefan , Ittermann Till , Speidel Stefanie , Weitz Jürgen , Hoffmann Ralf-Thorsten , Distler Marius , Kühn Jens-Peter
Published: March 2022

Clinically relevant postoperative pancreatic fistula (CR-POPF) is a common severe surgical complication after pancreatic surgery. Current risk stratification systems mostly rely on intraoperatively assessed factors like manually determined gland texture or blood loss. We developed a preoperatively available image-based risk score predicting CR-POPF as a complication of pancreatic head resection. Frequency of CR-POPF and occurrence of salvage completion pancreatectomy during the hospital stay were associated with an intraoperative surgical (sFRS) and image-based preoperative CT-based (rFRS) fistula risk score, both considering pancreatic gland texture, pancreatic duct diameter and pathology, in 195 patients undergoing pancreatic head resection. Based on its association with fistula-related outcome, radiologically estimated pancreatic remnant volume was included in a preoperative (preFRS) score for POPF risk stratification. Intraoperatively assessed pancreatic duct diameter (p < 0.001), gland texture (p < 0.001) and high-risk pathology (p < 0.001) as well as radiographically determined pancreatic duct diameter (p < 0.001), gland texture (p < 0.001), high-risk pathology (p = 0.001), and estimated pancreatic remnant volume (p < 0.001) correlated with the risk of CR-POPF development. PreFRS predicted the risk of CR-POPF development (AUC = 0.83) and correlated with the risk of rescue completion pancreatectomy. In summary, preFRS facilitates preoperative POPF risk stratification in patients undergoing pancreatic head resection, enabling individualized therapeutic approaches and optimized perioperative management.
Wave types and energy conversion of impulse waves generated by landslides into mountain reservoirs
Authors: Han Linfeng , Wang Pingyi , Yu Tao
Published: March 2022

Subaerial landslides sliding into shallow water are physically modeled in a three-dimensional wave basin. The generated impulse waves are highly nonlinear, and a large-scale splash zone is formed above the waves. Such impulse wave characteristics are different from those from landslides into deep water that are completely submerged after sliding. The recorded wave profiles included three wave types, namely nonlinear oscillatory wave, nonlinear transition wave and bore-like wave, mainly depending on the relative slide thickness and slide Froude number at impact. Bore-like waves were possible produced only by landslides into shallow water in three-dimensional experiments. The conversion rate of landslide kinetic energy at impact into the wave train energy is 1 to 18%. Energy conversion characteristics are compared with other two- and three-dimensional studies on landslide-generated waves and the results are discussed.
Allocating vaccines to remote and on-site workers in the tradable sector
Authors: Czaller László , Tóth Gergő , Lengyel Balázs
Published: March 2022

Vaccination may be the solution to the pandemic-induced health crisis, but the allocation of vaccines is a complex task in which ethical, economic and social considerations are important. The biggest challenge is to use the limited number of vaccines available in a way that protects vulnerable groups, prevents further spread of infection, and reduces economic uncertainty. We argue that once the vaccination of healthcare workers and the most vulnerable groups has been completed, prioritizing the vaccination of on-site workers is important not only to slow the spread of the infection, but also to ensure the smooth running of economic production. We propose a simple economic model where remote and on-site workers are complementary to each other in the short run, thus a negative shock to the supply of either one may decrease the demand for the other, leading to unemployment. By illustrating the model using pre-Covid employment data from Sweden and Hungary, we show that the optimal vaccine allocation between remote and on-site workers in the tradable sector should be based on different proportions depending on the relative infection risk of on-site workers and the degree of vaccine availability. As long as the number of vaccines is limited and on-site workers are at higher risk of infection, they should be preferred in general. However, as more vaccines become available, countries like Sweden, where the share of occupations that can be done remotely is higher shall start immunize remote workers. In Hungary, where on-site work is dominant in the tradable sector, continued vaccination of on-site workers is more beneficial.
Uncertainty in climate change impact studies for irrigated maize cropping systems in southern Spain
Authors: Kamali Bahareh , Lorite Ignacio J. , Webber Heidi A. , Rezaei Ehsan Eyshi , Gabaldon-Leal Clara , Nendel Claas , Siebert Stefan , Ramirez-Cuesta Juan Miguel , Ewert Frank , Ojeda Jonathan J.
Published: March 2022

This study investigates the main drivers of uncertainties in simulated irrigated maize yield under historical conditions as well as scenarios of increased temperatures and altered irrigation water availability. Using APSIM, MONICA, and SIMPLACE crop models, we quantified the relative contributions of three irrigation water allocation strategies, three sowing dates, and three maize cultivars to the uncertainty in simulated yields. The water allocation strategies were derived from historical records of farmer’s allocation patterns in drip-irrigation scheme of the Genil-Cabra region, Spain (2014–2017). By considering combinations of allocation strategies, the adjusted R2 values (showing the degree of agreement between simulated and observed yields) increased by 29% compared to unrealistic assumptions of considering only near optimal or deficit irrigation scheduling. The factor decomposition analysis based on historic climate showed that irrigation strategies was the main driver of uncertainty in simulated yields (66%). However, under temperature increase scenarios, the contribution of crop model and cultivar choice to uncertainty in simulated yields were as important as irrigation strategy. This was partially due to different model structure in processes related to the temperature responses. Our study calls for including information on irrigation strategies conducted by farmers to reduce the uncertainty in simulated yields at field scale.
Mammalian HEMK1 methylates glutamine residue of the GGQ motif of mitochondrial release factors
Authors: Fang Qi , Kimura Yusuke , Shimazu Tadahiro , Suzuki Takehiro , Yamada Ayumi , Dohmae Naoshi , Iwasaki Shintaro , Shinkai Yoichi
Published: March 2022

Despite limited reports on glutamine methylation, methylated glutamine is found to be highly conserved in a "GGQ" motif in both prokaryotes and eukaryotes. In bacteria, glutamine methylation of peptide chain release factors 1/2 (RF1/2) by the enzyme PrmC is essential for translational termination and transcript recycling. Two PrmC homologs, HEMK1 and HEMK2, are found in mammals. In contrast to those of HEMK2, the biochemical properties and biological significance of HEMK1 remain largely unknown. In this study, we demonstrated that HEMK1 is an active methyltransferase for the glutamine residue of the GGQ motif of all four putative mitochondrial release factors (mtRFs)—MTRF1, MTRF1L, MRPL58, and MTRFR. In HEMK1-deficient HeLa cells, GGQ motif glutamine methylation was absent in all the mtRFs. We examined cell growth and mitochondrial properties, but disruption of the HEMK1 gene had no considerable impact on the overall cell growth, mtDNA copy number, mitochondrial membrane potential, and mitochondrial protein synthesis under regular culture condition with glucose as a carbon source. Furthermore, cell growth potential of HEMK1 KO cells was still maintained in the respiratory condition with galactose medium. Our results suggest that HEMK1 mediates the GGQ methylation of all four mtRFs in human cells; however, this specific modification seems mostly dispensable in cell growth and mitochondrial protein homeostasis at least for HeLa cells under fermentative culture condition.
Targeted proteomics and specific immunoassays reveal the presence of shared allergens between the zoonotic nematodes Anisakis simplex and Pseudoterranova decipiens
Authors: Saelens Ganna , Planckaert Sören , Martínez-Sernández Victoria , Ubeira Florencio M. , Devreese Bart , Gabriël Sarah
Published: March 2022

The family Anisakidae, mainly represented by Anisakis simplex s.l. and Pseudoterranova decipiens, encompasses zoonotic nematodes infecting many marine fish. Both are responsible for gastrointestinal disease in humans after ingestion of a live larva by consumption of undercooked fish, and, in the case of A. simplex, an allergic reaction may occur after consuming or even handling infected fish. Due to its phylogenetic relatedness with A. simplex, few studies investigated the allergenic potential of P. decipiens, yet none of them focused on its excretory/secretory (E/S) proteins that easily get missed when working solely on extracts from crushed nematodes. Moreover, these E/S allergens remain behind even when the larva has been removed during fish quality processing. Therefore, the aim was to investigate if Anisakis-like allergens could also be detected in both crushed and E/S P. decipiens protein extract using targeted mass spectrometry analysis and immunological methods. The results confirmed that at least five A. simplex allergens have homologous proteins in P. decipiens; a result that emphasizes the importance of also including E/S protein extracts in proteomic studies. Not only A. simplex, but also P. decipiens should therefore be considered a potential source of allergens that could lead to hypersensitivity reactions in humans.
Complete genomic sequencing of canine distemper virus with nanopore technology during an epizootic event
Authors: Lanszki Zsófia , Tóth Gábor E. , Schütz Éva , Zeghbib Safia , Rusvai Miklós , Jakab Ferenc , Kemenesi Gábor
Published: March 2022

Canine distemper virus (CDV) endangers a wide range of wild animal populations, can cross species barriers and therefore representing a significant conservational and animal health risk around the globe. During spring to autumn 2021, according to our current estimates a minimum of 50 red foxes (Vulpes vulpes) died of CDV in Hungary, with CDV lesions. Oral, nasal and rectal swab samples were RT-PCR screened for Canine Distemper Virus from red fox carcasses. To investigate in more detail the origins of these CDV strains, 19 complete genomes were sequenced with a pan-genotype CDV-specific amplicon-based sequencing method developed by our laboratory and optimized for the Oxford Nanopore Technologies platform. Phylogenetic analysis of the complete genomic sequences and separately the hemagglutinin gene sequences revealed the role of the Europe lineage of CDV as a causative agent for the current epizootic. Here we highlight the growing importance of fast developing rapid sequencing technologies to aid rapid response activities during epidemics or epizootic events. We also emphasize the urgent need for improved surveillance of CDV, considering the epizootic capability of enzootic strains as reported in the current study. For such future efforts, we provide a novel NGS protocol to facilitate future genomic surveillance studies.