bluuebunny/crossref_metadata_2025 huggingface dataset:
DNN-Based Distributed Voltage Stability Online Monitoring Method for Large-Scale Power Grids
Authors: Li Shuaihu , Hou Jie , Yang Anbang , Li Jie
Published: March 2021

With the increase of power load demand and the complexity of power grid structure, the problem of voltage stability is becoming more serious, and it is urgent to study the countermeasures. In this paper, a DNN-based distributed voltage stability online monitoring method for large-scale power grids is proposed. Unlike the traditional load margin methods, the proposed method uses a local index load impedance modulus margin (LIMM) index to determine the optimal installation locations of PMUs, which is more efficiently. Moreover, the DNN is applied to learn the nonlinear relationship between the power system operation state and its corresponding LIMM. By this way, the corresponding LIMM value can be predicted through the state variables of nodes from the installed PMUs. This method can greatly improve the calculation speed of LIMM and assess the system voltage stability level in real-time, which help the system operator to judge the operating state and take measures in time. Finally, the proposed method is tested on the 14-bus system and then on the 118-bus system respectively, and the simulation results verify the effectiveness and correctness of the proposed method.
In silico Design for Systems-Based Metabolic Engineering for the Bioconversion of Valuable Compounds From Industrial By-Products
Authors: Tafur Rangel Albert Enrique , Ríos Wendy , Mejía Daisy , Ojeda Carmen , Carlson Ross , Gómez Ramírez Jorge Mario , González Barrios Andrés Fernando
Published: March 2021

Selecting appropriate metabolic engineering targets to build efficient cell factories maximizing the bioconversion of industrial by-products to valuable compounds taking into account time restrictions is a significant challenge in industrial biotechnology. Microbial metabolism engineering following a rational design has been widely studied. However, it is a cost-, time-, and laborious-intensive process because of the cell network complexity; thus, it is important to use tools that allow predicting gene deletions. An in silico experiment was performed to model and understand the metabolic engineering effects on the cell factory considering a second complexity level by transcriptomics data integration. In this study, a systems-based metabolic engineering target prediction was used to increase glycerol bioconversion to succinic acid based on Escherichia coli. Transcriptomics analysis suggests insights on how to increase cell glycerol utilization to further design efficient cell factories. Three E. coli models were used: a core model, a second model based on the integration of transcriptomics data obtained from growth in an optimized culture media, and a third one obtained after integration of transcriptomics data from adaptive laboratory evolution (ALE) experiments. A total of 2,402 strains were obtained with fumarase and pyruvate dehydrogenase being frequently predicted for all the models, suggesting these reactions as essential to increase succinic acid production. Finally, based on using flux balance analysis (FBA) results for all the mutants predicted, a machine learning method was developed to predict new mutants as well as to propose optimal metabolic engineering targets and mutants based on the measurement of the importance of each knockout’s (feature’s) contribution. Glycerol has become an interesting carbon source for industrial processes due to biodiesel business growth since it has shown promising results in terms of biomass/substrate yields. The combination of transcriptome, systems metabolic modeling, and machine learning analyses revealed the versatility of computational models to predict key metabolic engineering targets in a less cost-, time-, and laborious-intensive process. These data provide a platform to improve the prediction of metabolic engineering targets to design efficient cell factories. Our results may also work as a guide and platform for the selection/engineering of microorganisms for the production of interesting chemical compounds.
Assessment of Bidirectional Relationships Between Polycystic Ovary Syndrome and Periodontitis: Insights From a Mendelian Randomization Analysis
Authors: Wu Pengfei , Zhang Xinghao , Zhou Ping , Zhang Wan , Li Danyang , Lv Mingming , Liao Xiaoyao
Published: March 2021

Background

Observational studies have indicated an association between polycystic ovary syndrome (PCOS) and periodontitis, but it is unclear whether the association is cofounded or causal. We conducted a two-sample Mendelian randomization (MR) study to investigate the bidirectional relationship between genetically predicted PCOS and periodontitis.

Methods

From two genome-wide association studies we selected 13 and 7 single nucleotide polymorphisms associated with PCOS and periodontitis, respectively, as instrumental variables. We utilized publicly shared summary-level statistics from European-ancestry cohorts. To explore the causal effect of PCOS on periodontitis, 12,289 cases of periodontitis and 22,326 controls were incorporated, while 4,890 cases of PCOS and 20,405 controls in the reverse MR. Inverse-variance weighted method was employed in the primary MR analysis and multiple sensitivity analyses were implemented.

Results

Genetically determined PCOS was not causally associated with risk of periodontitis (odds ratio 0.97; 95% confidence interval 0.88–1.06; P = 0.50) per one-unit increase in the log-odds ratio of periodontitis. Similarly, no causal effect of periodontitis on PCOS was shown with the odds ratio for PCOS was 1.17 (95% confidence interval 0.91–1.49; P = 0.21) per one-unit increase in the log-odds ratio of periodontitis. Consistent results were yielded via additional MR methods. Sensitivity analyses demonstrated no presence of horizontal pleiotropy or heterogeneity.

Conclusion

The bidirectional MR study couldn’t provide convincing evidence for the causal relationship between genetic liability to PCOS and periodontitis in the Europeans. Triangulating evidence across further observational and genetic-epidemiological studies is necessary.
Clinical Significance of Shared T Cell Epitope Analysis in Early De Novo Donor-Specific Anti-HLA Antibody Production After Kidney Transplantation and Comparison With Shared B cell Epitope Analysis
Authors: Tomosugi Toshihide , Iwasaki Kenta , Sakamoto Shintaro , Niemann Matthias , Spierings Eric , Nahara Isao , Futamura Kenta , Okada Manabu , Hiramitsu Takahisa , Takeda Asami , Goto Norihiko , Narumi Shunji , Watarai Yoshihiko , Kobayashi Takaaki
Published: March 2021

In pre-sensitizing events, immunological memory is mainly createdviaindirect allorecognition where CD4+T cells recognize foreign peptides in the context of self-HLA class II (pHLA) presented on antigen-presenting cells. This recognition makes it possible for naive CD4+T-helper cells to differentiate into memory cells, resulting in the creation of further antibody memory. These responses contribute to effective secretion of donor-specific anti-HLA antibodies (DSA) after second encounters with the same peptide. Preformed donor-reactive CD4+memory T cells may induce early immune responses after transplantation; however, the tools to evaluate them are limited. This study evaluated shared T cell epitopes (TEs) between the pre-sensitizing and donor HLA using anin silicoassay, an alternative to estimate donor-reactive CD4+memory T cells before transplantation. In 578 living donor kidney transplants without preformed DSA, 69 patients had anti-HLA antibodies before transplantation. Of them, 40 had shared TEs and were estimated to have donor-reactive CD4+memory T cells.De novoDSA formation in the early phase was significantly higher in the shared TE-positive group than in the anti-HLA antibody- and shared TE-negative groups (p=0.001 and p=0.02, respectively). In conclusion, evaluation of shared TEs for estimating preformed donor-reactive CD4+memory T cells may help predict the risk of earlyde novoDSA formation after kidney transplantation.
Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Update: Genetic Pathogenesis
Authors: Li Weiran , Huang He , Cai Minglong , Yuan Tao , Sheng Yujun
Published: March 2021

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is characterized by the inflammation of small and medium vessels and presence of proteinase 3-ANCA or myeloperoxidase-ANCA in the circulation. AAV comprises three clinical subtypes: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic GPA (EGPA). Although the pathogenesis of AAV is still unclear, genetic and environmental factors and the immune system are thought to be involved. Genetic factors have been confirmed to play an important role in AAV. Genome-wide association studies have identified numerous genetic variants in MHC and non-MHC regions associated with AAV. The strongest evidence of MHC association in AAV is human leukocyte antigen (HLA)-DP. A significant association between AAV and genetic variations in non-MHC regions, such asCTLA-4,FCGR2A,PTPN22,SERPINA1, andTLR9has also been found. Moreover, different clinical subtypes of AAV have distinct genetic backgrounds. GPA is associated withHLA-DP1, MPA withHLA-DQ, and EGPA withHLA-DRB4. These findings could help elucidate the etiology of AAV and develop new biomarkers for diagnosis and targeted therapy. Herein, we briefly summarize the updates on the genetic pathogenesis and biomarkers of AAV.
Drastic Reductions in Mental Well-Being Observed Globally During the COVID-19 Pandemic: Results From the ASAP Survey
Authors: Wilke Jan , Hollander Karsten , Mohr Lisa , Edouard Pascal , Fossati Chiara , González-Gross Marcela , Sánchez Ramírez Celso , Laiño Fernando , Tan Benedict , Pillay Julian David , Pigozzi Fabio , Jimenez-Pavon David , Sattler Matteo C. , Jaunig Johannes , Zhang Mandy , van Poppel Mireille , Heidt Christoph , Willwacher Steffen , Vogt Lutz , Verhagen Evert , Hespanhol Luiz , Tenforde Adam S.
Published: March 2021

Most countries affected by the COVID-19 pandemic have repeatedly restricted public life to control the contagion. However, the health impact of confinement measures is hitherto unclear. We performed a multinational survey investigating changes in mental and physical well-being (MWB/PWB) during the first wave of the pandemic. A total of 14,975 individuals from 14 countries provided valid responses. Compared to pre-restrictions, MWB, as measured by the WHO-5 questionnaire, decreased considerably during restrictions (68.1 ± 16.9 to 51.9 ± 21.0 points). Whereas 14.2% of the participants met the cutoff for depression screening pre-restrictions, this share tripled to 45.2% during restrictions. Factors associated with clinically relevant decreases in MWB were female sex (odds ratio/OR = 1.20, 95% CI: 1.11–1.29), high physical activity levels pre-restrictions (OR = 1.29, 95% CI 1.16–1.42), decreased vigorous physical activity during restrictions (OR = 1.14, 95% CI: 1.05–1.23), and working (partially) outside the home vs. working remotely (OR = 1.29, 95% CI: 1.16–1.44/OR = 1.35, 95% CI: 1.23–1.47). Reductions, although smaller, were also seen for PWB. Scores in the SF-36 bodily pain subscale decreased from 85.8 ± 18.7% pre-restrictions to 81.3 ± 21.9% during restrictions. Clinically relevant decrements of PWB were associated with female sex (OR = 1.62, 95% CI: 1.50–1.75), high levels of public life restrictions (OR = 1.26, 95% CI: 1.18–1.36), and young age (OR = 1.10, 95% CI: 1.03–1.19). Study findings suggest lockdowns instituted during the COVID-19 pandemic may have had substantial adverse public health effects. The development of interventions mitigating losses in MWB and PWB is, thus, paramount when preparing for forthcoming waves of COVID-19 or future public life restrictions.
Time Till Viral Clearance of Severe Acute Respiratory Syndrome Coronavirus 2 Is Similar for Asymptomatic and Non-critically Symptomatic Individuals
Authors: Kumar Nitya , AbdulRahman AbdulKarim , AlAli Salman , Otoom Sameer , Atkin Stephen L. , AlQahtani Manaf
Published: March 2021

Despite the modeled estimations of the burden of asymptomatic spread, the duration of viral positivity and infectiousness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains understudied. The objective of the present study was to estimate and compare the time till viral clearance of SARS-CoV-2 in asymptomatic and non-critical symptomatic individuals. We studied 184 SARS-CoV-2-positive participants, of whom 145 were asymptomatic. Our analysis uncovered that time till viral negativity is similar for subclinical [median time till viral clearance: 11 days, interquartile range (IQR): 8, 14] and overt infections (median: 11 days, IQR: 9, 14) after controlling for age and sex. This has implications in understanding the period of infectivity for SARS-CoV-2 in order to plan adequate public health measures to control the community spread.
Anemia in Chronic Kidney Disease: From Pathophysiology and Current Treatments, to Future Agents
Authors: Portolés Jose , Martín Leyre , Broseta José Jesús , Cases Aleix
Published: March 2021

Anemia is a common complication in chronic kidney disease (CKD), and is associated with a reduced quality of life, and an increased morbidity and mortality. The mechanisms involved in anemia associated to CKD are diverse and complex. They include a decrease in endogenous erythropoietin (EPO) production, absolute and/or functional iron deficiency, and inflammation with increased hepcidin levels, among others. Patients are most commonly managed with oral or intravenous iron supplements and with erythropoiesis stimulating agents (ESA). However, these treatments have associated risks, and sometimes are insufficiently effective. Nonetheless, in the last years, there have been some remarkable advances in the treatment of CKD-related anemia, which have raised great expectations. On the one hand, a novel family of drugs has been developed: the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs). These agents induce, among other effects, an increase in the production of endogenous EPO, improve iron availability and reduce hepcidin levels. Some of them have already received marketing authorization. On the other hand, recent clinical trials have elucidated important aspects of iron supplementation, which may change the treatment targets in the future. This article reviews the current knowledge of the pathophysiology CKD-related anemia, current and future therapies, the trends in patient management and the unmet goals.
The Impact of COVID-19 on Primary Care General Practice Consultations in a Teaching Hospital in Shanghai, China
Authors: Xu Zhongqing , Fan Jingchun , Ding Jingjing , Feng Xianzhen , Tao Shunyu , Zhou Jun , Qian Lingmei , Tao Kun , Hambly Brett D. , Bao Shisan
Published: March 2021

Background:The COVID-19 (2019 novel coronavirus disease) pandemic is deeply concerning because of its massive mortality and morbidity, creating adverse perceptions among patients likely to impact on their overall medical care. Thus, we evaluated the impact of the COVID-19 pandemic on the pattern of primary care consultations within a Shanghai health district.

Methods:A retrospective observational cohort study was performed, with data analyzed concerning the pattern of patient visits to general practitioners within the Tongren Hospital network (the sole provider of general practice to the population of 700,000). Data from all general practice consultations for adults were collected for the first 6 months of 2020, which included a 60-day lockdown period (January 24–March 24, 2020) and compared to corresponding data from the first 6 months of 2019. We evaluated changes to the numbers and patterns of primary care consultations, including subgroup analysis based on age, sex, and primary diagnosis.

Results:A substantial reduction in patient visits, associated with increased median age, was observed during the first wave of the pandemic in the first 6 months of 2020, compared to the same interval during 2019. Additionally, reduced reappointments and waiting times, but increased costs per visit were observed. When analyzed by primary disease diagnosis, patient visits were reduced for all the major systems. The most striking visit reductions were in cardiovascular, respiratory, endocrine, and gastrointestinal diseases. However, psychological disorders were increased following lockdown, but there was also a dramatic fall in consultations for depression. Reduced monthly patient numbers correlated with both rate of reappointment and average waiting time during the first 6 months of both 2019 and 2020, but an inverse correlation was observed between cost per visit and monthly patient numbers. Specifically during the lockdown period, there was ~50% reduced patient visits.

Conclusions:The lockdown has had a serious impact on patients' physical and psychological health. Our analysis provides objective health-related data that may inform the current controversy concerning the balance between the detrimental effects of the use of lockdown vs. the use of a more targeted approach to eliminate viral transmission. These data may improve decision-making in medical practice, policy, and education.
Oncoimmunology Meets Organs-on-Chip
Authors: Mattei Fabrizio , Andreone Sara , Mencattini Arianna , De Ninno Adele , Businaro Luca , Martinelli Eugenio , Schiavoni Giovanna
Published: March 2021

Oncoimmunology represents a biomedical research discipline coined to study the roles of immune system in cancer progression with the aim of discovering novel strategies to arm it against the malignancy. Infiltration of immune cells within the tumor microenvironment is an early event that results in the establishment of a dynamic cross-talk. Here, immune cells sense antigenic cues to mount a specific anti-tumor response while cancer cells emanate inhibitory signals to dampen it. Animals models have led to giant steps in this research context, and several tools to investigate the effect of immune infiltration in the tumor microenvironment are currently available. However, the use of animals represents a challenge due to ethical issues and long duration of experiments. Organs-on-chip are innovative tools not only to study how cells derived from different organs interact with each other, but also to investigate on the crosstalk between immune cells and different types of cancer cells. In this review, we describe the state-of-the-art of microfluidics and the impact of OOC in the field of oncoimmunology underlining the importance of this system in the advancements on the complexity of tumor microenvironment.
Serum Derived Extracellular Vesicles Mediated Delivery of Synthetic miRNAs in Human Endothelial Cells
Authors: Tapparo Marta , Pomatto Margherita Alba Carlotta , Deregibus Maria Chiara , Papadimitriou Elli , Cavallari Claudia , D’Antico Sergio , Collino Federica , Camussi Giovanni
Published: March 2021

Extracellular vesicles (EVs) have emerged in the last decades as a cell-to-cell communication mechanism. One of their mechanism of action is the direct delivery of their cargo, composed of bioactive molecules to target cells. Different methods (direct electroporation, cell transfection, chemical transfection) were developed to vehicle therapeutic molecules through EVs. However, most of these techniques presented some limitations such as EV disruption and aggregation. In the present study, we demonstrated that a direct temperature-controlled co-incubation of EVs with defined miRNAs is a stable method to deliver information to target cells without affecting EV constitutive content. We chose serum as an easy and abundant source of EVs applicable to autologous treatment after EV modification. Exogenous cel-miR-39 loaded on serum EVs (SEVs) was taken up by human endothelial cells, demonstrating an adequate miRNA loading efficacy based on the co-incubation method. Moreover, SEVs co-incubation with the angiomiRNA-126 (miR-126) enhanced their angiogenic propertiesin vitroandin vivoby increasing the capacity to induce capillary-like structure formation of human endothelial cells. MiR-126 loaded EVs were also shown to stimulate mouse endothelial cells to invade Matrigel plugs and create more vessels with respect to the EV naive counterpart. When SEVs were loaded with miR-19b, an anti-angiogenic miRNA, they were able to reduce Vascular endothelial growth factors (VEGF) pro-angiogenic capacity, supporting the selective biological effect mediated by the carried miRNA. Lastly, we identified Annexin A2 (ANXA2) as one of the molecules involved in the exogenous RNA binding to serum EV surface, favoring miRNA delivery to target endothelial cells for potential therapeutic application.
Graphene FET Sensors for Alzheimer’s Disease Protein Biomarker Clusterin Detection
Authors: Bungon Theodore , Haslam Carrie , Damiati Samar , O’Driscoll Benjamin , Whitley Toby , Davey Paul , Siligardi Giuliano , Charmet Jerome , Awan Shakil A.
Published: March 2021

We report on the fabrication and characterisation of graphene field-effect transistor (GFET) biosensors for the detection of Clusterin, a prominent protein biomarker of Alzheimer’s disease (AD). The GFET sensors were fabricated on Si/SiO2 substrate using photolithographic patterning and metal lift-off techniques with evaporated chromium and sputtered gold contacts. Raman Spectroscopy was performed on the devices to determine the quality of the graphene. The GFETs were annealed to improve their performance before the channels were functionalized by immobilising the graphene surface with linker molecules and anti-Clusterin antibodies. Concentration of linker molecules was also independently verified by absorption spectroscopy using the highly collimated micro-beam light of Diamond B23 beamline. The detection was achieved through the binding reaction between the antibody and varying concentrations of Clusterin antigen from 1 to 100 pg/mL, as well as specificity tests using human chorionic gonadotropin (hCG), a glycoprotein risk biomarker of certain cancers. The GFETs were characterized using direct current (DC) 4-probe electrical resistance (4-PER) measurements, which demonstrated a limit of detection of the biosensors to be ∼ 300 fg/mL (4 fM). Comparison with back-gated Dirac voltage shifts with varying concentration of Clusterin show 4-PER measurements to be more accurate, at present, and point to a requirement for further optimisation of the fabrication processes for our next generation of GFET sensors. Thus, we have successfully fabricated a promising set of GFET biosensors for the detection of Clusterin protein biomarker. The developed GFET biosensors are entirely generic and also have the potential to be applied to a variety of other disease detection applications such as Parkinson’s, cancer, and cardiovascular.
Hyper-SUMOylation of ERG Is Essential for the Progression of Acute Myeloid Leukemia
Authors: Chen Xu , Qin Yuanyuan , Zhang Zhenzhen , Xing Zhengcao , Wang Qiqi , Lu Wenbin , Yuan Hong , Du Congcong , Yang Xinyi , Shen Yajie , Zhao Biying , Shao Huanjie , Wang Xiaotong , Wu Hongmei , Qi Yitao
Published: March 2021

Leukemia is a malignant disease of hematopoietic tissue characterized by the differentiation arrest and malignant proliferation of immature hematopoietic precursor cells in bone marrow. ERG (ETS-related gene) is an important member of the E26 transformation-specific (ETS) transcription factor family that plays a crucial role in physiological and pathological processes. However, the role of ERG and its modification in leukemia remains underexplored. In the present study, we stably knocked down or overexpressed ERG in leukemia cells and observed that ERG significantly promotes the proliferation and inhibits the differentiation of AML (acute myeloid leukemia) cells. Further experiments showed that ERG was primarily modified by SUMO2, which was deconjugated by SENP2. PML promotes the SUMOylation of ERG, enhancing its stability. Arsenic trioxide decreased the expression level of ERG, further promoting cell differentiation. Furthermore, the mutation of SUMO sites in ERG inhibited its ability to promote the proliferation and inhibit the differentiation of leukemia cells. Our results demonstrated the crucial role of ERG SUMOylation in the development of AML, providing powerful targeted therapeutic strategies for the clinical treatment of AML.
Knockdown of LncRNA PANDAR by CRISPR-dCas9 Decreases Proliferation and Increases Apoptosis in Oral Squamous Cell Carcinoma
Authors: Jia Tingting , Wang Fengze , Qiao Bo , Ren Yipeng , Xing Lejun , Zhang Haizhong , Li Hongbo
Published: March 2021

Oral squamous cell carcinoma (OSCC) is the most common malignant epithelial tumor in the oral cavity. Emerging evidence has demonstrated the important function roles of long noncoding RNAs (lncRNAs) in human cancers. LncRNA promoter of CDKN1A antisense DNA damage activated RNA (PANDAR) functions as an oncogene in multiple carcinomas, whereas its function in OSCC has not been investigated yet. The aim of our study is to investigate the possible regulatory mechanism of PANDAR in OSCC. First of all, PANDAR was highly expressed in OSCC cells and loss-of-function assays mediated by CRISPR-dCas9 observed that PANDAR silencing restrained cell proliferation and promoted cell apoptosis. Then we found and confirmed the interaction between PANDAR and serine and arginine rich splicing factor 7 (SRSF7). Subsequently, serine/threonine-protein kinase pim-1 (PIM1) was proved to be regulated by PANDAR in SRSF7-dependant way. Rescue experiments validated that PANDAR modulated the proliferation and apoptosis in OSCC through PIM1. In conclusion, PANDAR bound with SRSF7 to increase PIM1 expression, hence promoting the development of OSCC. These data shed new lights into the seeking for effective diagnostic biomarkers and therapeutic targets for OSCC patients.
The Impact of Non-coding RNAs in the Epithelial to Mesenchymal Transition
Authors: Hussen Bashdar Mahmud , Shoorei Hamed , Mohaqiq Mahdi , Dinger Marcel E. , Hidayat Hazha Jamal , Taheri Mohammad , Ghafouri-Fard Soudeh
Published: March 2021

Epithelial to mesenchymal transition (EMT) is a course of action that enables a polarized epithelial cell to undertake numerous biochemical alterations that allow it to adopt features of mesenchymal cells such as high migratory ability, invasive properties, resistance to apoptosis, and importantly higher-order formation of extracellular matrix elements. EMT has important roles in implantation and gastrulation of the embryo, inflammatory reactions and fibrosis, and transformation of cancer cells, their invasiveness and metastatic ability. Regarding the importance of EMT in the invasive progression of cancer, this process has been well studies in in this context. Non-coding RNAs (ncRNAs) have been shown to exert critical function in the regulation of cellular processes that are involved in the EMT. These processes include regulation of some transcription factors namely SNAI1 and SNAI2, ZEB1 and ZEB2, Twist, and E12/E47, modulation of chromatin configuration, alternative splicing, and protein stability and subcellular location of proteins. In the present paper, we describe the influence of ncRNAs including microRNAs and long non-coding RNAs in the EMT process and their application as biomarkers for this process and cancer progression and their potential as therapeutic targets.
Glial Cell-Based Vascular Mechanisms and Transplantation Therapies in Brain Vessel and Neurodegenerative Diseases
Authors: Zhao Yingying , Wang Shuanglin , Song Xiaopeng , Yuan Junliang , Qi Dong , Gu Xiaohuan , Yin Michael Yaoyao , Han Zhou , Zhu Yanbing , Liu Zhandong , Zhang Yongbo , Wei Ling , Wei Zheng Zachory
Published: March 2021

Neurodevelopmental and neurodegenerative diseases (NDDs) with severe neurological/psychiatric symptoms, such as cerebrovascular pathology in AD, CAA, and chronic stroke, have brought greater attention with their incidence and prevalence having markedly increased over the past few years. Causes of the significant neuropathologies, especially those observed in neurological diseases in the CNS, are commonly believed to involve multiple factors such as an age, a total environment, genetics, and an immunity contributing to their progression, neuronal, and vascular injuries. We primarily focused on the studies of glial involvement/dysfunction in part with the blood-brain barrier (BBB) and the neurovascular unit (NVU) changes, and the vascular mechanisms, which have been both suggested as critical roles in chronic stroke and many other NDDs. It has been noted that glial cells including astrocytes (which outnumber other cell types in the CNS) essentially contribute more to the BBB integrity, extracellular homeostasis, neurotransmitter release, regulation of neurogenic niches in response to neuroinflammatory stimulus, and synaptic plasticity. In a recent study for NDDs utilizing cellular and molecular biology and genetic and pharmacological tools, the role of reactive astrocytes (RACs) and gliosis was demonstrated, able to trigger pathophysiological/psychopathological detrimental changes during the disease progression. We speculate, in particular, the BBB, the NVU, and changes of the astrocytes (potentially different populations from the RACs) not only interfere with neuronal development and synaptogenesis, but also generate oxidative damages, contribute to beta-amyloid clearances and disrupted vasculature, as well as lead to neuroinflammatory disorders. During the past several decades, stem cell therapy has been investigated with a research focus to target related neuro-/vascular pathologies (cell replacement and repair) and neurological/psychiatric symptoms (paracrine protection and homeostasis). Evidence shows that transplantation of neurogenic or vasculogenic cells could be achieved to pursue differentiation and maturation within the diseased brains as expected. It would be hoped that, via regulating functions of astrocytes, astrocytic involvement, and modulation of the BBB, the NVU and astrocytes should be among major targets for therapeutics against NDDs pathogenesis by drug and cell-based therapies. The non-invasive strategies in combination with stem cell transplantation such as the well-tested intranasal deliveries for drug and stem cells by our and many other groups show great translational potentials in NDDs. Neuroimaging and clinically relevant analyzing tools need to be evaluated in various NDDs brains.
The Effect of GLT-1 Upregulation on Extracellular Glutamate Dynamics
Authors: Wilkie Crystal M. , Barron Jessica C. , Brymer Kyle J. , Barnes Jocelyn R. , Nafar Firoozeh , Parsons Matthew P.
Published: March 2021

Pharmacological upregulation of glutamate transporter-1 (GLT-1), commonly achieved using the beta-lactam antibiotic ceftriaxone, represents a promising therapeutic strategy to accelerate glutamate uptake and prevent excitotoxic damage in neurological conditions. While excitotoxicity is indeed implicated in numerous brain diseases, it is typically restricted to select vulnerable brain regions, particularly in early disease stages. In healthy brain tissue, the speed of glutamate uptake is not constant and rather varies in both an activity- and region-dependent manner. Despite the widespread use of ceftriaxone in disease models, very little is known about how such treatments impact functional measures of glutamate uptake in healthy tissue, and whether GLT-1 upregulation can mask the naturally occurring activity-dependent and regional heterogeneities in uptake. Here, we used two different compounds, ceftriaxone and LDN/OSU-0212320 (LDN), to upregulate GLT-1 in healthy wild-type mice. We then used real-time imaging of the glutamate biosensor iGluSnFR to investigate functional consequences of GLT-1 upregulation on activity- and regional-dependent variations in glutamate uptake capacity. We found that while both ceftriaxone and LDN increased GLT-1 expression in multiple brain regions, they did not prevent activity-dependent slowing of glutamate clearance nor did they speed basal clearance rates, even in areas characterized by slow uptake (e.g., striatum). Unexpectedly, ceftriaxone but not LDN decreased glutamate release in the cortex, suggesting that ceftriaxone may alter release properties independent of its effects on GLT-1 expression. In sum, our data demonstrate the complexities of glutamate uptake by showing that GLT-1 expression does not necessarily translate to accelerated uptake. Furthermore, these data suggest that the mechanisms underlying activity- and regional-dependent differences in glutamate dynamics are independent of GLT-1 expression levels.
The Relationship Between Smoking and Delayed Cerebral Ischemia After Intracranial Aneurysm Rupture: A Systematic Review and Meta-Analysis
Authors: Ya Xiaolong , Zhang Chaoqi , Zhang Shuo , Zhang Qian , Cao Yong , Wang Shuo , Zhao Jizong
Published: March 2021

Background: Delayed cerebral ischemia (DCI) is the main cause of death and disability after intracranial aneurysm rupture. Previous studies have shown that smoking can lead to DCI after intracranial aneurysm rupture. However, some recent studies have shown that nicotine, as the main ingredient of tobacco, can cause cerebral vasodilation. This view has led to a debate about the relationship between smoking and DCI. This study aims to determine the relationship between smoking and DCI.

Methods: A systematic literature search was performed according to PRISMA guidelines. The Cochrane Library, Web of Science, PubMed, and Embase online databases were searched for studies published up to September 2020. All studies related to smoking and DCI were included in the analysis. The R and RevMan software were used for data analysis, and random or fixed model analysis was selected depending on the degree of heterogeneity. Publication bias was examined by using the Begg–Mazumdar test and using contour-enhanced funnel plots with trim method.

Results: A total of eight original articles (12 cohorts) with 10,722 patients were included in this meta-analysis. There were statistically significant higher rates of DCI in the smoking group than in the non-smoking group (RRtotal = 1.16, 95%CI: 1.05–1.27). After heterogeneity among cohorts was removed by sensitivity analysis, there was still a statistically significant difference in the incidence of DCI between the smoking and non-smoking groups (RRtotal = 1.13, 95%CI: 1.07–1.20).

Conclusions: Although the effects of nicotine as the main component of tobacco are unclear in terms of cerebral vessels, the present study suggests that smoking is a risk factor for DCI in patients with ruptured aneurysm.
The Essential Tremors: Evolving Concepts of a Family of Diseases
Authors: Louis Elan D.
Published: March 2021

The past 10 years has seen a remarkable advance in our understanding of the disease traditionally referred to as “essential tremor” (ET). First, the clinical phenotype of ET has been expanded from that of a bland, unidimensional, and monosymptomatic entity to one with a host of heterogeneous features. These features include a broader and more nuanced collection of tremors, non-tremor motor features (e.g., gait abnormalities) and a range of non-motor features, including cognitive, psychiatric, sleep, and other abnormalities. The natural history of these features, as well as their relationships with one another and with disease duration and severity, are better appreciated than they were previously. Studies of disease etiology have identified a number of candidate genes as well as explored several environmental determinants of disease. In addition, the decade has seen the beginnings and expansion of rigorous postmortem studies that have identified and described the postmortem changes in the brains of patients with ET. This emerging science has given rise to a new notion that the disease, in many cases, is one of cerebellar system degeneration. Across all of these studies (clinical, etiological, and pathophysiological) is the observation that there is heterogeneity across patients and that “essential tremor” is likely not a single disease but, rather, a family of diseases. The time has come to use the more appropriate terminology, “the essential tremors,” to fully describe and encapsulate what is now apparent. In this paper, the author will review the clinical, etiological, and pathophysiological findings, referred to above, and make the argument that the terminology should evolve to reflect advances in science and that “the essential tremors” is a more scientifically appropriate term.
Differential Effects of Physical and Social Enriched Environment on Angiogenesis in Male Rats After Cerebral Ischemia/Reperfusion Injury
Authors: Zhang Xin , Liu Jing-Ying , Liao Wei-Jing , Chen Xiu-Ping
Published: March 2021

Different housing conditions, including housing space and the physiological and social environment, may affect rodent behavior. Here, we examined the effects of different housing conditions on post-stroke angiogenesis and functional recovery to clarify the ambiguity about environmental enrichment and its components. Male rats in the model groups underwent right middle cerebral artery occlusion (MCAO) followed by reperfusion. The MCAO rats were divided into four groups: the physical enrichment (PE) group, the social enrichment (SE) group, the combined physical and social enrichment (PSE) group and the ischemia/reperfusion + standard conditioning (IS) group. The rats in the sham surgery (SS) group were housed under standard conditions. In a set of behavioral tests, including the modified Neurological Severity Score (mNSS), rotarod test, and adhesive removal test, we demonstrated that the animals in the enriched condition groups exhibited significantly improved neurological functions compared to those in the standard housing group. Smaller infarction volumes were observed in the animals of the PSE group by MRI detection. The enriched conditions increased the microvessel density (MVD) in the ischemic boundary zone, as revealed by CD31 immunofluorescent staining. The immunochemical and q-PCR results further showed that environmental enrichment increased the expression levels of angiogenic factors after ischemia/reperfusion injury. Our data suggest that all three enrichment conditions promoted enhanced angiogenesis and functional recovery after ischemia/reperfusion injury compared to the standard housing, while only exposure to the combination of both physical and social enrichment yielded optimal benefits.
miR-124 Alleviates Ischemic Stroke-Induced Neuronal Death by Targeting DAPK1 in Mice
Authors: Shi Yan , Tian Tian , Cai Er-Li , Yang Can , Yang Xin
Published: March 2021

Background

Ischemic stroke induces neuronal cell death and causes brain dysfunction. Preventing neuronal cell death after stroke is key to protecting the brain from stroke damage. Nevertheless, preventative measures and treatment strategies for stroke damage are scarce. Emerging evidence suggests that microRNAs (miRNAs) play critical roles in the pathogenesis of central nervous system (CNS) disorders and may serve as potential therapeutic targets.

Methods

A photochemically induced thrombosis (PIT) mouse model was used as an ischemic stroke model. qRT-PCR was employed to assess changes in miRNAs in ischemic lesions of PIT-stroke mice and primary cultured neurons subjected to oxygen-glucose deprivation (OGD). 2,3,5-triphenyltetrazolium chloride (TTC) staining was performed to evaluate brain infarction tissuesin vivo. TUNEL staining was employed to assess neuronal deathin vitro. Neurological scores and motor coordination were investigated to evaluate stroke damage, including neurological deficits and motor function.

Results

In vivoandin vitroresults demonstrated that levels of miR-124 were significantly decreased following stroke, whereas changes in death-associated protein kinase 1 (DAPK1) levels exhibited the converse pattern. DAPK1 was identified as a direct target of miR-124. N-methyl-D-aspartate (NMDA) and OGD-induced neuronal death was rescued by miR-124 overexpression. Upregulation of miR-124 levels significantly improved PIT-stroke damage, including the overall neurological function in mice.

Conclusion

We demonstrate the involvement of the miR-124/DAPK1 pathway in ischemic neuronal death. Our results highlight the therapeutic potential of targeting this pathway for ischemic stroke.
Machine Learning-Based Ultrasomics Improves the Diagnostic Performance in Differentiating Focal Nodular Hyperplasia and Atypical Hepatocellular Carcinoma
Authors: Li Wei , Lv Xiao-Zhou , Zheng Xin , Ruan Si-Min , Hu Hang-Tong , Chen Li-Da , Huang Yang , Li Xin , Zhang Chu-Qing , Xie Xiao-Yan , Kuang Ming , Lu Ming-De , Zhuang Bo-Wen , Wang Wei
Published: March 2021

Background

The typical enhancement patterns of hepatocellular carcinoma (HCC) on contrast-enhanced ultrasound (CEUS) are hyper-enhanced in the arterial phase and washed out during the portal venous and late phases. However, atypical variations make a differential diagnosis both challenging and crucial. We aimed to investigate whether machine learning-based ultrasonic signatures derived from CEUS images could improve the diagnostic performance in differentiating focal nodular hyperplasia (FNH) and atypical hepatocellular carcinoma (aHCC).

Patients and Methods

A total of 226 focal liver lesions, including 107 aHCC and 119 FNH lesions, examined by CEUS were reviewed retrospectively. For machine learning-based ultrasomics, 3,132 features were extracted from the images of the baseline, arterial, and portal phases. An ultrasomics signature was generated by a machine learning model. The predictive model was constructed using the support vector machine method trained with the following groups: ultrasomics features, radiologist’s score, and combination of ultrasomics features and radiologist’s score. The diagnostic performance was explored using the area under the receiver operating characteristic curve (AUC).

Results

A total of 14 ultrasomics features were chosen to build an ultrasomics model, and they presented good performance in differentiating FNH and aHCC with an AUC of 0.86 (95% confidence interval [CI]: 0.80, 0.89), a sensitivity of 76.6% (95% CI: 67.5%, 84.3%), and a specificity of 80.5% (95% CI: 70.6%, 85.9%). The model trained with a combination of ultrasomics features and the radiologist’s score achieved a significantly higher AUC (0.93, 95% CI: 0.89, 0.96) than that trained with the radiologist’s score (AUC: 0.84, 95% CI: 0.79, 0.89, P < 0.001). For the sub-group of HCC with normal AFP value, the model trained with a combination of ultrasomics features, and the radiologist’s score remain achieved the highest AUC of 0.92 (95% CI: 0.87, 0.96) compared to that with the ultrasomics features (AUC: 0.86, 95% CI: 0.74, 0.89, P < 0.001) and radiologist’s score (AUC: 0.86, 95% CI: 0.79, 0.91, P < 0.001).

Conclusions

Machine learning-based ultrasomics performs as well as the staff radiologist in predicting the differential diagnosis of FNH and aHCC. Incorporating an ultrasomics signature into the radiologist’s score improves the diagnostic performance in differentiating FNH and aHCC.
Complete Blood Count Score Model Predicts Inferior Prognosis in Primary Central Nervous System Lymphoma
Authors: Feng Yuhua , Liu Yiping , Zhong Meizuo , Wang Leyuan
Published: March 2021

Background

Primary central nervous system lymphoma (PCNSL), an aggressive type of non-Hodgkin lymphoma, has a poor prognosis. Currently available prognostic scoring systems are inadequate. We therefore aimed to investigate the predictive values of complete blood counts (CBCs) in PCNSL.

Materials and Methods

The cohort of this retrospective study comprised 73 PCNSL patients. The predictive values of selected CBCs, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune inflammation index (SII), and systemic inflammation response index (SIRI), were analyzed.

Results

Ages and Memorial Sloan Kettering Cancer Center (MSKCC) scores of PCNSL patients correlated with NLR, PLR, and SII values (p <0.05). Both age and MSKCC scores correlated with inferior progression-free survival (PFS) and overall survival (OS) (p <0.05). High NLR, PLR, SII, and SIRI were significant predictors of shorter PFS and OS (p <0.05). NLR, PLR, SII, and SIRI were integrated to generate a “CBC score” model that accurately stratified PCNSL patients into three risk groups. The median PFS for low-risk, intermediate-risk, and high-risk groups were 24 ((12.458–35.542), 17 (10.626–23.374), and 9 (8.893–19.107) months, respectively (p = 0.011), and the median OS were 33 (19.175–46.825), 18 (16.368–19.632), and 9 (6.521–11.479) months, respectively (p = 0.008). Multivariate Cox regression model showed that MSKCC score (hazard ratio (HR) = 3.791, p <0.001), PLR (HR = 1.003, p = 0.013), and CBC score (HR = 1.873, p = 0.011) were independent predictors for PFS, whereas MSKCC score (HR = 4.128, p <0.001), PLR (HR = 1.003, p = 0.005), and CBC score (HR = 1.907, p = 0.004) were independent predictors for OS.

Conclusion

The CBC score model may be a promising predictive system for PCNSL patients.
RETRACTED: The Collective Effect of MIP-3α and FL Promotes Dendritic Cell Function Within the Immune Microenvironment of Murine Liver Cancer
Authors: Zhao Haichao , Chen Changzhou , Chen Xidong , Yang Chuanli , Zhang Donglin , Li Yanjun , Zhao Haoliang , He Jiefeng
Published: March 2021

Hepatocellular carcinoma is a highly malignant and lethal tumor. In addition to surgery, immunotherapy is currently a more effective treatment for hepatocellular carcinoma. The tumor immune microenvironment (TIME) largely determines the efficacy of cancer immunotherapy. Based on the universal targeting of TIME modulators in clinical treatment, TIME modulators are promising targets for tumor immunotherapy. We investigated the effect of a double gene expression vector (recombinant galactose-terminal glycol-poly-L-lysine coupled MIP-3α-FL) on dendritic cells (DCs) regulation within the TIME of mice with liver cancer. H22 cells were transfected with a recombinant MIP-3α-FL plasmid to induce DCs differentiation and chemotaxis. The effects of transfection were investigated by flow cytometry following the modified Boyden’s method. Cytokine-induced killer (CIK) cells co-culture revealed changes in the antigen presentation ability of DCs. Further, tumor-bearing mice were injected with the recombinant double gene vector via the tail vein. We compared the survival time, tumor volume, weight of the mice, as well as the number and phenotype of tumor-infiltrating DCs (TIDCs) between groups. The supernatant of transfected H22 cells promoted the phenotypic maturation of DCs, enhancing their chemotaxis. Further, treated DCs promoted the cytokine secretion and killing ability of CIK cells. The survival time of mice injected with the double gene vector was significantly prolonged, while their tumor weight and volume were relatively reduced. Flow cytometry revealed that the number of TIDCs (as well as CD80 and CD86 expression) in the MouseMIP-3α-FL group, were significantly higher than in the control group. The combination of MIP-3α and FL can significantly promote DCs aggregation, maturation, and enhance their antigen presentation ability. The coupling of the double gene vector with glycosylated polylysine can improve the precise targeting of the liver and inhibit tumor growth in vivo, providing a novel approach for immune therapy in liver cancer.