bluuebunny/crossref_metadata_2025 huggingface dataset:
ALKBH1-8 and FTO: Potential Therapeutic Targets and Prognostic Biomarkers in Lung Adenocarcinoma Pathogenesis
Authors: Wu Geting , Yan Yuanliang , Cai Yuan , Peng Bi , Li Juanni , Huang Jinzhou , Xu Zhijie , Zhou Jianhua
Published: June 2021

The AlkB family consists of Fe(II)- and α-ketoglutarate-dependent dioxygenases that can catalyze demethylation on a variety of substrates, such as RNA and DNA, subsequently affecting tumor progression and prognosis. However, their detailed functional roles in lung adenocarcinoma (LUAD) have not been clarified in a comprehensive manner. In this study, several bioinformatics databases, such as ONCOMINE, TIMER, and DiseaseMeth, were used to evaluate the expression profiles and prognostic significance of the AlkB family (ALKBH1-8 and FTO) in LUAD. The expression levels of ALKBH1/2/4/5/7/8 were significantly increased in LUAD tissues, while the expression levels of ALKBH3/6 and FTO were decreased. The main functions of differentially expressed AlkB homologs are related to the hematopoietic system and cell adhesion molecules. We also found that the expression profiles of the AlkB family are highly correlated with infiltrating immune cells (i.e., B cells, CD8 + T cells, CD4 + T cells, macrophages, neutrophils and dendritic cells). In addition, DNA methylation analysis indicated that the global methylation levels of ALKBH1/2/4/5/6/8 and FTO were decreased, while the global methylation levels of ALKBH3/7 were increased. In addition, the patients with upregulated ALKBH2 have significantly poor overall survival (OS) and post-progressive survival (PPS). Taken together, our work could provide insightful information about aberrant AlkB family members as potential biomarkers for the diagnostic and prognostic evaluation of LUAD. Especially, ALKBH2 could be served as a therapeutic candidate for treating LUAD.
Periostin/Filamin-A: A Candidate Central Regulatory Axis for Valve Fibrogenesis and Matrix Compaction
Authors: Misra Suniti , Ghatak Shibnath , Moreno-Rodriguez Ricardo A. , Norris Russell A. , Hascall Vincent C. , Markwald Roger R.
Published: June 2021

Background

Discoveries in the identification of transcription factors, growth factors and extracellular signaling molecules have led to the detection of downstream targets that modulate valvular tissue organization that occurs during development, aging, or disease. Among these, matricellular protein, periostin, and cytoskeletal protein filamin A are highly expressed in developing heart valves. The phenotype of periostin null indicates that periostin promotes migration, survival, and differentiation of valve interstitial cushion cells into fibroblastic lineages necessary for postnatal valve remodeling/maturation. Genetically inhibiting filamin A expression in valve interstitial cushion cells mirrored the phenotype of periostin nulls, suggesting a molecular interaction between these two proteins resulted in poorly remodeled valve leaflets that might be prone to myxomatous over time. We examined whether filamin A has a cross-talk with periostin/signaling that promotes remodeling of postnatal heart valves into mature leaflets.

Results

We have previously shown that periostin/integrin-β1 regulates Pak1 activation; here, we revealed that the strong interaction between Pak1 and filamin A proteins was only observed after stimulation of VICs with periostin; suggesting that periostin/integrin-β-mediated interaction between FLNA and Pak1 may have a functional role in vivo. We found that FLNA phosphorylation (S2152) is activated by Pak1, and this interaction was observed after stimulation with periostin/integrin-β1/Cdc42/Rac1 signaling; consequently, FLNA binding to Pak1 stimulates its kinase activity. Patients with floppy and/or prolapsed mitral valves, when genetically screened, were found to have point mutations in the filamin A gene at P637Q and G288R. Expression of either of these filamin A mutants failed to increase the magnitude of filamin A (S2152) expression, Pak1-kinase activity, actin polymerization, and differentiation of VICs into mature mitral valve leaflets in response to periostin signaling.

Conclusion

PN-stimulated bidirectional interaction between activated FLNA and Pak1 is essential for actin cytoskeletal reorganization and the differentiation of immature VICs into mature valve leaflets.
Mutations and Copy Number Abnormalities of Hippo Pathway Components in Human Cancers
Authors: He Zhengjin , Li Ruihan , Jiang Hai
Published: June 2021

The Hippo pathway is highly conserved fromDrosophilato mammals. As a key regulator of cell proliferation, the Hippo pathway controls tissue homeostasis and has a major impact on tumorigenesis. The originally defined core components of the Hippo pathway in mammals include STK3/4, LATS1/2, YAP1/TAZ, TEAD, VGLL4, and NF2. However, for most of these genes, mutations and copy number variations are relatively uncommon in human cancer. Several other recently identified upstream and downstream regulators of Hippo signaling, including FAT1, SHANK2, Gq/11, and SWI/SNF complex, are more commonly dysregulated in human cancer at the genomic level. This review will discuss major genomic events in human cancer that enable cancer cells to escape the tumor-suppressive effects of Hippo signaling.
Conditional Cell Reprogramming in Modeling Digestive System Diseases
Authors: Zhao Ruihua , Li Rui , An Tianqi , Liu Xuefeng
Published: June 2021

Digestive diseases have become an important source of morbidity and mortality. The considerable financial and health burdens caused by digestive diseases confirm the importance of extensive research to better understand and treat these diseases. The development of reliable preclinical models is essential for understanding the pathogenesis of digestive diseases and developing treatment and prevention methods. However, traditional established cell lines and animal models still have many limitations in the study of the digestive system. Conditional reprogramming (CR) cell culture is a newly developed primary technology that uses irradiated Swiss-3T3-J2 mouse fibroblast cells and the Rho-associated kinase (ROCK) inhibitor Y-27632 to rapidly and efficiently generate many cells from diseased and normal tissues. CR cells (CRCs) can be reprogrammed to maintain a highly proliferative state and recapitulate the histological and genomic features of the original tissue. Moreover, after removing these conditions, the phenotype was completely reversible. Therefore, CR technology may represent an ideal model to study digestive system diseases, to test drug sensitivity, to perform gene profile analysis, and to undertake xenograft research and regenerative medicine. Indeed, together with organoid cultures, CR technology has been recognized as one of the key new technologies by NIH precision oncology and also used for NCI human cancer model initiatives (HCMI) program with ATCC. In this article, we review studies that use CR technology to conduct research on diseases of the digestive system.
Cell Tracking for Organoids: Lessons From Developmental Biology
Authors: Betjes Max A. , Zheng Xuan , Kok Rutger N. U. , van Zon Jeroen S. , Tans Sander J.
Published: June 2021

Organoids have emerged as powerful model systems to study organ development and regeneration at the cellular level. Recently developed microscopy techniques that track individual cells through space and time hold great promise to elucidate the organizational principles of organs and organoids. Applied extensively in the past decade to embryo development and 2D cell cultures, cell tracking can reveal the cellular lineage trees, proliferation rates, and their spatial distributions, while fluorescent markers indicate differentiation events and other cellular processes. Here, we review a number of recent studies that exemplify the power of this approach, and illustrate its potential to organoid research. We will discuss promising future routes, and the key technical challenges that need to be overcome to apply cell tracking techniques to organoid biology.
Chromosome Organization in Early Meiotic Prophase
Authors: Grey Corinne , de Massy Bernard
Published: June 2021

One of the most fascinating aspects of meiosis is the extensive reorganization of the genome at the prophase of the first meiotic division (prophase I). The first steps of this reorganization are observed with the establishment of an axis structure, that connects sister chromatids, from which emanate arrays of chromatin loops. This axis structure, called the axial element, consists of various proteins, such as cohesins, HORMA-domain proteins, and axial element proteins. In many organisms, axial elements are required to set the stage for efficient sister chromatid cohesion and meiotic recombination, necessary for the recognition of the homologous chromosomes. Here, we review the different actors involved in axial element formation inSaccharomyces cerevisiaeand in mouse. We describe the current knowledge of their localization pattern during prophase I, their functional interdependence, their role in sister chromatid cohesion, loop axis formation, homolog pairing before meiotic recombination, and recombination. We also address further challenges that need to be resolved, to fully understand the interplay between the chromosome structure and the different molecular steps that take place in early prophase I, which lead to the successful outcome of meiosis I.
Composition and Biophysical Properties of the Sorting Platform Pods in the Shigella Type III Secretion System
Authors: Tachiyama Shoichi , Skaar Ryan , Chang Yunjie , Carroll Brittany L. , Muthuramalingam Meenakumari , Whittier Sean K. , Barta Michael L. , Picking Wendy L. , Liu Jun , Picking William D.
Published: June 2021

Shigella flexneri, causative agent of bacillary dysentery (shigellosis), uses a type III secretion system (T3SS) as its primary virulence factor. The T3SS injectisome delivers effector proteins into host cells to promote entry and create an important intracellular niche. The injectisome’s cytoplasmic sorting platform (SP) is a critical assembly that contributes to substrate selection and energizing secretion. The SP consists of oligomeric Spa33 “pods” that associate with the basal body via MxiK and connect to the Spa47 ATPase via MxiN. The pods contain heterotrimers of Spa33 with one full-length copy associated with two copies of a C-terminal domain (Spa33C). The structure of Spa33C is known, but the precise makeup and structure of the pods in situ remains elusive. We show here that recombinant wild-type Spa33 can be prepared as a heterotrimer that forms distinct stable complexes with MxiK and MxiN. In two-hybrid analyses, association of the Spa33 complex with these proteins occurs via the full-length Spa33 component. Furthermore, these complexes each have distinct biophysical properties. Based on these properties, new high-resolution cryo-electron tomography data and architectural similarities between the Spa33 and flagellar FliM-FliN complexes, we provide a preliminary model of the Spa33 heterotrimers within the SP pods. From these findings and evolving models of SP interfaces and dynamics in the Yersinia and Salmonella T3SS, we suggest a model for SP function in which two distinct complexes come together within the context of the SP to contribute to form the complete pod structures during the recruitment of T3SS secretion substrates.
A Single Dose of Nitrate Increases Resilience Against Acidification Derived From Sugar Fermentation by the Oral Microbiome
Authors: Rosier Bob T. , Palazón Carlos , García-Esteban Sandra , Artacho Alejandro , Galiana Antonio , Mira Alex
Published: June 2021

Tooth decay starts with enamel demineralization due to an acidic pH, which arises from sugar fermentation by acidogenic oral bacteria. Previous in vitro work has demonstrated that nitrate limits acidification when incubating complex oral communities with sugar for short periods (e.g., 1-5 h), driven by changes in the microbiota metabolism and/or composition. To test whether a single dose of nitrate can reduce acidification derived from sugar fermentation in vivo, 12 individuals received a nitrate-rich beetroot supplement, which was compared to a placebo in a blinded crossover setting. Sucrose-rinses were performed at baseline and 2 h after supplement or placebo intake, and the salivary pH, nitrate, nitrite, ammonium and lactate were measured. After nitrate supplement intake, the sucrose-induced salivary pH drop was attenuated when compared with the placebo (p < 0.05). Salivary nitrate negatively correlated with lactate production and positively with ΔpH after sucrose exposure (r= -0.508 and 0.436, respectively, both p < 0.05). Two additional pilot studies were performed to test the effect of sucrose rinses 1 h (n = 6) and 4 h (n = 6) after nitrate supplement intake. In the 4 h study, nitrate intake was compared with water intake and bacterial profiles were analysed using 16S rRNA gene Illumina sequencing and qPCR detection of Rothia. Sucrose rinses caused a significant pH drop (p < 0.05), except 1 h and 4 h after nitrate supplement intake. After 4 h of nitrate intake, there was less lactate produced compared to water intake (p < 0.05) and one genus; Rothia, increased in abundance. This small but significant increase was confirmed by qPCR (p < 0.05). The relative abundance of Rothia and Neisseria negatively correlated with lactate production (r = -0.601 and -0.669, respectively) and Neisseria positively correlated with pH following sucrose intake (r = 0.669, all p < 0.05). Together, these results show that nitrate can acutely limit acidification when sugars are fermented, which appears to result from lactate usage by nitrate-reducing bacteria. Future studies should assess the longitudinal impact of daily nitrate-rich vegetable or supplement intake on dental health.
Effects of Direct Air Capture Technology Availability on Stranded Assets and Committed Emissions in the Power Sector
Authors: Pradhan Shreekar , Shobe William M. , Fuhrman Jay , McJeon Haewon , Binsted Matthew , Doney Scott C. , Clarens Andres F.
Published: June 2021

We examine the effects of negative emission technologies availability on fossil fuel-based electricity generating assets under deep decarbonization trajectories. Our study focuses on potential premature retirements (stranding) and committed emissions of existing power plants globally and the effects of deploying direct air carbon capture and biomass-based carbon capture and sequestration technologies. We use the Global Change Analysis Model (GCAM), an integrated assessment model, to simulate the global supply of electricity under a climate mitigation scenario that limits global warming to 1.5–2°C temperature increase over the century. Our results show that the availability of direct air capture (DAC) technologies reduces the stranding of existing coal and gas based conventional power plants and delays any stranding further into the future. DAC deployment under the climate mitigation goal of limiting the end-of-century warming to 1.5–2°C would reduce the stranding of power generation from 250 to 350 GW peaking during 2035-2040 to 130-150 GW in years 2050-2060. With the availability of direct air capture and carbon storage technologies, the carbon budget to meet the climate goal of limiting end-of-century warming to 1.5–2°C would require abating 28–33% of 564 Gt CO2 -the total committed CO2 emissions from the existing power plants vs. a 46–57% reduction in the scenario without direct air capture and carbon storage technologies.
Enterprise Integration and Interoperability for Big Data-Driven Processes in the Frame of Industry 4.0
Authors: Bousdekis Alexandros , Mentzas Gregoris
Published: June 2021

Traditional manufacturing businesses lack the standards, skills, processes, and technologies to meet today's challenges of Industry 4.0 driven by an interconnected world. Enterprise Integration and Interoperability can ensure efficient communication among various services driven by big data. However, the data management challenges affect not only the technical implementation of software solutions but the function of the whole organization. In this paper, we bring together Enterprise Integration and Interoperability, Big Data Processing, and Industry 4.0 in order to identify synergies that have the potential to enable the so-called “Fourth Industrial Revolution.” On this basis, we propose an architectural framework for designing and modeling Industry 4.0 solutions for big data-driven manufacturing operations. We demonstrate the applicability of the proposed framework through its instantiation to predictive maintenance, a manufacturing function that increasingly concerns manufacturers due to the high costs, safety issues, and complexity of its application.
Pressure-Driven Opening and Filling of a Volcanic Hydrofracture Recorded by Tuffisite at Húsafell, Iceland: A Potential Seismic Source
Authors: Unwin Holly E. , Tuffen Hugh , Phillips Emrys , Wadsworth Fabian B. , James Mike R.
Published: June 2021

The opening of magmatic hydraulic fractures is an integral part of magma ascent, the triggering of volcano seismicity, and defusing the explosivity of ongoing eruptions via outgassing magmatic volatiles. If filled with pyroclastic particles, these fractures can be recorded as tuffisites. Tuffisites are therefore thought to play a key role in both initiating eruptions and controlling their dynamics, and yet their genesis remains poorly understood. Here we characterise the processes, pressures and timescales involved in tuffisite evolution within the country rock through analysis of the sedimentary facies and structures of a large sub-horizontal tuffisite vein, 0.9 m thick and minimum 40 m in length, at the dissected Húsafell volcano, western Iceland. The vein occurs where a propagating rhyolitic sheet intrusion stalled at a depth of ∼500 m beneath a relatively strong layer of welded ignimbrite. Laminations, cross-stratification, channels, and internal injections indicate erosion and deposition in multiple fluid pulses, controlled by fluctuations in local fluid pressure and changes in fluid-particle concentration. The field evidence suggests that this tuffisite was emplaced by as many as twenty pulses, depositing sedimentary units with varying characteristics. Assuming that each sedimentary unit (∼0.1 m thick and minimum 40 m in length) is emplaced by a single fluid pulse, we estimate fluid overpressures of ∼1.9–3.3 MPa would be required to emplace each unit. The Húsafell tuffisite records the repeated injection of an ash-laden fluid within an extensive subhorizontal fracture, and may therefore represent the fossil record of a low-frequency seismic swarm associated with fracture propagation and reactivation. The particles within the tuffisite cool and compact through time, causing the rheology of the tuffisite fill to evolve and influencing the nature of the structures being formed as new material is injected during subsequent fluid pulses. As this new material is emplaced, the deformation style of the surrounding tuffisite is strongly dependent on its evolving rheology, which will also control the evolution of pressure and the system permeability. Interpreting tuffisites as the fossil record of fluid-driven hydrofracture opening and evolution can place new constraints on the cycles of pressurisation and outgassing that accompany the opening of magmatic pathways, key to improving interpretations of volcanic unrest and hazard forecasting.
Bryophyte Conservation in Managed Boreal Landscapes: Fourteen-Year Impacts of Partial Cuts on Epixylic Bryophytes
Authors: Opoku-Nyame Jeffrey , Leduc Alain , Fenton Nicole J.
Published: June 2021

Clear cut harvest simplifies and eliminates old growth forest structure, negatively impacting biodiversity. Partial cut harvest has been hypothesized (1) to have less impact on biodiversity than clear cut harvest, and (2) to encourage old growth forest structures. Long-term studies are required to test this hypothesis as most studies are conducted soon after harvest. Using epixylic bryophytes as indicators, this study addresses this knowledge gap. Fourteen years after harvest, we examined changes in epixylic bryophyte community composition richness and traits, and their microhabitats (coarse woody debris characteristics and microclimate) along an unharvested, partial cuts and clear cuts harvest treatment in 30 permanent plots established in the boreal black spruce (Picea mariana) forests of northwestern Quebec, Canada. Our results were compared to those of an initial post-harvest study (year 5) and to a chronosequence of old growth forests to examine species changes over time and the similarity of bryophyte communities in partial cut and old growth forests. Coarse woody debris (CWD) volume by decay class varied among harvest treatments with partial cuts and clear cuts recording lower volumes of early decay CWD. The epixylic community was richer in partial cuts than in mature unharvested forests and clear cuts. In addition, species richness and overall abundance doubled in partial and clear cuts between years 5 and 14. Species composition also differed among treatments between years 5 and 14. Furthermore, conditions in partial cut stands supported small, drought sensitive, and old growth confined species that are threatened by conditions in clear cut stands. Lastly, over time, species composition in partial cuts became more similar to old growth forests. Partial cuts reduced harvest impacts by continuing to provide favorable microhabitat conditions that support epixylic bryophytes. Also, partial cut harvest has the potential to encourage old growth species assemblages, which has been a major concern for biodiversity conservation in managed forest landscapes. Our findings support the promotion of partial cut harvest as an effective strategy to achieve species and habitat conservation goals.
Comparative Transcriptome Analyses Reveal a Transcriptional Landscape of Human Silicosis Lungs and Provide Potential Strategies for Silicosis Treatment
Authors: Pang Junling , Luo Ya , Wei Dong , Cao Zhujie , Qi Xianmei , Song Meiyue , Liu Ying , Li Zhaoguo , Zhang Jin , Li Baicun , Chen Jingyu , Wang Jing , Wang Chen
Published: June 2021

Silicosis is a fatal occupational lung disease which currently has no effective clinical cure. Recent studies examining the underlying mechanism of silicosis have primarily examined experimental models, which may not perfectly reflect the nature of human silicosis progression. A comprehensive profiling of the molecular changes in human silicosis lungs is urgently needed. Here, we conducted RNA sequencing (RNA-seq) on the lung tissues of 10 silicosis patients and 7 non-diseased donors. A total of 2,605 differentially expressed genes (DEGs) and critical pathway changes were identified in human silicosis lungs. Further, the DEGs in silicosis were compared with those in idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary diseases (COPD), to extend current knowledge about the disease mechanisms and develop potential drugs. This analysis revealed both common and specific regulations in silicosis, along with several critical genes (e.g., MUC5AC and FGF10), which are potential drug targets for silicosis treatment. Drugs including Plerixafor and Retinoic acid were predicted as potential candidates in treating silicosis. Overall, this study provides the first transcriptomic fingerprint of human silicosis lungs. The comparative transcriptome analyses comprehensively characterize pathological regulations resulting from silicosis, and provide valuable cues for silicosis treatment.
Upregulation of LIMK1 Is Correlated With Poor Prognosis and Immune Infiltrates in Lung Adenocarcinoma
Authors: Lu Guojun , Zhou Ying , Zhang Chenxi , Zhang Yu
Published: June 2021

Background

Protein-coding gene LIM Domain Kinase 1 (LIMK1) is upregulated in various tumors and reported to promote tumor invasion and metastasis. However, the prognostic values of LIMK1 and correlation with immune infiltrates in lung adenocarcinoma are still not understood. Therefore, we evaluated the prognostic role of LIMK1 and its correlation with immune infiltrates in lung adenocarcinoma.

Methods

Transcriptional expression profiles of LIMK1 between lung adenocarcinoma tissues and normal tissues were downloaded from the Cancer Genome Atlas (TCGA). The LIMK1 protein expression was assessed by the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and the Human Protein Atlas. Receiver operating characteristic (ROC) curve was used to differentiate lung adenocarcinoma from adjacent normal tissues. Kaplan-Meier method was conducted to assess the effect of LIMK1 on survival. Protein-protein interaction (PPI) networks were constructed by the STRING. Functional enrichment analyses were performed using the “ClusterProfiler” package. The relationship between LIMK1 mRNA expression and immune infiltrates was determined by tumor immune estimation resource (TIMER) and tumor-immune system interaction database (TISIDB).

Results

The expression of LIMK1 in lung adenocarcinoma tissues was significantly upregulated than those in adjacent normal tissues. Increased LIMK1 mRNA expression was associated with lymph node metastases and high TNM stage. The ROC curve analysis showed that with a cutoff level of 4.908, the accuracy, sensitivity, and specificity for LIMK1 differentiate lung adenocarcinoma from adjacent controls were 69.5, 93.2, and 71.9%, respectively. Kaplan-Meier survival analysis showed lung adenocarcinoma patients with high- LIMK1 had a worse prognosis than those with low- LIMK1 (43.1 vs. 55.1 months, P = 0.028). Correlation analysis indicated LIMK1 mRNA expression was correlated with tumor purity and immune infiltrates.

Conclusion

Upregulated LIMK1 is significantly correlated with poor survival and immune infiltrates in lung adenocarcinoma. Our study suggests that LIMK1 can be used as a biomarker of poor prognosis and potential immune therapy target in lung adenocarcinoma.
A Novel Controlled PTEN-Knockout Mouse Model for Prostate Cancer Study
Authors: Liu Sen , Zhang Bing , Rowan Brian G. , Jazwinski S. Michal , Abdel-Mageed Asim B. , Steele Chad , Wang Alun R. , Sartor Oliver , Niu Tianhua , Zhang Qiuyang
Published: June 2021

Prostate cancer (PCa) is associated with advanced age, but how age contributes to prostate carcinogenesis remains unknown. The prostate-specific Pten conditional knockout mouse model closely imitates human PCa initiation and progression. To better understand how age impacts PCa in an experimental model, we have generated a spatially and temporally controlled Pten-null PCa murine model at different ages (aged vs. non-aged) of adult mice. Here, we present a protocol to inject the Cre-expressing adenovirus with luciferin tag, intraductally, into the prostate anterior lobes of Pten-floxed mice; Pten-loss will be triggered post-Cre expression at different ages. In vivo imaging of luciferin signal following viral infection confirmed successful delivery of the virus and Cre activity. Immunohistochemical staining confirmed prostate epithelial-specific expression of Cre recombinase and the loss of Pten and activation of P-Akt, P-S6, and P-4E-BP1. The Cre-expression, Pten ablation, and activated PI3K/AKT/mTOR pathways were limited to the prostate epithelium. All mice developed prostatic epithelial hyperplasia within 4 weeks after Pten ablation and prostatic intraepithelial neoplasia (PIN) within 8 weeks post-Pten ablation. Some PINs had progressed to invasive adenocarcinoma at 8–16 weeks post-Pten ablation. Aged mice exhibited significantly accelerated PI3K/AKT/mTOR signaling and increased PCa onset and progression compared to young mice. The viral infection success rate is ∼80%. This model will be beneficial for investigations of cancer-related to aging.
The Cross-Links of Endoplasmic Reticulum Stress, Autophagy, and Neurodegeneration in Parkinson’s Disease
Authors: Ren Haigang , Zhai Wanqing , Lu Xiaojun , Wang Guanghui
Published: June 2021

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, and it is characterized by the selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc), as well as the presence of intracellular inclusions with α-synuclein as the main component in surviving DA neurons. Emerging evidence suggests that the imbalance of proteostasis is a key pathogenic factor for PD. Endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) and autophagy, two major pathways for maintaining proteostasis, play important roles in PD pathology and are considered as attractive therapeutic targets for PD treatment. However, although ER stress/UPR and autophagy appear to be independent cellular processes, they are closely related to each other. In this review, we focused on the roles and molecular cross-links between ER stress/UPR and autophagy in PD pathology. We systematically reviewed and summarized the most recent advances in regulation of ER stress/UPR and autophagy, and their cross-linking mechanisms. We also reviewed and discussed the mechanisms of the coexisting ER stress/UPR activation and dysregulated autophagy in the lesion regions of PD patients, and the underlying roles and molecular crosslinks between ER stress/UPR activation and the dysregulated autophagy in DA neurodegeneration induced by PD-associated genetic factors and PD-related neurotoxins. Finally, we indicate that the combined regulation of ER stress/UPR and autophagy would be a more effective treatment for PD rather than regulating one of these conditions alone.
Intravenous Thrombolysis After Dabigatran Reversal by Idarucizumab: A Systematic Review of the Literature
Authors: Frol Senta , Sagris Dimitrios , Pretnar Oblak Janja , Šabovič Mišo , Ntaios George
Published: June 2021

Background and Purpose: Idarucizumab achieves instant reversal of anticoagulation and enables intravenous thrombolysis (IVT) in dabigatran-treated acute ischemic stroke (AIS) patients. AIS in dabigatran-treated patients is a rare event, therefore the experience is limited. A review of all published cases was performed to evaluate the safety and effectiveness of this therapeutic strategy.

Methods: We searched PubMed and Scopus for all published cases of IVT after reversal with idarucizumab in dabigatran-treated AIS patients. The outcomes were safety assessed by hemorhagic transformation (HT), symptomatic intracranial hemorrhage (SICH) and death, and efficacy assessed by National Institutes of Health Stroke Scale (NIHSS) reduction.

Results: We identified 251 AIS patients (39,9% females) with an average age of 74 years. HT, SICH, and death were reported in 19 (7.6%), 9 (3.6%), and 21 (8.4%) patients, respectively. Patients experiencing HT presented with more severe strokes (median NIHSS on admission: 21 vs. 8, p < 0.001; OR: 1.12, 95% CI: 1.05–1.20). After IVT there was a significant NIHSS reduction of 6 points (IQR:3–10, p < 0.001) post-stroke and linear regression revealed a correlation of admission NIHSS to NIHSS reduction (p < 0.001).

Conclusions: In this systematic review of all published cases of IVT in dabigatran-treated AIS patients after reversal with idarucizumab the rates of HT, SICH and mortality, as well as NIHSS reduction, were comparable with previous studies in non-anticoagulated patients. This provides reassuring evidence about the safety and efficacy of this therapeutic strategy.
Ketogenic Diet in the Treatment of Super-Refractory Status Epilepticus at a Pediatric Intensive Care Unit: A Single-Center Experience
Authors: Breu Markus , Häfele Chiara , Glatter Sarah , Trimmel-Schwahofer Petra , Golej Johann , Male Christoph , Feucht Martha , Dressler Anastasia
Published: June 2021

Background: To evaluate the use of the ketogenic diet (KD) for treatment of super-refractory status epilepticus (SRSE) at a pediatric intensive care unit (PICU).

Design: A retrospective analysis of all pediatric patients treated for SRSE with the KD at our center was performed using patient data from our prospective longitudinal KD database.

Setting: SRSE is defined as refractory SE that continues or recurs 24 h or more after initiation of anesthetic drugs. We describe the clinical and electroencephalographic (EEG) findings of all children treated with KD at our PICU. The KD was administered as add-on after failure of standard treatment. Response was defined as EEG seizure resolution (absence of seizures and suppression–burst ratio ≥50%).

Patients: Eight consecutive SRSE patients (four females) treated with KD were included. Median age at onset of SRSE was 13.6 months (IQR 0.9–105), and median age at KD initiation was 13.7 months (IQR 1.9 months to 8.9 years). Etiology was known in 6/8 (75%): genetic in 4 (50%), structural in 1 (12.5%), and autoimmune/inflammatory in 1 (12.5%).

Main Results: Time from onset of SRSE to initiation of KD was median 6 days (IQR 1.3–9). Time until clinically relevant ketosis (beta-hydroxybutyrate (BHB) >2 mmol/L in serum) was median 68.0 h (IQR 27.3–220.5). Higher ketosis was achieved when a higher proportion of enteral feeds was possible. Four (50%) patients responded to KD treatment within 7 days. During follow-up (median 4.2 months, IQR 1.6–12.3), 5/8 patients—three of them responders—died within 3–12 months after SRSE.

Conclusions: In eight patients with SRSE due to severe etiologies including Alpers syndrome, we report an initial 50% response to KD. KD was used early in SRSE and sufficient levels of ketosis were reached early in most patients. Higher ketosis was achieved with combined enteral and parenteral feedings.
Focused Ultrasound Ablation of an Arteriovenous Malformation Model
Authors: Jones Jesse , Bolding Mark , Ullman Henrik , Kaneko Naoki , Tateshima Satoshi
Published: June 2021

Brain AVMs are rare but serious vascular lesions that often pose a management dilemma between the risk of various treatment modalities and uncertain natural history during observation. We describe preliminary data on the use of focused ultrasound as a novel therapeutic strategy. In an AVM model, one session of ultrasound gradually reduced flow through the lesion without inducing rupture. Due to its non-invasive yet immediate ablative effects, focused ultrasound may allow safer treatment of AVMs. However, further studies are needed to clarify its efficacy and side effect profile.
Neurophysiological Correlates of Asymmetries in Vowel Perception: An English-French Cross-Linguistic Event-Related Potential Study
Authors: Polka Linda , Molnar Monika , Zhao T. Christina , Masapollo Matthew
Published: June 2021

Behavioral studies examining vowel perception in infancy indicate that, for many vowel contrasts, the ease of discrimination changes depending on the order of stimulus presentation, regardless of the language from which the contrast is drawn and the ambient language that infants have experienced. By adulthood, linguistic experience has altered vowel perception; analogous asymmetries are observed for non−native contrasts but are mitigated for native contrasts. Although these directional effects are well documented behaviorally, the brain mechanisms underlying them are poorly understood. In the present study we begin to address this gap. We first review recent behavioral work which shows that vowel perception asymmetries derive from phonetic encoding strategies, rather than general auditory processes. Two existing theoretical models–the Natural Referent Vowel framework and the Native Language Magnet model–are invoked as a means of interpreting these findings. Then we present the results of a neurophysiological study which builds on this prior work. Using event-related brain potentials, we first measured and assessed the mismatch negativity response (MMN, a passive neurophysiological index of auditory change detection) in English and French native-speaking adults to synthetic vowels that either spanned two different phonetic categories (/y/vs./u/) or fell within the same category (/u/). Stimulus presentation was organized such that each vowel was presented as standard and as deviant in different blocks. The vowels were presented with a long (1,600-ms) inter-stimulus interval to restrict access to short-term memory traces and tap into a “phonetic mode” of processing. MMN analyses revealed weak asymmetry effects regardless of the (i) vowel contrast, (ii) language group, and (iii) MMN time window. Then, we conducted time-frequency analyses of the standard epochs for each vowel. In contrast to the MMN analysis, time-frequency analysis revealed significant differences in brain oscillations in the theta band (4–8 Hz), which have been linked to attention and processing efficiency. Collectively, these findings suggest that early-latency (pre-attentive) mismatch responses may not be a strong neurophysiological correlate of asymmetric behavioral vowel discrimination. Rather, asymmetries may reflect differences in neural processing efficiency for vowels with certain inherent acoustic-phonetic properties, as revealed by theta oscillatory activity.
Nitric Oxide Regulates GluA2-Lacking AMPAR Contribution to Synaptic Transmission of CA1 Apical but Not Basal Dendrites
Authors: Ivanova Violetta O. , Balaban Pavel M. , Bal Natalia V.
Published: June 2021

The mechanisms of synaptic plasticity differ in distinct local circuits. In the CA1 region of the hippocampus, the mechanisms of long-term potentiation (LTP) at apical dendrites instratum radiatumand basal dendrites instratum oriensinvolve different molecular cascades. For instance, participation of nitric oxide in LTP induction was shown to be necessary only for apical dendrites. This phenomenon may play a key role in information processing in CA1, and one of the reasons for this difference may be differing synaptic characteristics in these regions. Here, we compared the synaptic responses to stimulation of apical and basal dendrites of CA1 pyramidal neurons and found a difference in the current–voltage characteristics of these inputs, which is presumably due to a distinct contribution of GluA2-lacking AMPA receptors to synaptic transmission. In addition, we obtained data that indicate the presence of these receptors in pyramidal dendrites in bothstratum radiatumandstratum oriens. We also demonstrated that inhibition of NO synthase reduced the contribution of GluA2-lacking AMPA receptors at apical but not basal dendrites, and inhibition of soluble guanylate cyclase did not affect this phenomenon.
Striatal Synapse Degeneration and Dysfunction Are Reversed by Reactivation of Wnt Signaling
Authors: Galli Soledad , Stancheva Stefka H. , Dufor Tom , Gibb Alasdair J. , Salinas Patricia C.
Published: June 2021

Synapse degeneration in the striatum has been associated with the early stages of Parkinson’s and Huntington’s diseases (PD and HD). However, the molecular mechanisms that trigger synaptic dysfunction and loss are not fully understood. Increasing evidence suggests that deficiency in Wnt signaling triggers synapse degeneration in the adult brain and that this pathway is affected in neurodegenerative diseases. Here, we demonstrate that endogenous Wnt signaling is essential for the integrity of a subset of inhibitory synapses on striatal medium spiny neurons (MSNs). We found that inducible expression of the specific Wnt antagonist Dickkopf-1 (Dkk1) in the adult striatum leads to the loss of inhibitory synapses on MSNs and affects the synaptic transmission of D2-MSNs. We also discovered that re-activation of the Wnt pathway by turning off Dkk1 expression after substantial loss of synapses resulted in the complete recovery of GABAergic and dopamine synapse number. Our results also show that re-activation of the Wnt pathway leads to a recovery of amphetamine response and motor function. Our studies identify the Wnt signaling pathway as a potential therapeutic target for restoring neuronal circuits after synapse degeneration.
Regression of Castration-Resistant Prostate Cancer by a Novel Compound HG122
Authors: Cong Xiaonan , He Yundong , Wu Haigang , Wang Dingxiang , Liu Yongrui , Shao Ting , Liu Mingyao , Yi Zhengfang , Zheng Jianghua , Peng Shihong , Ding Tao
Published: June 2021

Prostate cancer (PCa) is a common aggressive disease worldwide which usually progresses into incurable castration-resistant prostate cancer (CRPC) in most cases after 18–24 months treatment. Androgen receptor (AR) has been considered as a crucial factor involved in CRPC and the study of AR as a potential therapeutic target in CRPC may be helpful in disease control and life-cycle management. In this study, we identified a potent small molecule compound, HG122, that suppressed CRPC cells proliferation and metastasis, and inhibited tumor growth both in subcutaneous and orthotopic tumor model. In addition, HG122 reduced the mRNA expression of PSA and TMPRSS2 which are target genes of AR, resulting in cell growth inhibition and metastasis suppression of CRPC, without affecting the expression of AR mRNA level. Mechanically, HG122 promoted AR protein degradation through the proteasome pathway impairing the AR signaling pathway. In conclusion, HG122 overcomes enzalutamide (ENZ) resistance in CRPC both in vitro and in vivo, thus suggesting HG122 is a potential candidate for the clinical prevention and treatment of CRPC.
Design and Methodology of a Multicenter Randomized Clinical Trial to Evaluate the Efficacy of Tongmai Jiangtang Capsules in Type 2 Diabetic Coronary Heart Disease Patients
Authors: Wang Yu , Guo Yilei , Lei Ye , Huang Shuwei , Dou Liping , Li Chang , Zhao Buchang , Fu Wei , Zhou Peng , Wan Haitong , Zhao Mingjun , Yang Jiehong
Published: June 2021

Background: Population-based studies have consistently showed an increased incidence of coronary heart disease and cardiac mortality in patients with type 2 diabetes mellitus (T2DM). Tongmai Jiangtang capsules (TJC) are Chinese patent medicines that have been approved in China for the treatment of diabetic vascular complications. However, the evidence supporting the efficacy of Tongmai Jiangtang capsules in type 2 diabetic coronary heart disease (T2DM-CHD) remains unclear. Herein, we designed a randomized, parallel-controlled clinical trial to investigate a new complementary therapy for T2DM-CHD patients.

Methods: A total of 360 T2DM-CHD subjects (aged 18–75 years) will be randomly assigned to the TJC group or the placebo group at a 2:1 ratio. On the basis of western medicine therapy, all the participants will receive TJC or placebo, orally, three capsules/treatment, three per day for 12 weeks. The primary outcomes will be assessed according to the Canadian Cardiovascular Society (CCS) classification. All statistical analyses will be performed setting a two-sided 0.05 significance level, using SAS 9.4 statistical software.

Discussion: The efficacy of TJC for the treatment of T2DM-CHD patients will be evaluated. The study will provide reliable clinical research evidence for application of TJC in treating T2DM-CHD patients.

Clinical Trial Registration:https://www.chictr.org.cn/enIndex.aspx, Chinese Clinical Trial Registry ChiCTR2000037491.
The Combination of Schisandrol B and Wedelolactone Synergistically Reverses Hepatic Fibrosis Via Modulating Multiple Signaling Pathways in Mice
Authors: Ai Yongqiang , Shi Wei , Zuo Xiaobin , Sun Xiaoming , Chen Yuanyuan , Wang Zhilei , Li Ruisheng , Song Xueai , Dai Wenzhang , Mu Wenqing , Ding Kaixin , Li Zhiyong , Li Qiang , Xiao Xiaohe , Zhan Xiaoyan , Bai Zhaofang
Published: June 2021

Hepatic fibrosis represents an important event in the progression of chronic liver injury to cirrhosis, and is characterized by excessive extracellular matrix proteins aggregation. Early fibrosis can be reversed by inhibiting hepatocyte injury, inflammation, or hepatic stellate cells activation, so the development of antifibrotic drugs is important to reduce the incidence of hepatic cirrhosis or even hepatic carcinoma. Here we demonstrate that Schisandrol B (SolB), one of the major active constituents of traditional hepato-protective Chinese medicine, Schisandra sphenanthera, significantly protects against hepatocyte injury, while Wedelolactone (WeD) suppresses the TGF-β1/Smads signaling pathway in hepatic stellate cells (HSCs) and inflammation, the combination of the two reverses hepatic fibrosis in mice and the inhibitory effect of the combination on hepatic fibrosis is superior to that of SolB or WeD treatment alone. Combined pharmacotherapy represents a promising strategy for the prevention and treatment of liver fibrosis.
A Biomechanical Analysis of Muscle Force Changes After Bilateral Sagittal Split Osteotomy
Authors: Pachnicz Dominik , Stróżyk Przemysław
Published: June 2021

A basic procedure affecting maxillofacial geometry is the bilateral sagittal split osteotomy. During the surgery, the bony segments are placed in a new position that provides the correct occlusion. Changes in the geometry of the mandible will affect the surrounding structures and will have a significant impact on the functioning of the masticatory system. As a result of the displacement of the bone segment, the biomechanical conditions change, i.e., the load and the position of the muscles. The primary aim of this study was to determine the changes in the values of the muscular forces caused by mandible geometry alteration. The study considered the translation and rotation of the distal segment, as well as rotations of the proximal segments in three axes. Calculations were performed for the unilateral, static loading of a model based on rigid body mechanics. Muscles were modeled as spring elements, and a novel approach was used to determine muscle stiffness. In addition, an attempt was made, based on the results obtained for single displacements separately, to determine the changes in muscle forces for geometries with complex displacements. Based on the analysis of the results, it was shown that changes in the geometry of the mandibular bone associated with the bilateral sagittal split osteotomy will have a significant effect on the values of the masticatory muscle forces. Displacement of the distal segment has the greatest effect from −21.69 to 26.11%, while the proximal segment rotations affected muscle force values to a less extent, rarely exceeding 1%. For Yaw and Pitch rotations, the opposite effect of changes within one muscle is noticed. Changes in muscle forces for complex geometry changes can be determined with a high degree of accuracy by the appropriate summation of results obtained for simple cases.
Regulation of Skeletal Muscle Satellite Cell Differentiation by Omega-3 Polyunsaturated Fatty Acids: A Critical Review
Authors: Isesele Peter O. , Mazurak Vera C.
Published: June 2021

Skeletal muscle is composed of multinuclear cells called myofibres, which are formed by the fusion of myoblasts during development. The size of the muscle fiber and mass of skeletal muscle are altered in response to several pathological and physiological conditions. Skeletal muscle regeneration is primarily mediated by muscle stem cells called satellite cells (SCs). In response to injury, these SCs replenish myogenic progenitor cells to form new myofibers to repair damaged muscle. During myogenesis, activated SCs proliferate and differentiate to myoblast and then fuse with one another to form muscle fibers. A reduced number of SCs and an inability to undergo myogenesis may contribute to skeletal muscle disorders such as atrophy, cachexia, and sarcopenia. Myogenic regulatory factors (MRF) are transcription factors that regulate myogenesis and determines whether SCs will be in the quiescent, activated, committed, or differentiated state. Mitochondria oxidative phosphorylation and oxidative stress play a role in the determination of the fate of SCs. The potential activation and function of SCs are also affected by inflammation during skeletal muscle regeneration. Omega-3 polyunsaturated fatty acids (PUFAs) show promise to reduce inflammation, maintain muscle mass during aging, and increase the functional capacity of the muscle. The aim of this critical review is to highlight the role of omega-3 PUFAs on the myogenic differentiation of SCs and pathways affected during the differentiation process, including mitochondrial function and inflammation from the current body of literature.