bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Pasture Type on Metabolism, Liver and Kidney Function, Antioxidant Status, and Plant Secondary Compounds in Plasma of Grazing, Jersey Dairy Cattle During Mid-lactation
Authors: Ford Hunter R. , Busato Sebastiano , Trevisi Erminio , Muchiri Ruth N. , van Breemen Richard B. , Bionaz Massimo , Ates Serkan
Published: October 2021

Some pasture species are rich in phytochemicals, able to improve milk yield and quality and to reduce the environmental impacts of livestock farming. The phytochemicals interact with the different gene networks within the animal, such as nuclear factor erythroid 2-related factor 2 (NRF2), but their overall impact on animal health remains to be fully understood. The objective of this study was to identify the effects of pasture Legumes and non-leguminous Forbs containing high bioactive compounds on metabolism and activity of the liver, antioxidant response, kidney function, and inflammation of dairy cows using a large array of blood parameters associated with metabolism and the innate immune system. For this purpose, 26 parameters and the concentration of certain bioactive compounds were assessed in blood plasma, collected from the Jersey cows grazing either Grass, Legume, or Forb-based pastures. In addition, serum collected from all the cows was utilized to detect the changes in NRF2 activation in bovine mammary alveolar cells (MACT) and hepatocytes. Compared with Grass, the cows that grazed both Forb and Legume pastures had lower β-hydroxybutyric acid (BHB) and creatinine and larger vitamin E and the ferric reducing ability of the plasma, supporting an improved antioxidative status for these animals. Compared with both Grass and Legume, the cows that graze Forb pasture had lower urea and urea to creatinine ratio, and lower creatinine, indicating a better kidney function. The cows grazing Legume pasture had greater hematocrit, bilirubin, cholesterol, albumin, β-carotene, retinol, and thiol groups but lower ceruloplasmin, paraoxonase, and myeloperoxidase (MPO) than those grazed Grass and Forb pastures, indicating a positive effect of Legume pasture on the liver, oxidative stress, and red blood cells. The plasma of cows in the various pastures was enriched with various isoflavonoids, especially the cows grazed on Forb and Legume pastures, which likely contributed to improving the antioxidative status of those cows. However, this effect was likely not due to the higher activation of NRF2. Overall, these results indicate that Forb and Legume pastures rich in secondary metabolites do not strongly affect the metabolism but can improve the status of the liver and the kidney and improve the efficiency of N utilization and antioxidant response, compared with the Grass pasture.
A Novel Mitochondrial-Related Nuclear Gene Signature Predicts Overall Survival of Lung Adenocarcinoma Patients
Authors: Zhang Xiangwei , Dong Wei , Zhang Jishuai , Liu Wenqiang , Yin Jingjing , Shi Duozhi , Ma Wei
Published: October 2021

Background: Lung cancer is the leading cause of cancer-related death worldwide, of which lung adenocarcinoma (LUAD) is one of the main histological subtypes. Mitochondria are vital for maintaining the physiological function, and their dysfunction has been found to be correlated with tumorigenesis and disease progression. Although, some mitochondrial-related genes have been found to correlate with the clinical outcomes of multiple tumors solely. The integrated relationship between nuclear mitochondrial genes (NMGs) and the prognosis of LUAD remains unclear.

Methods: The list of NMGs, gene expression data, and related clinical information of LUAD were downloaded from public databases. Bioinformatics methods were used and obtained 18 prognostic related NMGs to construct a risk signature.

Results: There were 18 NMGs (NDUFS2, ATP8A2, SCO1, COX14, COA6, RRM2B, TFAM, DARS2, GARS, YARS2, EFG1, GFM1, MRPL3, MRPL44, ISCU, CABC1, HSPD1, and ETHE1) identified by LASSO regression analysis. The mRNA expression of these 18 genes was positively correlated with their relative linear copy number alteration (CNA). Meanwhile, the established risk signature could effectively distinguish high- and low-risk patients, and its predictive capacity was validated in three independent gene expression omnibus (GEO) cohorts. Notably, a significantly lower prevalence of actionable EGFR alterations was presented in patients with high-risk NMGs signature but accompanied with a more inflame immune tumor microenvironment. Additionally, multicomponent Cox regression analysis showed that the model was stable when risk score, tumor stage, and lymph node stage were considered, and the 1-, 3-, and 5-year AUC were 0.74, 0.75, and 0.70, respectively.

Conclusion: Together, this study established a signature based on NMGs that is a prognostic biomarker for LUAD patients and has the potential to be widely applied in future clinical settings.
Iguratimod Alleviates Myocardial Ischemia/Reperfusion Injury Through Inhibiting Inflammatory Response Induced by Cardiac Fibroblast Pyroptosis via COX2/NLRP3 Signaling Pathway
Authors: Zhang Mian , Lei Yi-shan , Meng Xiao-wen , Liu Hua-yue , Li Lin-gui , Zhang Jun , Zhang Jia-xin , Tao Wen-hui , Peng Ke , Lin Jun , Ji Fu-hai
Published: October 2021

Background: NLRP3 inflammasome contributes a lot to sterile inflammatory response and pyroptosis in ischemia/reperfusion (I/R) injury. Cardiac fibroblasts (CFs) are regarded as semi-professional inflammatory cells and they exert an immunomodulatory role in heart. Iguratimod provides a protective role in several human diseases through exerting a powerful anti-inflammatory effect. However, it is still unclear whether iguratimod could alleviate myocardial I/R injury and whether inflammation triggered by NLRP3-related pyroptosis of CFs is involved in this process.

Methods: Transcriptomics analysis for GSE160516 dataset was conducted to explore the biological function of differentially expressed genes during myocardial I/R. In vivo, mice underwent ligation of left anterior descending coronary artery for 30 min followed by 24 h reperfusion. In vitro, primary CFs were subjected to hypoxia for 1 h followed by reoxygenation for 3 h (H/R). Iguratimod was used prior to I/R or H/R. Myocardial infarct area, serum level of cardiac troponin I (cTnI), pathology of myocardial tissue, cell viability, lactate dehydrogenase (LDH) release, and the expression levels of mRNA and protein for pyroptosis-related molecules were measured. Immunofluorescence was applied to determine the cellular localization of NLRP3 protein in cardiac tissue.

Results: During myocardial I/R, inflammatory response was found to be the most significantly enriched biological process, and nucleotide-binding oligomerization domain (NOD)-like receptor signaling was a crucial pathway in mediating cardiac inflammation. In our experiments, pretreatment with iguratimod significantly ameliorated I/R-induced myocardial injury and H/R-induced pyroptosis of CFs, as evidenced by reduced myocardial infarct area, serum cTnI level, and LDH release in supernatants, as well as improved pathology of cardiac tissue and cell viability. Immunofluorescence analysis showed that NLRP3 was mainly localized in CFs. Moreover, iguratimod inhibited the expression of pro-inflammatory cytokines and pyroptosis-related molecules, including NLRP3, cleaved caspase-1, and GSDMD-N.

Conclusion: Our results suggested that inflammatory response mediated by NOD-like receptor signaling is of vital importance in myocardial I/R injury. Iguratimod protected cardiomyocytes through reducing the cascade of inflammation in heart by inhibiting cardiac fibroblast pyroptosis via the COX2/NLRP3 signaling pathway.
Tumor Suppressor FBXW7 and Its Regulation of DNA Damage Response and Repair
Authors: Lan Huiyin , Sun Yi
Published: October 2021

The proper DNA damage response (DDR) and repair are the central molecular mechanisms for the maintenance of cellular homeostasis and genomic integrity. The abnormality in this process is frequently observed in human cancers, and is an important contributing factor to cancer development. FBXW7 is an F-box protein serving as the substrate recognition component of SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase. By selectively targeting many oncoproteins for proteasome-mediated degradation, FBXW7 acts as a typical tumor suppressor. Recent studies have demonstrated that FBXW7 also plays critical roles in the process of DDR and repair. In this review, we first briefly introduce the processes of protein ubiquitylation by SCFFBXW7 and DDR/repair, then provide an overview of the molecular characteristics of FBXW7. We next discuss how FBXW7 regulates the process of DDR and repair, and its translational implication. Finally, we propose few future perspectives to further elucidate the role of FBXW7 in regulation of a variety of biological processes and tumorigenesis, and to design a number of approaches for FBXW7 reactivation in a subset of human cancers for potential anticancer therapy.
Silylboronate-Mediated Defluorosilylation of Aryl Fluorides with or without Ni-Catalyst
Authors: Zhou Jun , Zhao Zhengyu , Shibata Norio
Published: October 2021

The defluorosilylation of aryl fluorides to access aryl silanes was achieved under transition-metal-free conditions via an inert C–F bond activation. The defluorosilylation, mediated by silylboronates and KOtBu, proceeded smoothly at room temperature to afford various aryl silanes in good yields. Although a comparative experiment indicated that Ni catalyst facilitated this transformation more efficiently, the transition-metal-free protocol is advantageous from a green chemistry perspective.
Synthetic Fluid Inclusions XXIV. In situ Monitoring of the Carbonation of Olivine Under Conditions Relevant to Carbon Capture and Storage Using Synthetic Fluid Inclusion Micro-Reactors: Determination of Reaction Rates
Authors: Sendula Eszter , Lamadrid Héctor M. , Rimstidt J. Donald , Steele-MacInnis Matthew , Sublett D. Matthew , Aradi László E. , Szabó Csaba , Caddick Mark J. , Zajacz Zoltán , Bodnar Robert J.
Published: October 2021

Ultramafic and mafic rocks are possible targets for CO2 sequestration via mineral carbonation. The determination of reaction kinetics and the factors that control mineralization are important in order to understand and predict how fast injected CO2 will react with host rocks to permanently isolate and store the carbon. Here we present experimental results of olivine carbonation experiments using synthetic fluid inclusions (SFI) as micro-reactors. The micro-reactor technique coupled with non-destructive Raman spectroscopy allows us to monitor the reaction progress in situ and in real time at elevated temperatures (50–200°C) and pressures (several 10's to a few hundred bars), and quantify the amount of CO2 consumed in the reaction using the Raman CO2 densimeter and mass-balance calculations. Results show a measurable decrease of CO2 density in the fluid inclusions as a result of the reaction between the CO2-bearing seawater-like aqueous solution and olivine. Magnesite formation was observed within hours at ≥100°C, while at 50°C magnesite nucleation and precipitation was only observed after a few weeks. Raman mapping and FIB-SEM analysis confirmed the formation of a non-continuous Si-rich layer on the inclusion wall and the presence of ferroan magnesite as a reaction product. Reaction rates [log J (mol/m−2 s−1)] obtained for olivine carbonation range between ~-8.4 at 50°C and −4.7 at 200°C, which is sufficiently rapid to be suitable for commercial CO2 injection projects. Reaction rates involving a seawater-like fluid were similar to rates published for high salinity solutions containing NaHCO3, and were faster compared to rates involving solutions with low salinity. Thus, CO2 injection into submarine environments might offer some advantages over CO2 storage in onshore basalts where the pores are likely to be filled with low salinity meteoric water. The application of the synthetic fluid inclusion technique, combined with non-destructive analytical techniques, is a promising tool to monitor rates of fluid-rock reactions in situ and in real time. Here, we have documented its application to experimentally study carbonation reactions in the olivine-H2O-CO2-NaCl-MgCl2 system.
EMbedding and Backscattered Scanning Electron Microscopy: A Detailed Protocol for the Whole-Specimen, High-Resolution Analysis of Cardiovascular Tissues
Authors: Mukhamadiyarov Rinat A. , Bogdanov Leo A. , Glushkova Tatiana V. , Shishkova Daria K. , Kostyunin Alexander E. , Koshelev Vladislav A. , Shabaev Amin R. , Frolov Alexey V. , Stasev Alexander N. , Lyapin Anton A. , Kutikhin Anton G.
Published: October 2021

Currently, an ultrastructural analysis of cardiovascular tissues is significantly complicated. Routine histopathological examinations and immunohistochemical staining suffer from a relatively low resolution of light microscopy, whereas the fluorescence imaging of plaques and bioprosthetic heart valves yields considerable background noise from the convoluted extracellular matrix that often results in a low signal-to-noise ratio. Besides, the sectioning of calcified or stent-expanded blood vessels or mineralised heart valves leads to a critical loss of their integrity, demanding other methods to be developed. Here, we designed a conceptually novel approach that combines conventional formalin fixation, sequential incubation in heavy metal solutions (osmium tetroxide, uranyl acetate or lanthanides, and lead citrate), and the embedding of the whole specimen into epoxy resin to retain its integrity while accessing the region of interest by grinding and polishing. Upon carbon sputtering, the sample is visualised by means of backscattered scanning electron microscopy. The technique fully preserves calcified and stent-expanded tissues, permits a detailed analysis of vascular and valvular composition and architecture, enables discrimination between multiple cell types (including endothelial cells, vascular smooth muscle cells, fibroblasts, adipocytes, mast cells, foam cells, foreign-body giant cells, canonical macrophages, neutrophils, and lymphocytes) and microvascular identities (arterioles, venules, and capillaries), and gives a technical possibility for quantitating the number, area, and density of the blood vessels. Hence, we suggest that our approach is capable of providing a pathophysiological insight into cardiovascular disease development. The protocol does not require specific expertise and can be employed in virtually any laboratory that has a scanning electron microscope.
Geochronology and Petrogenesis of Early Pleistocene Dikes in the Changbai Mountain Volcanic Field (NE China) Based on Geochemistry and Sr-Nd-Pb-Hf Isotopic Compositions
Authors: Li Meng-Meng , Xu Zhi-Tao , Ventura Guido , Pan Xiao-Dong , Han Di , Gu Guo-Hui , Yan Dong-Han , Pan Bo , Feng Jing-Qiao
Published: October 2021

Changbai Mountains intraplate volcanism (NE China) developed above the 500 km deep stagnant portion of the Pacific slab in the last 20 Ma. The more recent activity includes a shield-forming stage (2.8–0.3 Ma), the Tianchi cone construction stage (1.5–0.01 Ma), and a caldera-forming stage (0.2 Ma-present). Detailed studies on the petrogenesis of the volcanic products between the first two stages and the possible role of geodynamics and local tectonics in controlling the volcanism, however, are lacking. Here, we present structural and whole-rock geochemical and zircon Hf isotopic data on Pleistocene dikes of the Changbai Mountains at the transition from the shield-forming to the Tianchi stage with the aim to constrain their age and the source(s) of their parental magma. The dikes represent the shallower feeding system of monogenetic cones and have a NW-SE strike, which is also the preferred strike of the major fault affecting the area and along which the Changbai Mountains monogenetic scoria cones align. The dikes have a potassic affinity and a trachybasaltic composition. Their zircon U–Pb age is 1.19–1.20 Ma (Calabrian). The trachybasalts are enriched in Rb, Ba, Th, U, Nb, Ta, K, Pb, and LREE and slightly depleted in Sr, Zr, Hf, Ti, and HREE with a weak negative Eu/Eu* (δEu = 0.96–0.97). Trace elements and isotopic compositions are compatible with an OIB-type source with an EMI signature. The calculated (87Sr/86Sr)i(=0.705165–0.705324), (143Nd/144Nd)i(= 0.512552–0.512607, εNd(t) = −0.58 to −1.65), and Hf model ages (TDM2) of 1768–1562 Ma suggest that the trachybasaltic dikes were contaminated by a Mesoproterozoic, relatively basic lower crust. The source of the Calabrian trachybasalts consists of asthenospheric melts modified by a subcontinental lithospheric mantle. These melts upwell from depth and stop at the crust-mantle interface where underplating processes favor the assimilation of ancient lower crust material. During the ascent to the surface along deep-seated crustal discontinuities, these magmas weakly differentiate.
Functional Characterization of the Internal Symmetry of MRAP2 Antiparallel Homodimer
Authors: Wang Meng , Pi Linyu , Lei Xiaowei , Li Lei , Xu Jing , Kuang Zhe , Zhang Cong , Li Liang , Zhang Chao
Published: October 2021

The melanocortin receptors are defined as a series of vital pharmaceutical targets to regulate neuronal appetite and maintain controllable body weight for mammals and teleosts. Melanocortin receptor accessory protein 2 (MRAP2) functions as an essential accessory player that modulates the surface translocation and binding to a variety of endogenous or synthetic hormones of central melanocortin-4 receptor (MC4R) signaling. MRAP2 is a single-transmembrane protein and could form a functional symmetric antiparallel homodimer topology. Here, we inverted the N-terminal, transmembrane, and C-terminal domains and generated six distinct conformational variants of the mouse MRAP2 to explore the functional orientations and the internal symmetry of MRAP2 dimers. These remolded MRAP2 mutants showed proper assembly of the antiparallel homodimer and binding to the MC4R, but slightly altered the regulatory profile on the surface expression and the ligand-stimulated cAMP cascades of MC4R. This study elucidated the importance of the orientation of each domain of the single-transmembrane protein and revealed the pharmacological properties of the internal symmetry of the antiparallel homodimer for MRAP2.
Adaptive Droop Control of the MTDC System With High-Capacity Energy Storage Based on Dynamic and Static Power Decoupling Method
Authors: Xie Luyao , Guo Xin , Wei Chun , Zhang Youbing , Chen Yi , Liang Congbin , Xue Yuantian , Zhao Ermin
Published: October 2021

In a multiterminal DC (MTDC) system with a large number of different types of energy storage devices, the AC terminals and the energy storage devices need to cooperate to maintain the stability of the DC bus voltage. Due to the difference in the dynamic and static power capability of each energy storage unit, the dynamic and static power should be distributed separately. To solve the above problems, an adaptive droop control strategy based on the dynamic and static power decoupling is proposed in this paper. The impact of the virtual impedance values on the dynamic and static power flows between the DC voltage regulating terminals operating with the RC droop method is analyzed. Through optimized virtual capacitance and adaptive virtual resistance, the dynamic power and static power can be distributed according to the PCS capacity and the available charge–discharge battery capacity, respectively. In addition, a simple secondary control method is adopted to compensate the static deviation of the DC bus voltage. Finally, a six-terminal MTDC system model is established in Matlab/Simulink, and the simulation results verify the feasibility and effectiveness of the proposed control strategy.
Effects of Soil Heterogeneity and Species on Plant Interactions
Authors: Li Guoe , Wang Mingxia , Ma Chunyan , Tao Rui , Hou Fujiang , Liu Yongjie
Published: October 2021

Plant interactions are central in driving the composition and structure of plant populations and communities. Soil heterogeneity and species identity can modulate such interactions, yet require more studies. Thus, a manipulative experiment was done where three soil heterogeneity levels were developed by mixing local soil and sand in three different ratios (i.e., soil:sand ratio = 2:8, 5:5, and 8:2), and three typical species (i.e., Festuca elata, Bromus inermis, and Elymus breviaristatus) were used in different combinations. Soil heterogeneity was assumed to affect plant interactions, which were in turn modified by species. Plant height was applied as an indicator for plant interactions. Relative competition intensity (RCI) was used to quantify plant interactions, where RCI was applied as a ratio of monoculture and mixture performance. Results showed that soil heterogeneity and soil heterogeneity × species significantly affected the RCI in mixtures compared with plant individuals growing alone (i.e., RCI1). However, species as a single factor did not affect RCI1. Moreover, species and soil heterogeneity × species significantly affected the RCI in mixtures compared with two individuals growing together (i.e., RCI2), and the difference between RCI1 and RCI2 (i.e., RCIdiff). Soil heterogeneity significantly affected RCI2 of F. elata. This study suggests that soil heterogeneity could buffer the stability of plant populations by modifying plant interactions, which would subsequently drive plant establishment. To explore the underlying mechanisms of such patterns, further studies considering more species and plant traits are needed.
Prioritisation of Candidate Genes Underpinning COVID-19 Host Genetic Traits Based on High-Resolution 3D Chromosomal Topology
Authors: Thiecke Michiel J. , Yang Emma J. , Burren Oliver S. , Ray-Jones Helen , Spivakov Mikhail
Published: October 2021

Genetic variants showing associations with specific biological traits and diseases detected by genome-wide association studies (GWAS) commonly map to non-coding DNA regulatory regions. Many of these regions are located considerable distances away from the genes they regulate and come into their proximity through 3D chromosomal interactions. We previously developed COGS, a statistical pipeline for linking GWAS variants with their putative target genes based on 3D chromosomal interaction data arising from high-resolution assays such as Promoter Capture Hi-C (PCHi-C). Here, we applied COGS to COVID-19 Host Genetic Consortium (HGI) GWAS meta-analysis data on COVID-19 susceptibility and severity using our previously generated PCHi-C results in 17 human primary cell types and SARS-CoV-2-infected lung carcinoma cells. We prioritise 251 genes putatively associated with these traits, including 16 out of 47 genes highlighted by the GWAS meta-analysis authors. The prioritised genes are expressed in a broad array of tissues, including, but not limited to, blood and brain cells, and are enriched for genes involved in the inflammatory response to viral infection. Our prioritised genes and pathways, in conjunction with results from other prioritisation approaches and targeted validation experiments, will aid in the understanding of COVID-19 pathology, paving the way for novel treatments.
Building a Mammalian Retina: An Eye on Chromatin Structure
Authors: Daghsni Marwa , Aldiri Issam
Published: October 2021

Regulation of gene expression by chromatin structure has been under intensive investigation, establishing nuclear organization and genome architecture as a potent and effective means of regulating developmental processes. The substantial growth in our knowledge of the molecular mechanisms underlying retinogenesis has been powered by several genome-wide based tools that mapped chromatin organization at multiple cellular and biochemical levels. Studies profiling the retinal epigenome and transcriptome have allowed the systematic annotation of putative cis-regulatory elements associated with transcriptional programs that drive retinal neural differentiation, laying the groundwork to understand spatiotemporal retinal gene regulation at a mechanistic level. In this review, we outline recent advances in our understanding of the chromatin architecture in the mammalian retina during development and disease. We focus on the emerging roles of non-coding regulatory elements in controlling retinal cell-type specific transcriptional programs, and discuss potential implications in untangling the etiology of eye-related disorders.
Elevated Terminal C5b-9 Complement Complex 10 Weeks Post Kidney Transplantation Was Associated With Reduced Long-Term Patient and Kidney Graft Survival
Authors: Witczak Bartlomiej J. , Pischke Søren E. , Reisæter Anna V. , Midtvedt Karsten , Ludviksen Judith K. , Heldal Kristian , Jenssen Trond , Hartmann Anders , Åsberg Anders , Mollnes Tom E.
Published: October 2021

Background

The major reason for graft loss is chronic tissue damage, as interstitial fibrosis and tubular atrophy (IF/TA), where complement activation may serve as a mediator. The association of complement activation in a stable phase early after kidney transplantation with long-term outcomes is unexplored.

Methods

We examined plasma terminal C5b-9 complement complex (TCC) 10 weeks posttransplant in 900 patients receiving a kidney between 2007 and 2012. Clinical outcomes were assessed after a median observation time of 9.3 years [interquartile range (IQR) 7.5–10.6].

Results

Elevated TCC plasma values (≥0.7 CAU/ml) were present in 138 patients (15.3%) and associated with a lower 10-year patient survival rate (65.7% vs. 75.5%, P < 0.003). Similarly, 10-year graft survival was lower with elevated TCC; 56.9% vs. 67.3% (P < 0.002). Graft survival was also lower when censored for death; 81.5% vs. 87.3% (P = 0.04). In multivariable Cox analyses, impaired patient survival was significantly associated with elevated TCC [hazard ratio (HR) 1.40 (1.02–1.91), P = 0.04] along with male sex, recipient and donor age, smoking, diabetes, and overall survival more than 1 year in renal replacement therapy prior to engraftment. Likewise, elevated TCC was independently associated with graft loss [HR 1.40 (1.06–1.85), P = 0.02] along with the same covariates. Finally, elevated TCC was in addition independently associated with death-censored graft loss [HR 1.69 (1.06–2.71), P = 0.03] as were also HLA-DR mismatches and higher immunological risk.

Conclusions

Early complement activation, assessed by plasma TCC, was associated with impaired long-term patient and graft survival.
Broadband Bidirectional and Multi-Channel Unidirectional Acoustic Insulation by Mode-Conversion Phased Units
Authors: Chen Jia-he , Qian Jiao , Guan Yi-jun , Ge Yong , Yuan Shou-qi , Sun Hong-xiang , Lai Yun , Liu Xiao-jun
Published: October 2021

The technique of sound insulation has a wide range of potential applications in environment noise control and architectural acoustics. The rapid development of acoustic artificial materials has provided alternative solutions to design sound insulation structures. However, the realization of single-layer planar structures with bidirectional acoustic insulation (BAI) and unidirectional acoustic insulation (UAI) still poses a challenge. Here, we report the theoretical and experimental realization of two types of single-layer phased array lenses which presents the characteristics of broadband BAI and multi-channel UAI. Both types of lenses consist of 12 mode-conversion phased units which are composed of two types of unit cells (I and II) with an opposite phase and a step waveguide. Based on the phase regulation, the designed phased unit can realize the mode conversion between the zero-order and first-order waves and asymmetric sound manipulation, which enables multi-functional sound insulations. Based on the desired theoretical phase profiles, two types of lenses with BAI and UAI are realized for the incidence of the zero-order wave, and their fractional bandwidths can reach about 0.28 and 0.37, respectively. More interestingly, the UAI effect can be reversed for the incidence of the first-order wave. The proposed lenses based on the mode-conversion phased units have the advantages of single-layer planar structure, multi-functional sound insulation, and broad bandwidth, which have wide application prospect.
Dose-Sparing Intradermal DTaP-sIPV Immunization With a Hollow Microneedle Leads to Superior Immune Responses
Authors: Zuo Weilun , Li Jingyan , Jiang Wenwen , Zhang Mengyao , Ma Yan , Gu Qin , Wang Xiaoyu , Cai Lukui , Shi Li , Sun Mingbo
Published: October 2021

Dose-sparing intradermal (ID) vaccination may induce the same immune responses as intramuscular (IM) vaccination, which can increase vaccine supplies and save costs. In this study, rats were immunized with fractional-dose of Sabin-derived IPV combined with diphtheria-tetanus-acellular pertussis vaccine (DTaP-sIPV) intradermally with hollow microneedle devices called MicronJet600 and the vaccine immunogenicity and efficacy were evaluated and compared with those of full-dose intramuscular immunization. We tested levels of antibodies and the subclass distribution achieved via different immunization routes. Furthermore, gene transcription in the lung and spleen, cytokine levels and protection against Bordetella pertussis (B. pertussis) infection were also examined. The humoral immune effect of DTaP-sIPV delivered with MicronJet600 revealed that this approach had a significant dose-sparing effect and induced more effective protection against B. pertussis infection by causing Th1/Th17 responses. In conclusion, ID immunization of DTaP-sIPV with the MicronJet600 is a better choice than IM immunization, and it has the potential to be a new DTaP-sIPV vaccination strategy.
FMRP-Driven Neuropathology in Autistic Spectrum Disorder and Alzheimer's disease: A Losing Game
Authors: Bleuzé Louis , Triaca Viviana , Borreca Antonella
Published: October 2021

Fragile X mental retardation protein (FMRP) is an RNA binding protein (RBP) whose absence is essentially associated to Fragile X Syndrome (FXS). As an RNA Binding Protein (RBP), FMRP is able to bind and recognize different RNA structures and the control of specific mRNAs is important for neuronal synaptic plasticity. Perturbations of this pathway have been associated with the autistic spectrum. One of the FMRP partners is the APP mRNA, the main protagonist of Alzheimer’s disease (AD), thereby regulating its protein level and metabolism. Therefore FMRP is associated to two neurodevelopmental and age-related degenerative conditions, respectively FXS and AD. Although these pathologies are characterized by different features, they have been reported to share a number of common molecular and cellular players. The aim of this review is to describe the double-edged sword of FMRP in autism and AD, possibly allowing the elucidation of key shared underlying mechanisms and neuronal circuits. As an RBP, FMRP is able to regulate APP expression promoting the production of amyloidβfragments. Indeed, FXS patients show an increase of amyloidβload, typical of other neurological disorders, such as AD, Down syndrome, Parkinson’s Disease, etc. Beyond APP dysmetabolism, the two neurodegenerative conditions share molecular targets, brain circuits and related cognitive deficits. In this review, we will point out the potential common neuropathological pattern which needs to be addressed and we will hopefully contribute to clarifying the complex phenotype of these two neurorological disorders, in order to pave the way for a novel, common disease-modifying therapy.
A Novel Imaging Biomarker for Cerebral Small Vessel Disease Associated With Cognitive Impairment: The Deep-Medullary-Veins Score
Authors: Xu Zhihua , Li Fangfei , Xing Dengxiang , Song Hongyan , Chen Jingshu , Duan Yang , Yang Benqiang
Published: October 2021

Objective: To explore the biomarkers of cerebral small vessel disease (CSVD) associated with cognitive impairment.

Methods: A total of 69 patients with CSVD were enrolled in the study, and baseline clinical and imaging data were reviewed retrospectively. The following neuroimaging biomarkers of CSVD were identified: high-grade white matter hyperintensity (HWMH), cerebral microbleeds (CMB), enlarged perivascular space (PVS), and lacunar infarct (LI). A total score for CSVD was calculated. The deep medullary veins (DMVs) were divided into six segments according to the regional anatomy. The total DMV score (0–18) was derived from the sum of the scores of the six individual segments, the scores of which ranged from 0 to 3, for a semiquantitative assessment of the DMV that was based on segmental continuity and visibility.

Results: The DMV score, patient age, and total CSVD score were independently associated with the presence or absence of cognitive impairment in patients with CSVD (P < 0.05). By integrating patient age and the total CSVD and DMV scores, the area under the curve of the receiver operating characteristic curve (AUROC) for predicting CSVD associated with cognitive impairment was 0.885, and the sensitivity and specificity were 64.71 and 94.23%, respectively.

Conclusions: The DMV score may be a novel imaging biomarker for CSVD associated with cognitive impairment. The integration of the DMV score with age and total CSVD score should increase the predictive value of the DMV score for CSVD associated with cognitive impairment.
Bioluminescent Multi-Characteristic Opsin for Simultaneous Optical Stimulation and Continuous Monitoring of Cortical Activities
Authors: Narcisse Darryl , Mustafi Sourajit Mitra , Carlson Michael , Batabyal Subrata , Kim Sanghoon , Wright Weldon , Kumar Mohanty Samarendra
Published: October 2021

Stimulation and continuous monitoring of neural activities at cellular resolution are required for the understanding of the sensory processing of stimuli and development of effective neuromodulation therapies. We present bioluminescence multi-characteristic opsin (bMCOII), a hybrid optogenetic actuator, and a bioluminescence Ca2+ sensor for excitation-free, continuous monitoring of neural activities in the visual cortex, with high spatiotemporal resolution. An exceptionally low intensity (10 μW/mm2) of light could elicit neural activation that could be detected by Ca2+ bioluminescence imaging. An uninterrupted (>14 h) recording of visually evoked neural activities in the cortex of mice enabled the determination of strength of sensory activation. Furthermore, an artificial intelligence-based neural activation parameter transformed Ca2+ bioluminescence signals to network activity patterns. During continuous Ca2+-bioluminescence recordings, visual cortical activity peaked at the seventh to eighth hour of anesthesia, coinciding with circadian rhythm. For both direct optogenetic stimulation in cortical slices and visually evoked activities in the visual cortex, we observed secondary delayed Ca2+-bioluminescence responses, suggesting the involvement of neuron-astrocyte-neuron pathway. Our approach will enable the development of a modular and scalable interface system capable of serving a multiplicity of applications to modulate and monitor large-scale activities in the brain.
Outcome of Wingspan Stent Using Aggressive Post-stent Balloon Dilation for Intracranial Atherosclerosis Stenosis
Authors: Perng Pang-Shuo , Sun Yuan-Ting , Wang Hao-Kuang , Shih Yu-Hsiang , Lee Jung-Shun , Wang Liang-Chao , Huang Chih-Yuan
Published: October 2021

Background: Wingspan stent has gained interest for better long-term outcomes for intracranial atherosclerosis disease (ICAD). However, in-stent restenosis still presents as a problem and may cause postoperative neurological events. We aimed to find a way to prevent in-stent restenosis.

Method: Patients with stenosis >70% ICAD were treated with wingspan stent and were retrospectively reviewed. The patients were separated into two groups: one with post-dilation and the other without post-dilation. The outcomes of wingspan stenting were compared immediately after the surgery and at a 1-year follow-up.

Results: Overall, 28 patients were included for analysis, with 15 patients undergoing post-dilation and 13 patients not undergoing the procedure. The extent of stenosis was significantly lower in the post-dilation group than in the no post-dilation group, both immediately after the surgery (14.8 ± 10.2 vs. 28.5 ± 14.5%, p < 0.01) and at 1-year follow-up (25.8 ± 18.0 vs. 50.1 ± 23.2%, p < 0.01). The post-dilation method immediately expanded the stent diameter (2.89 ± 0.48 vs. 3.05 ± 0.44 mm, p < 0.001), and the diameter still increased at 1-year follow-up (3.05 ± 0.44 vs. 3.12 ± 0.43 mm, p < 0.01) due to the self-expandable property of the wingspan. Similarly, in the no post-dilation group, the stent size was also increased (2.70 ± 0.67 vs. 2.80 ± 0.64 mm, p < 0.01). However, at 1-year follow up, the luminal diameter was stationary in the post-dilation group (2.36 ± 0.73 vs. 2.46 ± 0.82 mm, p = 0.88) and decreased in the no post-dilation group (2.24 ± 0.56 vs. 1.60 ± 0.79 mm, p < 0.01). The periprocedural complication rate was similar between the groups.

Conclusion: The post-dilation method can be feasibly performed and can offer better stent expansion and apposition in the wingspan system. By applying this technique, we might prevent in-stent restenosis and improve neurological outcomes.
Optimal Course of Statins for Patients With Aneurysmal Subarachnoid Hemorrhage: Is Longer Treatment Better? A Meta-Analysis of Randomized Controlled Trials
Authors: Liu Tao , Zhong Shiyu , Zhai Qingqing , Zhang Xudong , Jing Huiquan , Li Kunhang , Liu Shengyu , Han Shuo , Li Lishuai , Shi Xin , Bao Yijun
Published: October 2021

Statins are used in clinical practice to prevent from complications such as cerebral vasospasm (CVS) after aneurysmal subarachnoid hemorrhage (aSAH). However, the efficacy and safety of statins are still controversial due to insufficient evidence from randomized controlled trials and inconsistent results of the existing studies. This meta-analysis aimed to systematically review the latest evidence on the time window and complications of statins in aSAH. The randomized controlled trials in the databases of The Cochrane Library, PubMed, Web of Science, Embase, CNKI, and Wanfang from January 2005 to April 2021 were searched and analyzed systematically. Data analysis was performed using Stata version 16.0. The fixed-effects model (M-H method) with effect size risk ratio (RR) was used for subgroups with homogeneity, and the random-effects model (D-L method) with effect size odds ratio (OR) was used for subgroups with heterogeneity. The primary outcomes were poor neurological prognosis and all-cause mortality, and the secondary outcomes were cerebral vasospasm (CVS) and statin-related complications. This study was registered with PROSPERO (International Prospective Register of Systematic Reviews; CRD42021247376). Nine studies comprising 1,464 patients were included. The Jadad score of the patients was 5–7. Meta-analysis showed that poor neurological prognosis was reduced in patients who took oral statins for 14 days (RR, 0.73 [0.55–0.97]; I2 = 0%). Surprisingly, the continuous use of statins for 21 days had no significant effect on neurological prognosis (RR, 1.04 [0.89–1.23]; I2 = 17%). Statins reduced CVS (OR, 0.51 [0.36–0.71]; I2 = 0%) but increased bacteremia (OR, 1.38 [1.01–1.89]; I2 = 0%). In conclusion, a short treatment course of statins over 2 weeks may improve neurological prognosis. Statins were associated with reduced CVS. Based on the pathophysiological characteristics of CVS and the evaluation of prognosis, 2 weeks could be the optimal time window for statin treatment in aSAH, although bacteremia may increase.
TDP-43 and ER Stress in Neurodegeneration: Friends or Foes?
Authors: de Mena Lorena , Lopez-Scarim Joshua , Rincon-Limas Diego E.
Published: October 2021

Nuclear depletion, abnormal modification, and cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43) are linked to a group of fatal neurodegenerative diseases called TDP-43 proteinopathies, which include amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Although our understanding of the physiological function of TDP-43 is rapidly advancing, the molecular mechanisms associated with its pathogenesis remain poorly understood. Accumulating evidence suggests that endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are important players in TDP-43 pathology. However, while neurons derived from autopsied ALS and FTLD patients revealed TDP-43 deposits in the ER and displayed UPR activation, data originated from in vitro and in vivo TDP-43 models produced contradictory results. In this review, we will explore the complex interplay between TDP-43 pathology, ER stress, and the UPR by breaking down the evidence available in the literature and addressing the reasons behind these discrepancies. We also highlight underexplored areas and key unanswered questions in the field. A better synchronization and integration of methodologies, models, and mechanistic pathways will be crucial to discover the true nature of the TDP-43 and ER stress relationship and, ultimately, to uncover the full therapeutic potential of the UPR.
Short-Term Outcomes of Single-Incision Laparoscopic Surgery for Colorectal Cancer: A Single-Center, Open-Label, Non-Inferiority, Randomized Clinical Trial
Authors: Song Zijia , Liu Kun , Li You , Shi Yiqing , Jiang Yimei , Wang Changgang , Chen Xianze , Zhang Tao , Ji Xiaopin , Zhao Ren
Published: October 2021

Objective

To date, well-designed randomized controlled trials examining the safety, efficacy, and long-term outcomes of single-incision laparoscopic surgery (SILS) for colorectal cancer are scarce. The aim of the current study was to compare short-term outcomes of SILS for colorectal cancer with conventional laparoscopic surgery (CLS).

Methods

Between June 28, 2017, and June 29, 2019, a single-center, open-label, non-inferiority, randomized clinical trial was conducted at the Department of General Surgery, Ruijin Hospital (North), Shanghai Jiaotong University School of Medicine in Shanghai, China. In total, 200 patients diagnosed or suspected of colorectal cancer (cT1–4aN0–2M0) were randomly assigned to either the SILS or CLS group in a 1:1 ratio. The primary outcome was early morbidity rate. Secondary outcomes included intraoperative outcomes, pain intensity, postoperative recovery, pathologic outcomes, and long-term outcomes.

Results

In total, 193 participants (SILS, 97; CLS, 96) were analyzed in the modified intention-to-treat (MITT) population. Among them, 48 underwent right hemicolectomy (SILS n = 23, 23.7% and MLS n = 25, 26%), 15 underwent left hemicolectomy (SILS n = 6, 6.2% and MLS n = 9, 9.4%), 1 underwent transverse colectomy (MLS n = 1, 1%), 57 underwent sigmoidectomy (SILS n = 32, 33% and MLS n = 25, 26%), and 72 underwent anterior resection (SILS n = 36, 37.1% and MLS n = 36, 37.5%). No significant differences were observed in the baseline characteristics. The intraoperative complication was comparable between the two groups [5 (5.2%) vs. 4 (4.2%); difference, 1%; 95% CI, −5.8% to 7.8%; p > 0.999) and so was postoperative complication rates [10 (10.3%) vs. 14 (14.6%); difference, −4.3%; 95% CI, −13.9% to 5.3%; p = 0.392]. The SILS group showed shorter incision length [median (IQR), 4 (3.5–5) vs. 6.6 (6–7.5), p < 0.001] and lower VAS scores on the first [median (IQR), 4 (3–5) vs. 4 (4–5), p = 0.002] and the second day [median (IQR), 2 (1.5–3) vs. 3 (2–4), p < 0.001] after surgery. No statistically significant difference was found in other measured outcomes.

Conclusions

Compared with CLS, SILS performed by experienced surgeons for selected colorectal cancer patients is non-inferior with good short-term safety and has the advantage of reducing postoperative pain.

Clinical Trial Registration

ClinicalTrials.gov, identifier NCT03151733.
Candida Glabrata Lymphadenitis Following Infliximab Therapy for Inflammatory Bowel Disease in a Patient With Chronic Granulomatous Disease: Case Report and Literature Review
Authors: Lehman Heather Kristin , Davé Rahool
Published: October 2021

Chronic granulomatous disease (CGD) is an inborn error of immunity caused by inactivating genetic mutations in any one of the components of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Phagocytic cell reactive oxygen species generation is impaired in the absence of a functional NADPH oxidase complex. As a result, patients with CGD are at high risk of developing deep-seated infections with certain bacteria and fungi. Additionally, aberrant inflammation and granuloma formation may occur in multiple organs including the bowels, with inflammatory bowel disease seen as a common inflammatory complication of CGD. Traditionally, TNF-α inhibitors are considered effective biological therapies for moderate-to-severe inflammatory bowel disease. While limited case series and reports of patients with CGD have shown improvement in fistula healing with use of TNF-α inhibitors, several patients have developed severe, even fatal, infections with CGD-related pathogens while on TNF-inhibitor therapy. In this case report, we describe an adolescent male with X-linked CGD and steroid-refractory colitis with perirectal fistula and abscesses, who was initiated on treatment with infliximab, a TNF-α inhibitor. Following his first two infliximab doses, the patient developed a Candida glabrata lymphadenitis and associated ulcerating oropharyngeal lesions, requiring hospitalization and therapy with amphotericin B for resolution. We compare our patient's case to prior reports of infliximab use in CGD-related inflammatory bowel disease.
Exploring Multifunctional Bioactive Components from Podophyllum sinense Using Multi-Target Ultrafiltration
Authors: Feng Huixia , Chen Guilin , Zhang Yongli , Guo Mingquan
Published: October 2021

Podophyllum sinense(P. sinense) has been used as a traditional herbal medicine for ages due to its extensive pharmaceutical activities, including antiproliferative, anti-inflammatory, antiviral, insecticidal effects, etc. Nevertheless, the specific bioactive constituents responsible for its antiproliferative, anti-inflammatory, and antiviral activities remain elusive, owing to its complicated and diversified chemical components. In order to explore these specific bioactive components and their potential interaction targets, affinity ultrafiltration with multiple drug targets coupled with high performance liquid chromatography/mass spectrometry (UF–HPLC/MS) strategy was developed to rapidly screen out and identify bioactive compounds against four well-known drug targets that are correlated to the application ofP. sinenseas a traditional medicine, namely, Topo I, Topo II, COX-2, and ACE2. As a result, 7, 10, 6, and 7 phytochemicals were screened out as the potential Topo I, Topo II, COX-2, and ACE2 ligands, respectively. Further confirmation of these potential bioactive components with antiproliferative and COX-2 inhibitory assaysin vitrowas also implemented. Herein, diphyllin and podophyllotoxin with higher EF values demonstrated higher inhibitory rates against A549 and HT-29 cells as compared with those of 5-FU and etoposide. The IC50values of diphyllin were calculated at 6.46 ± 1.79 and 30.73 ± 0.56 μM on A549 and HT-29 cells, respectively. Moreover, diphyllin exhibited good COX-2 inhibitory activity with the IC50value at 1.29 ± 0.14 μM, whereas indomethacin was 1.22 ± 0.08 μM. In addition, those representative constituents with good affinity on Topo I, Topo II, COX-2, or ACE2, such as diphyllin, podophyllotoxin, and diphyllinO-glucoside, were further validated with molecular docking analysis. Above all, the integrated method of UF–HPLC/MS with multiple drug targets rapidly singled out multi-target bioactive components and partly elucidated their action mechanisms regarding its multiple pharmacological effects fromP. sinense, which could provide valuable information about its further development for the new multi-target drug discovery from natural medicines.