Publications by authors named "Fan Fan"

353 Publications

Piezo2 mechanosensitive ion channel is located to sensory neurons and nonneuronal cells in rat peripheral sensory pathway: implications in pain.

Pain 2021 Jun 17. Epub 2021 Jun 17.

Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, United States Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, United States Department of Pharmacology and Toxicology, Mississippi University Medical Center, Jackson, MS, United States Zablocki Veterans Affairs Medical Center, Milwaukee, WI, United States.

Abstract: Piezo2 mechanotransduction channel is a crucial mediator of sensory neurons for sensing and transducing touch, vibration, and proprioception. We here characterized Piezo2 expression and cell specificity in rat peripheral sensory pathway using a validated Piezo2 antibody. Immunohistochemistry using this antibody revealed Piezo2 expression in pan primary sensory neurons of dorsal root ganglia in naïve rats, which was actively transported along afferent axons to both central presynaptic terminals innervating the spinal dorsal horn (DH) and peripheral afferent terminals in the skin. Piezo2 immunoreactivity (IR) was also detected in the postsynaptic neurons of the DH and in the motor neurons of the ventral horn, but not in spinal glial fibrillary acidic protein-positive and Iba1-positive glia. Notably, Piezo2-IR was clearly identified in peripheral nonneuronal cells, including perineuronal glia, Schwann cells in the sciatic nerve and surrounding cutaneous afferent endings, as well as in skin epidermal Merkel cells and melanocytes. Immunoblots showed increased Piezo2 in dorsal root ganglia ipsilateral to plantar injection of complete Freund's adjuvant, and immunostaining revealed increased Piezo2-IR intensity in the DH ipsilateral to complete Freund's adjuvant injection. This elevation of DH Piezo2-IR was also evident in various neuropathic pain models and monosodium iodoacetate knee osteoarthritis pain model, compared with controls. We conclude that (1) the pan neuronal profile of Piezo2 expression suggests that Piezo2 may function extend beyond simply touch or proprioception mediated by large-sized low-threshold mechanosensitive primary sensory neurons; (2) Piezo2 may have functional roles involving sensory processing in the spinal cord, Schwann cells, and skin melanocytes; and (3) aberrant Piezo2 expression may contribute pain pathogenesis.
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http://dx.doi.org/10.1097/j.pain.0000000000002356DOI Listing
June 2021

Oxygen- and bubble-generating polymersomes for tumor-targeted and enhanced photothermal-photodynamic combination therapy.

Biomater Sci 2021 Jul 16. Epub 2021 Jul 16.

Department of Forensic Pathology, Xi'an Jiaotong University School of Medicine, Xi'an 710061, China.

As a common feature of the tumor microenvironment (TME), hypoxia significantly impedes the effects of photodynamic therapy. Moreover, for tumor combination therapy, smart responsive and well-designed nanocarriers are highlighted to co-deliver different therapeutics, enhance drug delivery into target sites, and realize stimuli-responsive drug release. Herein, oxygen- and bubble-generating polymersomes (FIMPs) were developed for tumor-targeted and enhanced photothermal-photodynamic combination therapy. FIMPs efficiently co-encapsulated manganese dioxide (MnO2) and the hydrophobic photosensitizer indocyanine green (ICG) within the hydrophobic membrane as well as the bubble-generating reagent NH4HCO3 in the internal cavity of the vesicles, and achieved pH/temperature/reduction multiple responsiveness. The CO2 bubbles generated from the decomposition of NH4HCO3 via laser irradiation or acidic environment and the cleavage of the copolymer disulfide bond in the reducing TME would destroy the vesicle structure for triggering drug release. In addition, oxygen can be produced to overcome tumor hypoxia through the high reaction activity of MnO2 with endogenous H2O2. In vitro studies have shown that FIMPs achieved good photothermal conversion efficiency, promoted the generation of oxygen and reactive oxygen species (ROS), and thus effectively killed tumor cells. In vivo studies indicated that FIMPs effectively overcome the hypoxic microenvironment within tumors and significantly inhibit tumor growth with good biocompatibility. The rationally designed oxygen- and bubble-generating polymersomes have great potential to overcome the tumor hypoxia limitations for enhancing the photothermal-photodynamic combination therapeutic effect.
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http://dx.doi.org/10.1039/d1bm00659bDOI Listing
July 2021

Mononuclear phagocyte system blockade using extracellular vesicles modified with CD47 on membrane surface for myocardial infarction reperfusion injury treatment.

Biomaterials 2021 Jun 28;275:121000. Epub 2021 Jun 28.

Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Institute of Biomedical Science, Fudan University, Shanghai, China. Electronic address:

Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) with anti-apoptotic and anti-inflammatory properties have been intensively studied. However, rapid clearance by the mononuclear phagocyte system remains a huge barrier for the delivery of extracellular vesicle contents into target organs and restricts its wider application, particularly in the heart. CD47 is a transmembrane protein that enables cancer cells to evade clearance by macrophages through CD47 signal regulatory proteinα binding, which initiates a "don't eat me" signal. This study aimed to explore the biodistribution and delivery efficiency of EVs carrying the membrane protein CD47 and specific anti-apoptotic miRNAs. EVs were isolated from MSCs overexpressing CD47 (CD47-EVs) and identified. Fluorescence-labeled EVs were injected through the tail vein and tracked using fluorescence imaging. In silico analysis was performed to determine miRNA profiles in MSCs and in a heart-derived H9c2 cardiomyoblast cell line under hypoxia vs. normoxia conditions. Electro CD47-EV was constructed by encapsulating purified CD47-EV with miR-21a via electroporation. The effect of miR21-EVs on the pro-apoptotic gene encoding phosphatase and tensin homolog (PTEN) was evaluated by dual-luciferase assay, qPCR, and western blotting. Exogenous miR21 distribution, PTEN protein level, blood vessel density, anti-apoptotic effect by TdT-mediated dUTP nick-end labeling staining, and macrophage and leukocyte infiltration in the myocardium were assessed by immunofluorescence staining. Cardiac functional recovery during the early stage and recovery period was evaluated using echocardiography. The results showed that CD47-EVs were still detectable in the plasma 120 min after the tail vein injection, compared to the detection time of less than 30 min observed with the unmodified EVs. More strikingly, CD47-EVs preferentially accumulated in the heart in the ischemia-reperfusion (I/R) + CD47-EV group [heart total fluorescence radiance ( × 10 Photons/sec/cm/sr) 51.62 ± 11.30 v.s. 10.08 ± 3.15 in the I/R + unmodified EVs group] 8 h post-injection. Exogenous miR-21 is efficiently internalized into cardiomyocytes, inhibits apoptosis, alleviates inflammation, and improves cardiac function. In conclusion, electro CD47-EVs efficiently improve biodistribution in the heart, shedding new light on the application of a two-step EV delivery method (CD47 genetic modification followed by therapeutic content electrotransfection) as a potential therapeutic tool for myocardial I/R injury that may benefit patients in the future.
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http://dx.doi.org/10.1016/j.biomaterials.2021.121000DOI Listing
June 2021

A comprehensive prognostic signature for glioblastoma patients based on transcriptomics and single cell sequencing.

Cell Oncol (Dordr) 2021 Jun 17. Epub 2021 Jun 17.

One-third Lab, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Hei Longjiang, 150000, People's Republic of China.

Purpose: Glioblastoma (GBM) is the most common and deadly brain tumor. We aimed to reveal potential prognostic GBM marker genes, elaborate their functions, and build an effective a prognostic model for GBM patients.

Methods: Through data mining of The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA), we screened for significantly differentially expressed genes (DEGs) to calculate risk scores for individual patients. Published data of somatic mutation and copy number variation profiles were analyzed for distinct genomic alterations associated with risk scores. In addition, single-cell sequencing was used to explore the biological functions of the identified prognostic marker genes. By combining risk scores and other clinical features, we built a comprehensive prognostic GBM model.

Results: Seven DEGs (CLEC5A, HOXC6, HOXA5, CCL2, GPRASP1, BSCL2 and PTX3) were identified as being prognostic for GBM. Expression of these genes was confirmed in different GBM cell lines using real-time PCR. Risk scores calculated from the seven DEGs revealed prognostic value irrespective of other clinical factors, including IDH mutation status, and were negatively correlated with TP53 expression. The prognostic genes were found to be associated with tumor proliferation and progression based on pseudo-time analysis in neoplastic cells. A final prognostic model was developed and validated with a good performance, especially in geriatric GBM patients.

Conclusions: Using genetic profiles, age, IDH mutation status, and chemotherapy and radiotherapy, we constructed a comprehensive prognostic model for GBM patients. The model has a good performance, especially in geriatric GBM patients.
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http://dx.doi.org/10.1007/s13402-021-00612-1DOI Listing
June 2021

Nonclinical Safety Profile of Sotorasib, a KRAS-Specific Covalent Inhibitor for the Treatment of -Mutated Cancer.

Int J Toxicol 2021 Jun 17:10915818211022965. Epub 2021 Jun 17.

Amgen Inc, Research, Thousand Oaks, CA, USA.

Sotorasib is a first-in-class KRAS covalent inhibitor in clinical development for the treatment of tumors with the mutation. A comprehensive nonclinical safety assessment package, including secondary/safety pharmacology and toxicology studies, was conducted to support the marketing application for sotorasib. Sotorasib was negative in a battery of genotoxicity assays and negative in an in vitro phototoxicity assay. Based on in vitro assays, sotorasib had no off-target effects against various receptors, enzymes (including numerous kinases), ion channels, or transporters. Consistent with the tumor-specific target distribution (ie, KRAS), there were no primary pharmacology-related on-target effects identified. The kidney was identified as a target organ in the rat but not the dog. Renal toxicity in the rat was characterized by tubular degeneration and necrosis restricted to a specific region suggesting that the toxicity was attributed to the local formation of a putative toxic reactive metabolite. In the 3-month dog study, adaptive changes of hepatocellular hypertrophy due to drug metabolizing enzyme induction were observed in the liver that was associated with secondary effects in the pituitary and thyroid gland. Sotorasib was not teratogenic and had no direct effect on embryo-fetal development in the rat or rabbit. Human, dog, and rat circulating metabolites, M24, M10, and M18, raised no clinically relevant safety concerns based on the general toxicology studies, primary/secondary pharmacology screening, an in vitro human ether-à-go-go-related gene assay, or mutagenicity assessment. Overall, the results of the nonclinical safety program support a high benefit/risk ratio of sotorasib for the treatment of patients with -mutated tumors.
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http://dx.doi.org/10.1177/10915818211022965DOI Listing
June 2021

Identification of a nomogram based on an 8-lncRNA signature as a novel diagnostic biomarker for childhood acute lymphoblastic leukemia.

Aging (Albany NY) 2021 06 9;13(11):15548-15568. Epub 2021 Jun 9.

Medical Research Center, The Third People's Hospital of Chengdu, The Second Chengdu Hospital Affiliated to Chongqing Medical University, Chengdu 610031, China.

Childhood acute lymphoblastic leukemia (cALL) still represents a major cause of disease-related death in children. This study aimed to explore the prognostic value of long non-coding RNAs (lncRNAs) in cALL. We downloaded lncRNA expression profiles from the TARGET and GEO databases. Univariate, least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analyses were applied to identify lncRNA-based signatures. We identified an eight-lncRNA signature (LINC00630, HDAC2-AS2, LINC01278, AL356599.1, AC114490.1, AL132639.3, FUT8.AS1, and TTC28.AS1), which separated the patients into two groups with significantly different overall survival rates. A nomogram based on the signature, BCR ABL1 status and white blood cell count at diagnosis was developed and showed good accuracy for predicting the 3-, 5- and 7-year survival probability of cALL patients. The C-index values of the nomogram in the training and internal validation set reached 0.8 (95% CI, 0.757 to 0.843) and 0.806 (95% CI, 0.728 to 0.884), respectively. The nomogram proposed in this study objectively and accurately predicted the prognosis of cALL. experiments suggested that LINC01278 promoted the proliferation of leukemic cells and inhibited leukemic cell apoptosis by targeting the inhibition of miR-500b-3p in cALL, and LINC01278 may be a biological target for the treatment of cALL in the future.
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http://dx.doi.org/10.18632/aging.203116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221355PMC
June 2021

Traumatic brain injury induced by exposure to blast overpressure via ear canal.

Neural Regen Res 2022 Jan;17(1):115-121

Departmant of Otolaryngology and Head Neck Surgery; Department of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center, Jackson, MS, USA.

Exposure to explosive shockwave often leads to blast-induced traumatic brain injury in military and civilian populations. Unprotected ears are most often damaged following exposure to blasts. Although there is an association between tympanic membrane perforation and TBI in blast exposure victims, little is known about how and to what extent blast energy is transmitted to the central nervous system via the external ear canal. The present study investigated whether exposure to blasts directed through the ear canal causes brain injury in Long-Evans rats. Animals were exposed to a single blast (0-30 pounds per square inch (psi)) through the ear canal, and brain injury was evaluated by histological and behavioral outcomes at multiple time-points. Blast exposure not only caused tympanic membrane perforation but also produced substantial neuropathological changes in the brain, including increased expression of c-Fos, induction of a profound chronic neuroinflammatory response, and apoptosis of neurons. The blast-induced injury was not limited only to the brainstem most proximal to the source of the blast, but also affected the forebrain including the hippocampus, amygdala and the habenula, which are all involved in cognitive functions. Indeed, the animals exhibited long-term neurological deficits, including signs of anxiety in open field tests 2 months following blast exposure, and impaired learning and memory in an 8-arm maze 12 months following blast exposure. These results suggest that the unprotected ear canal provides a locus for blast waves to cause TBI. This study was approved by the Institutional Animal Care and Use Committee at the University of Mississippi Medical Center (Animal protocol# 0932E, approval date: September 30, 2016 and 0932F, approval date: September 27, 2019).
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http://dx.doi.org/10.4103/1673-5374.314311DOI Listing
January 2022

Electrically Tunable Multifunctional Polarization-Dependent Metasurfaces Integrated with Liquid Crystals in the Visible Region.

Nano Lett 2021 Jun 28;21(11):4554-4562. Epub 2021 May 28.

National Research Center for High-Efficiency Grinding, College of Mechanical and Vehicle Engineering, Hunan University, Changsha 410082, People's Republic of China.

Metasurfaces open up new avenues for designing planar optics, enabling compact dynamic metadevices. Numerous dynamic strategies have been proposed, among which liquid crystal (LC) based metasurfaces are expected due to the maturity of LC materials. However, existing schemes rarely exploit the polarization manipulation capabilities of metasurfaces and the limited performance hinders the development of practical addressable devices. Here, we demonstrate an electrically tunable multifunctional polarization-dependent metasurface integrated with LCs in the visible range. By a combination of the helicity-dependent metasurface and the birefringent LCs, continuous intensity tuning and switching of two helicity channels are realized. Electrically tunable mono- and multicolor switchable metaholograms and dynamic varifocal metalenses are demonstrated with a simple and performance-enhancing integration scheme. Further, electrically addressable dynamic metasurfaces are achieved. The proposed modulation and integration schemes pave the way for addressable dynamic metasurface devices in various applications, such as space light modulators, light detection and ranging systems, and holographic displays.
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http://dx.doi.org/10.1021/acs.nanolett.1c00104DOI Listing
June 2021

The complete mitochondrial genome of (Neuroptera: Chrysopidae: Nothochrysinae) with a phylogenetic analysis of Chrysopoidea.

Mitochondrial DNA B Resour 2021 May 13;6(5):1632-1633. Epub 2021 May 13.

Department of Entomology, China Agricultural University, Beijing, China.

The complete mitochondrial (mt) genome of Yang (Neuroptera: Chrysopidae: Nothochrysinae) is reported in this work. It represents the first complete mt genome of the subfamily Nothochrysinae. The whole mt genome is 16,166 bp long and contains 13 protein-coding genes (PCGs), 22 transfer RNA genes (tRNAs), 2 ribosomal RNA genes (rRNAs), and an AT-rich region. Most PCGs used the typical ATN as initiation codons. The AT-rich region is 1,271 bp long with 90.24% of A + T. The results show that is closely related to . Chrysopidae was demonstrated monophyletic being the sister group to Hemerobiidae. Within Chrysopidae, the sister-group relationship between Nothochrysinae and Apochrysinae was supported and together being the sister group to Chrysopinae.
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http://dx.doi.org/10.1080/23802359.2021.1926361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128176PMC
May 2021

Nanoscopic wear behavior of dentinogenesis imperfecta type II tooth dentin.

J Mech Behav Biomed Mater 2021 08 13;120:104585. Epub 2021 May 13.

Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, PR China; Department of Prosthodontics, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, PR China. Electronic address:

Objectives: The aim of this study was to investigate the wear behavior of Dentinogenesis imperfecta type II (DGI-II) dentin and elucidate the correlation between its tribological properties and components.

Methods: The mid-coronal dentin of normal and DGI-II teeth were divided into two groups: perpendicular and parallel to the dentin tubules. The microstructure of dentin was detected using atomic force microscopy (AFM). The wear behavior of dentin was evaluated by nanoscratch tests and scanning electron microscopy (SEM). Meanwhile, changes in molecular groups and chemical composition were analyzed by Raman and Energy-Dispersive X-ray (EDX) tests, respectively. Nanohardness was also evaluated.

Results: AFM images of DGI-II dentin illustrated a decrease in the number of tubules and the tubule diameter. Nanoscratch test showed a higher friction coefficient and a greater depth-of-scratch in DGI-II dentin. The wear resistance of DGI-II dentin was reduced independent of tubule orientation. EDX results indicated that DGI-II dentin mineral content decreased and Raman spectra results showed DGI-II dentin had a decreased collagen matrix structure stability coupled with hypomineralization. Furthermore, a significant reduction in nanohardness and elastic modulus of DGI-II dentin was observed. Regression analysis revealed a close correlation between dentin components and inferior wear resistance.

Conclusions: All results indicated the wear behavior of DGI-II dentin was significantly deteriorated, presumably caused by the disorder in microstructures and the reduction of chemical composition.
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http://dx.doi.org/10.1016/j.jmbbm.2021.104585DOI Listing
August 2021

Recent Insights Into the Protective Mechanisms of Paeoniflorin in Neurological, Cardiovascular, and Renal Diseases.

J Cardiovasc Pharmacol 2021 Jun;77(6):728-734

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS.

Abstract: The monoterpene glycoside paeoniflorin (PF) is the principal active constituent of the traditional Chinese herbal medicines, Radix Paeoniae Alba and Radix Paeoniae Rubra, which have been used for millennia to treat cardiovascular diseases (eg, hypertension, bleeding, and atherosclerosis) and neurological ailments (eg, headaches, vertigo, dementia, and pain). Recent evidence has revealed that PF exerts inhibitory effects on inflammation, fibrosis, and apoptosis by targeting several intracellular signaling cascades. In this review, we address the current knowledge about the pharmacokinetic properties of PF and its molecular mechanisms of action. We also present results from recent preclinical studies supporting the utility of PF for the treatment of pain, cerebral ischemic injury, and neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. Moreover, new evidence suggests a general protective role of PF in heart attack, diabetic kidney, and atherosclerosis. Mechanistically, PF exerts multiple anti-inflammatory actions by targeting toll-like receptor-mediated signaling in both parenchymal and immune cells (in particular, macrophages and dendritic cells). A better understanding of the molecular actions of PF may lead to the expansion of its therapeutic uses.
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http://dx.doi.org/10.1097/FJC.0000000000001021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169546PMC
June 2021

Competing risk model to determine the prognostic factors and treatment strategies for elderly patients with glioblastoma.

Sci Rep 2021 Apr 29;11(1):9321. Epub 2021 Apr 29.

Department of Neurosurgery, Xiangya Hospital, Center South University, Changsha, Hunan, People's Republic of China.

The prognostic factors and optimal treatment for the elderly patient with glioblastoma (GBM) were poorly understood. This study extracted 4975 elderly patients (≥ 65 years old) with histologically confirmed GBM from Surveillance, Epidemiology and End Results (SEER) database. Firstly, Cumulative incidence function and cox proportional model were utilized to illustrate the interference of non-GBM related mortality in our cohort. Then, the Fine-Gray competing risk model was applied to determine the prognostic factors for GBM related mortality. Age ≥ 75 years old, white race, size > 5.4 cm, frontal lobe tumor, and overlapping lesion were independently associated with more GBM related death, while Gross total resection (GTR) (HR 0.87, 95%CI 0.80-0.94, P = 0.010), radiotherapy (HR 0.64, 95%CI 0.55-0.74, P < 0.001), chemotherapy (HR 0.72, 95%CI 0.59-0.90, P = 0.003), and chemoRT (HR 0.43, 95%CI 0.38-0.48, P < 0.001) were identified as independently protective factors of GBM related death. Based on this, a corresponding nomogram was conducted to predict 3-, 6- and 12-month GBM related mortality, the C-index of which were 0.763, 0.718, and 0.694 respectively. The calibration curve showed that there was a good consistency between the predicted and the actual mortality probability. Concerning treatment options, GTR followed by chemoRT is suggested as optimal treatment. Radiotherapy and chemotherapy alone also provide moderate clinical benefits.
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http://dx.doi.org/10.1038/s41598-021-88820-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084944PMC
April 2021

Outcomes of surgical repair of anomalous origin of the left coronary artery from the pulmonary artery in infants and children.

Cardiol Young 2021 Apr 28:1-6. Epub 2021 Apr 28.

Department of Cardiac Surgery, Beijing Children's Hospital affiliated to Capital Medical University, National Center for Children's Health, Beijing, China.

Objectives: Anomalous origin of the left coronary artery from the pulmonary artery is associated with high mortality if not timely surgery. We reviewed our experience with anomalous origin of the left coronary artery from the pulmonary artery to assess the preoperative variables predictive of outcome and post-operative recovery of left ventricular function.

Methods: A retrospective review was conducted and collected data from patients who underwent anomalous origin of the left coronary artery from the pulmonary artery repair at our institute from April 2005 to December 2019. Left ventricular function was assessed by ejection fraction and the left ventricular end-diastolic dimension index. The outcomes of reimplantation repair were analysed.

Results: A total of 30 consecutive patients underwent anomalous origin of the left coronary artery from the pulmonary artery repair, with a median age of 14.7 months (range, 1.5-59.6 months), including 14 females (46.67%). Surgery was performed with direct coronary reimplantation in 12 patients (40%) and the coronary lengthening technique in 18 (60%). Twelve patients had concomitant mitral annuloplasty. There were two in-hospital deaths (6.67%), no patients required mechanical support, and no late deaths occurred. Follow-up echocardiograms demonstrated significant improvement between the post-operative time point and the last follow-up in ejection fraction (49.43%±19.92% vs 60.21%±8.27%, p < 0.01) and in moderate or more severe mitral regurgitation (19/30 vs 5/28, p < 0.01). The left ventricular end-diastolic dimension index decreased from 101.91 ± 23.07 to 65.06 ± 12.82 (p < 0.01).

Conclusions: Surgical repair of anomalous origin of the left coronary artery from the pulmonary artery has good mid-term results with low mortality and reintervention rates. The coronary lengthening technique has good operability and leads to excellent cardiac recovery. The decision to concomitantly correct mitral regurgitation should be flexible and be based on the pathological changes of the mitral valve and the degree of mitral regurgitation.
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http://dx.doi.org/10.1017/S104795112100161XDOI Listing
April 2021

Author Correction: Assessing progress towards sustainable development over space and time.

Nature 2021 Apr;592(7856):E28

Center for Systems Integration and Sustainability, Department of Fisheries and Wildlife, Michigan State University, East Lansing, MI, USA.

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http://dx.doi.org/10.1038/s41586-021-03479-2DOI Listing
April 2021

Aging diabetes, deconstructing the cerebrovascular wall.

Aging (Albany NY) 2021 04 12;13(7):9158-9159. Epub 2021 Apr 12.

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA.

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http://dx.doi.org/10.18632/aging.202963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064220PMC
April 2021

The Survival Benefits of Surgical Resection and Adjuvant Therapy for Patients With Brainstem Glioma.

Front Oncol 2021 25;11:566972. Epub 2021 Mar 25.

Department of Neurosurgery, Xiangya Hospital, Center South University, Changsha, China.

Purpose: The role of surgical resection in the treatment of brainstem glioma (BSG) is poorly understood. For pediatric low-grade (LGBSG) group, several monocentric small-scale retrospective studies reported contradictory conclusions. And there was no clinical study focused on surgical resection for adult or pediatric high-grade (HG) patient groups. This study aims to illustrate whether surgical resection and adjuvant therapy provide survival benefits for patients with histologically confirmed BSG.

Patients And Methods: This retrospective cohort study included 529 patients with histologically confirmed BSG in Surveillance Epidemiology and End Results (SEER) database from 2006-2015. Patients were divided into four groups by age and World Health Organization (WHO) grade. Kaplan-Meier curves of CSS were plotted by different treatment options to compare the survival probability. Univariate and multivariable analyses were then conducted to determine the prognosis effects of surgical resection and adjuvant therapy on cancer specific survival (CSS). All analyses were done in four different groups separately.

Results: The final sample included 529 patients. The entire study population was divided into groups of pediatric LG (n=236, 44.6%), pediatric HG (n=37, 7.0%), adult LG (n=204, 38.6%) and adult HG (n=52, 9.8%). 52.7% (n=144) of pediatric patients had pilocytic astrocytoma and 45.3% (n=116) of adult patients had ependymoma. Pediatric LGBSG group had the highest gross total resection (GTR) rate (61.4%) and 5-year CSS rate (88.6%). Kaplan-Meier curves of pediatric LGBSG group revealed that patients treated with GTR had significantly better survival probability (P=0.033). Multivariable analysis identified GTR as independently significant predictor for prolonged CSS in pediatric LGBSG group (HR0.29, 95%CI 0.11-0.78, P=0.015); Surgical resection showed no relation to CSS in other patient groups. Kaplan-Meier curves of adult HGBSG group showed that patients treated with both RT and CT in adult HGBSG group had the best survival probability (P=0.02). However, multivariable analysis showed the combination of radiotherapy (RT) and chemotherapy (CT) was not significantly related to better CSS in adult HGBSG group (HR0.35, 95%CI 0.11-1.09, P=0.070). Adjuvant therapy didn't associate with better CSS in other patient groups.

Conclusion: Pediatric LGBSG group had the highest GTR rate and the most favorable clinical outcome. GTR can provide significant survival benefits for pediatric LGBSG group.
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http://dx.doi.org/10.3389/fonc.2021.566972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027112PMC
March 2021

Reversal of cerebral hypoperfusion: a novel therapeutic target for the treatment of AD/ADRD?

Geroscience 2021 04 27;43(2):1065-1067. Epub 2021 Mar 27.

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216, USA.

Alzheimer's disease (AD) and Alzheimer's disease-related dementias (ADRD) are emerging global health care crises and are primarily found among aging, especially with diabetes and hypertension. However, treatments based on current understanding have not been effective. The importance of vascular contribution to AD/ADRD has been recommended by the NINDS and NIA to be a focused research area. A recent study identified that phosphatidylinositol 4,5-bisphosphate (PIP) or its analogs could reverse cerebral hypoperfusion at the neurovascular unit in AD mice. Although more studies are needed to validate if PIP analogs have sustained effects on CBF and can rescue cognitive impairment in AD/ADRD, and to elucidate and clarify whether targeting the retrograde (capillary-to-arteriole) pathway is beneficial to BBB function in AD/ADRD with poor CBF autoregulation, this finding provides exciting progress in understanding vascular contributions to AD/ADRD and suggests that reversal of cerebral hypoperfusion could be a novel therapeutic target for the treatment of AD/ADRD.
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http://dx.doi.org/10.1007/s11357-021-00357-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110616PMC
April 2021

20-HETE-promoted cerebral blood flow autoregulation is associated with enhanced pericyte contractility.

Prostaglandins Other Lipid Mediat 2021 Jun 19;154:106548. Epub 2021 Mar 19.

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, 39216, USA. Electronic address:

We previously reported that deficiency in 20-HETE or CYP4A impaired the myogenic response and autoregulation of cerebral blood flow (CBF) in rats. The present study demonstrated that CYP4A was coexpressed with alpha-smooth muscle actin (α-SMA) in vascular smooth muscle cells (VSMCs) and most pericytes along parenchymal arteries (PAs) isolated from SD rats. Cell contractile capabilities of cerebral VSMCs and pericytes were reduced with a 20-HETE synthesis inhibitor, HET0016, but restored with 20-HETE analog WIT003. Similarly, intact myogenic responses of the middle cerebral artery and PA of SD rats decreased with HET0016 and were rescued by WIT003. The myogenic response of the PA was abolished in SS and was restored in SS.BN5 and SS.Cyp4a1 rats. HET0016 enhanced CBF and impaired its autoregulation in the surface and deep cortex of SD rats. These results demonstrate that 20-HETE has a direct effect on cerebral mural cell contractility that may play an essential role in controlling cerebral vascular function.
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http://dx.doi.org/10.1016/j.prostaglandins.2021.106548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154705PMC
June 2021

Antibodies to neutralising epitopes synergistically block the interaction of the receptor-binding domain of SARS-CoV-2 to ACE 2.

Clin Transl Immunology 2021 7;10(3):e1260. Epub 2021 Mar 7.

Institute for Glycomics Griffith University Gold Coast QLD Australia.

Objectives: A major COVID-19 vaccine strategy is to induce antibodies that prevent interaction between the Spike protein's receptor-binding domain (RBD) and angiotensin-converting enzyme 2 (ACE2). These vaccines will also induce T-cell responses. However, concerns were raised that aberrant vaccine-induced immune responses may exacerbate disease. We aimed to identify minimal epitopes on the RBD that would induce antibody responses that block the interaction of the RBD and ACE2 as a strategy leading to an effective vaccine with reduced risk of inducing immunopathology.

Methods: We procured a series of overlapping 20-amino acid peptides spanning the RBD and asked which were recognised by plasma from COVID-19 convalescent patients. Identified epitopes were conjugated to diphtheria-toxoid and used to vaccinate mice. Immune sera were tested for binding to the RBD and for their ability to block the interaction of the RBD and ACE2.

Results: Seven putative vaccine epitopes were identified. Memory B-cells (MBCs) specific for one of the epitopes were identified in the blood of convalescent patients. When used to vaccinate mice, six induced antibodies that bound recRBD and three induced antibodies that could partially block the interaction of the RBD and ACE2. However, when the sera were combined in pairs, we observed significantly enhanced inhibition of binding of RBD to ACE2. Two of the peptides were located in the main regions of the RBD known to contact ACE2. Of significant importance to vaccine development, two of the peptides were in regions that are invariant in the UK and South African strains.

Conclusion: COVID-19 convalescent patients have SARS-CoV-2-specific antibodies and MBCs, the specificities of which can be defined with short peptides. Epitope-specific antibodies synergistically block RBD-ACE2 interaction.
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http://dx.doi.org/10.1002/cti2.1260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937407PMC
March 2021

Erratum to 'Bulk Wave Velocities in Cortical Bone Reflect Porosity and Compression Strength' [Ultrasound in Med. & Biol. 47 (2021) 799-808].

Ultrasound Med Biol 2021 Jun 9;47(6):1637. Epub 2021 Mar 9.

Sorbonne Universite, INSERM, CNRS, Laboratoire d'lmagerie Biomedicale, LIB, F-75006 Paris, France.

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http://dx.doi.org/10.1016/j.ultrasmedbio.2021.02.017DOI Listing
June 2021

Novel Mechanistic Insights and Potential Therapeutic Impact of TRPC6 in Neurovascular Coupling and Ischemic Stroke.

Int J Mol Sci 2021 Feb 19;22(4). Epub 2021 Feb 19.

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA.

Ischemic stroke is one of the most disabling diseases and a leading cause of death globally. Despite advances in medical care, the global burden of stroke continues to grow, as no effective treatments to limit or reverse ischemic injury to the brain are available. However, recent preclinical findings have revealed the potential role of transient receptor potential cation 6 (TRPC6) channels as endogenous protectors of neuronal tissue. Activating TRPC6 in various cerebral ischemia models has been found to prevent neuronal death, whereas blocking TRPC6 enhances sensitivity to ischemia. Evidence has shown that Ca influx through TRPC6 activates the cAMP (adenosine 3',5'-cyclic monophosphate) response element-binding protein (CREB), an important transcription factor linked to neuronal survival. Additionally, TRPC6 activation may counter excitotoxic damage resulting from glutamate release by attenuating the activity of N-methyl-d-aspartate (NMDA) receptors of neurons by posttranslational means. Unresolved though, are the roles of TRPC6 channels in non-neuronal cells, such as astrocytes and endothelial cells. Moreover, TRPC6 channels may have detrimental effects on the blood-brain barrier, although their exact role in neurovascular coupling requires further investigation. This review discusses evidence-based cell-specific aspects of TRPC6 in the brain to assess the potential targets for ischemic stroke management.
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http://dx.doi.org/10.3390/ijms22042074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922996PMC
February 2021

pH-sensitive and bubble-generating mesoporous silica-based nanoparticles for enhanced tumor combination therapy.

Acta Pharm Sin B 2021 Feb 2;11(2):520-533. Epub 2020 Sep 2.

Tianjin Key Laboratory of Biomedical Materials, Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China.

Chemotherapy has been a major option in clinic treatment of malignant tumors. However, single chemotherapy faces some drawbacks, such as multidrug resistance, severe side effects, which hinder its clinic application in tumor treatment. Multifunctional nanoparticles loading with chemotherapeutic agent and photosensitizer could be a promising way to efficiently conduct tumor combination therapy. In the current study, a novel pH-sensitive and bubble-generating mesoporous silica-based drug delivery system (denoted as M(a)[email protected]) was constructed. Ammonium bicarbonate (NHHCO; abc) and chemotherapeutic agent doxorubicin (DOX) were loaded into the pores of mesoporous silica. Indocyanine green (ICG) as a photothermal and photodynamic agent was loaded onto the polydopamine (PDA) layer surface. The synthesized nanoparticles displayed a narrow polydispersity (PDI) and small particle size as characterized through dynamic light scattering-autosizer analysis. The nanoparticles also showed high targeting efficacy through RGD modification as indicated by cellular uptake and animal studies. DOX release analysis confirmed that the nanoparticles were pH-dependent and that NHHCO accelerated drug release. At the same time, the nanoparticles had obvious photothermal and photodynamic effects performed by ICG which restrained tumor growth remarkably. In summary, the multifunctional nanoparticles presented a promising system for combination therapy.
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http://dx.doi.org/10.1016/j.apsb.2020.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893139PMC
February 2021

Cortical bone viscoelastic damping assessed with resonant ultrasound spectroscopy reflects porosity and mineral content.

J Mech Behav Biomed Mater 2021 05 12;117:104388. Epub 2021 Feb 12.

Sorbonne Université, INSERM UMR-S 1146, CNRS UMR 7371, Laboratoire d'Imagerie Biomédicale, F-75006, Paris, France.

Viscoelasticity is an essential property of bone related to fragility, which is altered in aging and bone disease. Bone viscoelastic behavior is attributed to several mechanisms involving collagen and mineral properties, porosities, and bone hierarchical tissue organization. We aimed to assess the relationships between cortical bone viscoelastic damping measured with Resonant Ultrasound Spectroscopy (RUS), microstructural and compositional characteristics. We measured 52 bone specimens from the femur of 26 elderly human donors. RUS provided a shear damping coefficient at a frequency of the order of 150 kHz. The characteristics of the structure of the vascular pore network and tissue mineral density were measured using synchrotron radiation high-resolution computed tomography (SR-μCT). Fourier transformed infrared microspectroscopy (FTIRM) was used to quantify mineral-to-organic phase ratio, mineral maturity, crystallinity, and collagen maturity. Cross-links were quantified from biochemistry. Viscoelastic damping was found to increase with vascular porosity (r=0.68), to decrease with the degree of mineralization of the extravascular matrix (r=-0.68), and was marginally affected by collagen. We built a multilinear model suggesting that when porosity is controlled, the variation of mineral content explains a small additional part of the variability of damping. The work supports the consideration of viscoelasticity measurement as a potential biomarker of fragility and provides a documentation of bone viscoelastic behavior and its determinants in a frequency range rarely investigated.
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http://dx.doi.org/10.1016/j.jmbbm.2021.104388DOI Listing
May 2021

Safe treatment of congenital left atrial appendage aneurysm using lateral thoracotomy on a 3-year-old patient.

Cardiol Young 2021 Jan 29;31(1):144-147. Epub 2020 Oct 29.

Pediatric Cardiac Center, Beijing Children's Hospital & Capital Medical University, National Center for Children's Health, Beijing, China.

Limited literatures report the management of congenital left atrial appendage aneurysm (LAAA) which is extremely rare. Chest X-ray firstly showed an enlarged left cardiac silhouette for a 3-year-old patient with pneumonia. Echocardiography and magnetic resonance imaging confirmed a large cyst attached to the left atrium. Aneurysmectomy was performed through lateral thoracotomy using step-by-step method and under the guidance of transoesophageal echocardiography. We aim to show the safety and efficacy of this approach applied to children associated with congenital LAAA.
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http://dx.doi.org/10.1017/S1047951120003248DOI Listing
January 2021

Imaging the Nanoscale Distribution of Phosphoinositides in the Cell Plasma Membrane with Single-Molecule Localization Super-Resolution Microscopy.

Methods Mol Biol 2021 ;2251:91-104

Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA.

Phosphoinositides make up only a small fraction of cellular phospholipids yet control cell function in a fundamental manner. Through protein interactions, phosphoinositides define cellular organelle identity and regulate protein function and organization and recruitment at the cytosol-membrane interface. As a result, perturbations on phosphoinositide metabolism alter cell physiology and lead to a wide range of human diseases, including cancer and diabetes. Among seven phosphoinositide members, phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P, also known as PI(4,5)P or PIP) is abundant in the plasma membrane. Besides its role in the second messenger pathway of phospholipase C that cleaves PtdIns(4,5)P to form diacylglycerol and inositol-1,4,5-trisphosphate (IP), PtdIns(4,5)P regulates membrane trafficking and the function of the cytoskeleton, ion channels, and transporters. The nanoscale organization of PtdIns(4,5)P in the plasma membrane becomes essential to understand cellular signaling specificity in time and space. Here, we describe a single-molecule method to visualize the nanoscale distribution of PtdIns(4,5)P in the plasma membrane by using super-resolution microscopy and the dual-color fluorescent probes based on the PLC pleckstrin homology (PH) domain. This approach can be extended to image other phosphoinositides by changing the specific probes.
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http://dx.doi.org/10.1007/978-1-0716-1142-5_6DOI Listing
March 2021

Circadian clock genes promote glioma progression by affecting tumour immune infiltration and tumour cell proliferation.

Cell Prolif 2021 Mar 13;54(3):e12988. Epub 2021 Jan 13.

Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.

Objectives: Circadian rhythm controls complicated physiological activities in organisms. Circadian clock genes have been related to tumour progression, but its role in glioma is unknown. Therefore, we explored the relationship between dysregulated circadian clock genes and glioma progression.

Materials And Methods: Samples were divided into different groups based on circadian clock gene expression in training dataset (n = 672) and we verified the results in other four validating datasets (n = 1570). The GO and GSEA enrichment analysis were conducted to explore potential mechanism of how circadian clock genes affected glioma progression. The single-cell RNA-Seq analysis was conducted to verified previous results. The immune landscape was evaluated by the ssGSEA and CIBERSORT algorithm. Cell proliferation and viability were confirmed by the CCK8 assay, colony-forming assay and flow cytometry.

Results: The cluster and risk model based on circadian clock gene expression can predict survival outcome. Samples were scoring by the least absolute shrinkage and selection operator regression analysis, and high scoring tumour was associated with worse survival outcome. Samples in high-risk group manifested higher activation of immune pathway and cell cycle. Tumour immune landscape suggested high-risk tumour infiltrated more immunocytes and more sensitivity to immunotherapy. Interfering TIMELESS expression affected circadian clock gene expression, inhibited tumour cell proliferation and arrested cell cycle at the G0/G1 phase.

Conclusions: Dysregulated circadian clock gene expression can affect glioma progression by affecting tumour immune landscape and cell cycle. The risk model can predict glioma survival outcome, and this model can also be applied to pan-cancer.
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http://dx.doi.org/10.1111/cpr.12988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941241PMC
March 2021

Knockout of -Adducin Promotes N-Nitro-L-Arginine-Methyl-Ester-Induced Hypertensive Renal Injury.

J Pharmacol Exp Ther 2021 04 7;377(1):189-198. Epub 2021 Jan 7.

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi

Previous studies identified a region on chromosome 1 associated with N-nitro-L-arginine methyl ester (L-NAME) hypertension-induced renal disease in fawn-hooded hypertensive (FHH) rats. This region contains a mutant -adducin () gene that impairs renal blood flow (RBF) autoregulation, but its contribution to renal injury is unknown. The present study evaluated the hypothesis that knockout (KO) of impairs the renal vasoconstrictor response to the blockade of nitric oxide synthase and enhances hypertension-induced renal injury after chronic administration of L-NAME plus a high-salt diet. The acute hemodynamic effect of L-NAME and its chronic effects on hypertension and renal injury were compared in FHH 1 (FHH 1) congenic rats (WT) expressing wild-type gene versus FHH 1 KO rats. RBF was well autoregulated in WT rats but impaired in KO rats. Acute administration of L-NAME (10 mg/kg) raised mean arterial pressure (MAP) similarly in both strains, but RBF and glomerular filtration rate (GFR) fell by 38% in WT versus 15% in KO rats. MAP increased similarly in both strains after chronic administration of L-NAME and a high-salt diet; however, proteinuria and renal injury were greater in KO rats than in WT rats. Surprisingly, RBF, GFR, and glomerular capillary pressure were 41%, 82%, and 13% higher in L-NAME-treated KO rats than in WT rats. Hypertensive KO rats exhibited greater loss of podocytes and glomerular nephrin expression and increased interstitial fibrosis than in WT rats. These findings indicate that loss of ADD3 promotes L-NAME-induced renal injury by altering renal hemodynamics and enhancing the transmission of pressure to glomeruli. SIGNIFICANCE STATEMENT: A mutation in the -adducin () gene in fawn-hooded hypertensive rats that impairs autoregulation of renal blood flow is in a region of rat chromosome 1 homologous to a locus on human chromosome 10 associated with diabetic nephropathy. The present results indicate that loss of ADD3 enhanced N-nitro-L-arginine methyl ester-induced hypertensive renal injury by altering the transmission of pressure to the glomerulus.
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http://dx.doi.org/10.1124/jpet.120.000408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051517PMC
April 2021

Association between infectious burden and cerebral microbleeds: a pilot cross-sectional study.

Ann Clin Transl Neurol 2021 02 7;8(2):395-405. Epub 2021 Jan 7.

Department of Neurology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.

Objective: Cerebral microbleeds (CMBs) is a subtype of cerebral small vessel disease. Their underlying pathogenesis remains unclear. The aim of this study was to investigate the association between infectious burden (IB) and CMBs.

Methods: Seven hundred and seventy-three consecutive patients who were hospitalized in the Department of Neurology in General Hospital of Western Theater Command without severe neurological symptoms were recruited and selected in this pilot cross-sectional study. CMBs were assessed using the susceptibility-weighted imaging sequence of magnetic resonance imaging. Immunoglobulin G antibodies against common pathogens, including herpes simplex virus (HSV)-1, HSV-2, cytomegalovirus (CMV), Chlamydia pneumoniae (C. pneumoniae), Mycoplasma pneumoniae (M. pneumoniae), Epstein-Barr virus (EBV), Helicobacter pylori (HP), and Borrelia burgdorferi (B. burgdorferi), were measured by commercial ELISA assays. IB was defined as a composite serologic measure of exposure to these common pathogens.

Results: Patients with and without CMBs were defined as the CMBs group (n = 76) and the non-CMBs group (n = 81), respectively. IB was significantly different between the CMBs and non-CMBs groups. After adjusted for other risk factors, the increased IB was independently associated with the presence of CMBs (P = 0.031, OR = 3.00, 95% CI [1.11-8.15]). IB was significantly positively associated with the number of CMBs (Spearman ρ = 0.653, P < 0.001). The levels of serum inflammatory markers were significantly different between the CMBs and non-CMBs groups and among the categories of IB.

Interpretation: IB consisting of HSV-1, HSV-2, CMV, C. pneumoniae, M. pneumoniae, EBV, HP, and B. burgdorferi was associated with CMBs. All the findings suggested that pathogen infection could be involved in the pathogenesis of CMBs.
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http://dx.doi.org/10.1002/acn3.51285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886034PMC
February 2021

Maxwellian near-eye display with an expanded eyebox.

Opt Express 2020 Dec;28(26):38616-38625

Maxwellian view systems can be employed to circumvent the vergence-accommodation conflict in near-eye displays (NEDs), which directly project images onto the retina regardless of the human eye's depth of focus. However, Maxwellian view optics typically have a limited eyebox, which prevents broader applications of this architecture in NEDs. Here, we demonstrate a thin-film two-dimensional beam deflector composed of multi-twist broad-band Pancharatnam-Berry deflectors to mitigate this limitation via eyebox replication. Based on experimental validation, our proposed design can display always-focused full-color images within a 9 mm × 9 mm eyebox and thus mitigate the limitation of conventional Maxwellian displays while adding negligible weight and volume.
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http://dx.doi.org/10.1364/OE.413471DOI Listing
December 2020

Genetic susceptibility of hypertension-induced kidney disease.

Physiol Rep 2021 01;9(1):e14688

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi, USA.

Hypertension is the second leading cause of end-stage renal disease (ESRD) after diabetes mellitus. The significant differences in the incidence of hypertensive ESRD between different patient populations worldwide and patients with and without family history indicate that genetic determinants play an important role in the onset and progression of this disease. Recent studies have identified genetic variants and pathways that may contribute to the alteration of renal function. Mechanisms involved include affecting renal hemodynamics (the myogenic and tubuloglomerular feedback responses); increasing the production of reactive oxygen species in the tubules; altering immune cell function; changing the number, structure, and function of podocytes that directly cause glomerular damage. Studies with hypertensive animal models using substitution mapping and gene knockout strategies have identified multiple candidate genes associated with the development of hypertension and subsequent renal injury. Genome-wide association studies have implicated genetic variants in UMOD, MYH9, APOL-1, SHROOM3, RAB38, and DAB2 have a higher risk for ESRD in hypertensive patients. These findings provide genetic evidence of potential novel targets for drug development and gene therapy to design individualized treatment of hypertension and related renal injury.
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http://dx.doi.org/10.14814/phy2.14688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772938PMC
January 2021
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