Analysis of Host-Mediated Repair Mechanisms after Human CNS-Stem Cell Transplantation for Spinal Cord Injury: Correlation of Engraftment with Recovery

BACKGROUND:Human central nervous system-stem cells grown as neurospheres (hCNS-SCns) self-renew, are multipotent, and have potential therapeutic applications following trauma to the spinal cord. We have previously shown locomotor recovery in immunodeficient mice that received a moderate contusion spinal cord injury (SCI) and hCNS-SCns transplantation 9 days post-injury (dpi). Engrafted hCNS-SCns exhibited terminal differentiation to myelinating oligodendrocytes and synapse-forming neurons. Further, selective ablation of human cells using Diphtheria toxin (DT) abolished locomotor recovery in this paradigm, suggesting integration of human cells within the mouse host as a possible mechanism for the locomotor improvement. However, the hypothesis that hCNS-SCns could alter the host microenvironment as an additional or alternative mechanism of recovery remained unexplored; we tested that hypothesis in the present study. METHODS AND FINDINGS:Stereological quantification of human cells using a human-specific cytoplasmic marker demonstrated successful cell engraftment, survival, migration and limited proliferation in all hCNS-SCns transplanted animals. DT administration at 16 weeks post-transplant ablated 80.5% of hCNS-SCns. Stereological quantification for lesion volume, tissue sparing, descending serotonergic host fiber sprouting, chondroitin sulfate proteoglycan deposition, glial scarring, and angiogenesis demonstrated no evidence of host modification within the mouse spinal cord as a result of hCNS-SCns transplantation. Biochemical analyses supplemented stereological data supporting the absence of neural stem-cell mediated host repair. However, linear regression analysis of the number of engrafted hCNS-SCns vs. the number of errors on a horizontal ladder beam task revealed a strong correlation between these variables (r = -0.78, p<0.05), suggesting that survival and engraftment were directly related to a quantitative measure of recovery. CONCLUSIONS:Altogether, the data suggest that the locomotor improvements associated with hCNS-SCns transplantation were not due to modifications within the host microenvironment, supporting the hypothesis that human cell integration within the host circuitry mediates functional recovery following a 9 day delayed transplant

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Research and Design of a Routing Protocol in Large-Scale Wireless Sensor Networks

无线传感器网络，作为全球未来十大技术之一，集成了传感器技术、嵌入式计算技术、分布式信息处理和自组织网技术，可实时感知、采集、处理、传输网络分布区域内的各种信息数据，在军事国防、生物医疗、环境监测、抢险救灾、防恐反恐、危险区域远程控制等领域具有十分广阔的应用前景。 本文研究分析了无线传感器网络的已有路由协议，并针对大规模的无线传感器网络设计了一种树状路由协议，它根据节点地址信息来形成路由，从而简化了复杂繁冗的路由表查找和维护，节省了不必要的开销，提高了路由效率，实现了快速有效的数据传输。 为支持此路由协议本文提出了一种自适应动态地址分配算——ADAR（AdaptiveDynamicAddre...As one of the ten high technologies in the future, wireless sensor network, which is the integration of micro-sensors, embedded computing, modern network and Ad Hoc technologies, can apperceive, collect, process and transmit various information data within the region. It can be used in military defense, biomedical, environmental monitoring, disaster relief, counter-terrorism, remote control of haz...学位：工学硕士院系专业：信息科学与技术学院通信工程系_通信与信息系统学号：2332007115216

Human neural stem cell differentiation following transplantation into spinal cord injured mice: association with recovery of locomotor function

Stem cells are under intense investigation as potential therapeutics for central nervous system (CNS) injury and disease. However, several reports have suggested that stem cells grown as neurospheres and transplanted into an injured environment preferentially differentiate into astrocytes, contributing to glial scar. Further, the relationship between functional recovery and cell transplantation has not been empirically investigated in early studies. Using severe combined immunodeficient (scid) mice to minimize xenograft rejection, we report that prospectively isolated human fetal CNS-derived stem cells grown as neurospheres (hCNS-SCns) survive, migrate and express differentiation markers for neurons and oligodendrocytes after long-term engraftment in spinal cord injured (SCI) NOD-scid mice. Only rarely do these cells differentiate into glial fibrillary acidic protein (GFAP)-positive astrocytes, with no apparent contribution to glial scar. hCNS-SCns engraftment was associated with recovery of locomotor function. After long-term engraftment and stable behavioral plateaus in recovery were achieved (4 months post-transplantation), locomotor improvements were abolished by selective ablation of human cells with diphtheria toxin (DT). These data suggest that hCNS-SCns survival is required for locomotor recovery, possibly via differentiation and integration of human cells in the mouse host or continuous supply of trophic or other support necessary for gains in host cell function

Analysis of Host-Mediated Repair Mechanisms after Human CNS-Stem Cell Transplantation for Spinal Cord Injury: Correlation of Engraftment with Recovery

BackgroundHuman central nervous system-stem cells grown as neurospheres (hCNS-SCns) self-renew, are multipotent, and have potential therapeutic applications following trauma to the spinal cord. We have previously shown locomotor recovery in immunodeficient mice that received a moderate contusion spinal cord injury (SCI) and hCNS-SCns transplantation 9 days post-injury (dpi). Engrafted hCNS-SCns exhibited terminal differentiation to myelinating oligodendrocytes and synapse-forming neurons. Further, selective ablation of human cells using Diphtheria toxin (DT) abolished locomotor recovery in this paradigm, suggesting integration of human cells within the mouse host as a possible mechanism for the locomotor improvement. However, the hypothesis that hCNS-SCns could alter the host microenvironment as an additional or alternative mechanism of recovery remained unexplored; we tested that hypothesis in the present study.Methods and FindingsStereological quantification of human cells using a human-specific cytoplasmic marker demonstrated successful cell engraftment, survival, migration and limited proliferation in all hCNS-SCns transplanted animals. DT administration at 16 weeks post-transplant ablated 80.5% of hCNS-SCns. Stereological quantification for lesion volume, tissue sparing, descending serotonergic host fiber sprouting, chondroitin sulfate proteoglycan deposition, glial scarring, and angiogenesis demonstrated no evidence of host modification within the mouse spinal cord as a result of hCNS-SCns transplantation. Biochemical analyses supplemented stereological data supporting the absence of neural stem-cell mediated host repair. However, linear regression analysis of the number of engrafted hCNS-SCns vs. the number of errors on a horizontal ladder beam task revealed a strong correlation between these variables (r = −0.78, p&lt;0.05), suggesting that survival and engraftment were directly related to a quantitative measure of recovery.ConclusionsAltogether, the data suggest that the locomotor improvements associated with hCNS-SCns transplantation were not due to modifications within the host microenvironment, supporting the hypothesis that human cell integration within the host circuitry mediates functional recovery following a 9 day delayed transplant

hFb engraftment does not correlate with behavioral or histological measures of recovery.

<p>A: In contrast to hCNS-SCns, linear regression analysis revealed a positive, but non-significant correlation between hFb engraftment and the number of errors made on the horizontal ladderbeam task <i>(Pearson r = 0.49, p = 0.26, 2-tailed t-test</i>). B–D: Linear regression analyses for the estimated number of hFb and other measures of host recovery revealed no significant correlations between cell engraftment and lesion volume (B) (<i>Pearson r: r = 0.59, p = 0.16, 2-tailed t-test</i>), volume of spared tissue (B) (<i>Pearson r: r = 0.55, p = 0.21, 2-tailed t-test</i>), serotonergic fiber sprouting (C) (<i>Pearson r: r = −0.53, p = 0.22, 2-tailed t-test</i>), NG2 area (D) (<i>Pearson r: r = 0.01, p = 0.98, 2-tailed t-test</i>), and area of the GFAP astroglial scar (D) (<i>Pearson r: r = 0.22, p = 0.63, 2-tailed t-test</i>).</p

Human cell transplantation does not alter the areas of NG2 deposition or the GFAP astroglial scar.

<p>A: Estimated area occupied by the NG2 proteoglycan was analyzed using the Cavalieri estimator probe of StereoInvestigator. B: Quantification revealed no significant differences between any of the groups in the area occupied by NG2 (<i>One-way ANOVA: F = 0.005, p = 0.99</i>). C: Estimated area occupied by the GFAP scar was determined in the same manner as NG2. The lesion epicenter was not included in the estimated GFAP scar area. D: Stereological quantification exhibited no significant differences between any of the groups in the area of the GFAP astroglial scar (<i>One-way ANOVA: F = 1.50, p = 0.24</i>). Scale Bar = 250 µm for A and C.</p

Human cell transplantation does not alter the volumes of lesion epicenter or spared tisse.

<p>A: The lesion epicenter was identified as the region devoid of GFAP immunostaining. Regions 1 mm rostral and 1 mm caudal to the border of the lesion were selected for assessment of spared tissue. B: Volume assessments were performed using the Cavalieri estimator probe of StereoInvestigator and revealed no significant differences in the estimated lesion volume between any of the groups (<i>One-way ANOVA: F = 0.51, p = 0.60</i>). C: No significant differences were found in the estimated volume of spared tissue between any of the groups (<i>One-way ANOVA: F = 0.20, p = 0.82</i>). Scale bar = 250 µm.</p