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Thyroid hormone (TH) perturbation is a common medical problem. Because of substantial public health impact, prior researchers have studied hyper- and hypothyroidism in animal models. Although most prior research focused on in utero and/or developmental effects, changes in circulating TH levels are commonly seen in elderly individuals: approximately 20% of persons older than 80 years have clinically impactful hypothyroidism and up to 5% have clinical hyperthyroidism, with women being more often affected than men. TH disease model methodology in mice have varied but usually focus on a single sex, and the impact(s) of TH perturbation on the adult brain are not well understood. We administered thyroxine to middle-aged (13 to 14 months) male and female mice to model hyperthyroidism and TH-lowering drugs propylthiouracil (PTU) and methimazole, to induce hypothyroidism. These pharmacological agents are used commonly in adult humans. Circulating TH-level changes were observed when thyroxine was dosed at 20 µg/mL in drinking water for two weeks. By contrast, PTU and methimazole did not elicit a consistent reproducible effect until two months of treatment. No substantial changes in TH levels were detected in brain tissues of treated animals; however, pronounced changes in gene expression, specifically for TH-processing transcripts, were observed following the treatment with thyroxine. Our study indicated a robust compensatory mechanism by which the brain tissue/cells minimize the TH fluctuation in CNS by altering gene expression. Neurobehavioral changes were related to the TH perturbation and suggested potential associations between cognitive status and hyper- and hypothyroidism.

Neuropeptides are endogenous active substances that play important roles in a number of physiological processes and are ubiquitous in the nervous tissue in vivo. The gene encoding pedal peptide/orcokinin-type (PP/OK-type) neuropeptide is an important member of the neuropeptide gene family and is ubiquitous in invertebrates of Bilateria; orcokinin (OK) is mainly found in Arthropoda, while pedal peptide (PP) is mainly found in Mollusca. OK and PP are also present in other animals. PP/OK-type neuropeptides are a kind of multifunctional neuropeptides predominantly expressed in the nervous tissue and play important roles in the nerve regulation of movement. Moreover, OK has a number of other physiological functions. This review describes the distribution, expression, function and maturation of PP/OK-type neuropeptides to facilitate investigations of new functions and receptors of PP/OK-type neuropeptides, providing the theoretical foundation for the potential use of PP/OK-type neuropeptides in the prevention and control of agricultural and forestry pests, as an additive for skin care products and in the screening of drugs for the treatment of diabetes.

Iron homeostasis disturbance has been implicated in Alzheimer’s disease (AD), and excess iron exacerbates oxidative damage and cognitive defects. Ferroptosis is a nonapoptotic form of cell death dependent upon intracellular iron. However, the involvement of ferroptosis in the pathogenesis of AD remains elusive. Here, we report that ferroportin1 (Fpn), the only identified mammalian nonheme iron exporter, was downregulated in the brains of APPswe/PS1dE9 mice as an Alzheimer’s mouse model and Alzheimer’s patients. Genetic deletion of Fpn in principal neurons of the neocortex and hippocampus by breeding Fpnfl/fl mice with NEX-Cre mice led to AD-like hippocampal atrophy and memory deficits. Interestingly, the canonical morphological and molecular characteristics of ferroptosis were observed in both Fpnfl/fl/NEXcre and AD mice. Gene set enrichment analysis (GSEA) of ferroptosis-related RNA-seq data showed that the differentially expressed genes were highly enriched in gene sets associated with AD. Furthermore, administration of specific inhibitors of ferroptosis effectively reduced the neuronal death and memory impairments induced by Aβ aggregation in vitro and in vivo. In addition, restoring Fpn ameliorated ferroptosis and memory impairment in APPswe/PS1dE9 mice. Our study demonstrates the critical role of Fpn and ferroptosis in the progression of AD, thus provides promising therapeutic approaches for this disease.

During invasive mechanical ventilation, knowledge of the patient’s respiratory effort is valuable in guiding the clinical team to perform a personalized therapy. The same adjustment of the ventilator can produce excessive transpulmonary pressures for different patients, capable of generating or aggravating pre-existing lung injuries. The measurement of transpulmonary pressure (the difference between airway and pleural pressures) is not easily performed in practice. Although airway pressure measurement is available on most current mechanical ventilators, pleural pressure measurement is indirectly performed using an esophageal balloon. In many cases, esophageal pressure reading takes other phenomena into account and is not a reliable measure of pleural pressure. This work will study system identification techniques to obtain reliable pleural pressures based on esophageal pressure readings, aiming to provide the clinical team with information about the patient’s ventilatory therapy’s real status. By estimating transfer function models, autoregressive with external input (ARX) and output error (OE) polynomial models, waveforms were adjusted in two different patients’ occlusion maneuver data. Different metrics were used to assess the quality of the models obtained. The analysis results showed that the estimation methods used provided plausible representations of the underlying dynamic system. Therefore, there are indications that the system identification techniques presented in this work can be used in general, in a clinical environment, to provide reliable estimates of pleural pressure based on esophageal pressure measurements.

Radiotherapy is one of the most effective treatments for head and neck tumors. However, delayed radiation-induced brain necrosis (RN) remains a serious issue due to the lack of satisfying prevention and effective treatment. The pathological role of radiation in the delayed onset of brain necrosis is still largely unknown, and the traditional animal model of whole brain irradiation, although being widely used, does not produce reliable and localized brain necrosis mimicking clinical features of RN. In this study, we demonstrated a successful RN mouse model using optimized gamma knife irradiation in male C57BL/6 mice. On the premise that brain necrosis started to appear at 6 weeks postirradiation in our RN model, as confirmed by both MRI and histopathological examinations, we systematically examined different time points before the onset of RN for the histopathological changes and biochemical indicators. Our initial results demonstrated that in the ipsilateral hemisphere of the irradiated brains, a significant decrease in neuronal numbers that occurred at 4 weeks and a sustained increase in TNF-α, iNOS, and other inflammatory cytokines beginning at 1-week postirradiation. Changes of cell morphology and cell numbers of both microglia and astrocytes occurred as early as 1-week postirradiation, and intervention by bevacizumab administration resulted in reduced microglia activation and reduction of radiation-induced lesion volume, indicating that chronic glial activation may result in subsequent elevation of inflammatory factors, which led to the delayed onset of neuronal loss and brain necrosis. Since C57BL/6 is the most widely used strain of genetic engineered mouse model, our data provide an invaluable platform for the mechanistic study of RN pathogenesis, identification of potential imaging and biological biomarkers, and the development of therapeutic treatment for the disease.

The mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are specific ER domains that contact the mitochondria and function to facilitate communication between ER and mitochondria. Disruption of contact between the mitochondria and ER is associated with a variety of pathophysiological conditions including neurodegenerative diseases. Considering the many cellular functions of MAMs, we hypothesized that MAMs play an important role in regulating microRNA (miRNA) activity linked to its unique location between mitochondria and ER. Here we present new findings from human and rat brains indicating that the MAMs are subcellular sites enriched for specific miRNAs. We employed subcellular fractionation and TaqMan® RT-qPCR miRNA analysis to quantify miRNA levels in subcellular fractions isolated from male rat brains and six human brain samples. We found that MAMs contain a substantial number of miRNAs and the profile differs significantly from that of cytosolic, mitochondria, or ER. Interestingly, MAMs are particularly enriched in inflammatory-responsive miRNAs, including miR-146a, miR-142-3p, and miR-142-5p in both human and rat brains; miR-223 MAM enrichment was observed only in human brain samples. Further, mitochondrial uncoupling or traumatic brain injury in male rats resulted in the alteration of inflammatory miRNA enrichment in the isolated subcellular fractions. These observations demonstrate that miRNAs are distributed differentially in organelles and may re-distribute between organelles and the cytosol in response to cellular stress and metabolic demands. Electronic supplementary material The online version of this article (10.1007/s12035-020-01937-y) contains supplementary material, which is available to authorized users.

Supplemental material, sj-docx-1-wso-10.1177_17474930221090133 for Sex differences in the symptom presentation of stroke: A systematic review and meta-analysis by Sultana Shajahan, Lingli Sun, Katie Harris, Xia Wang, Else Charlotte Sandset, Amy YX Yu, Mark Woodward, Sanne AE Peters and Cheryl Carcel in International Journal of Stroke

Supplemental material, sj-pdf-1-wso-10.1177_17474930211064076 for J-shape relation of blood pressure reduction and outcome in acute intracerebral hemorrhage: A pooled analysis of INTERACT2 and ATACH-II individual participant data by Xia Wang, Gian Luca Di Tanna, Tom J Moullaali, Renee��� H Martin, Virginia B Shipes, Thompson G Robinson, John Chalmers, Jose I Suarez, Adnan I Qureshi, Yuko Y Palesch and Craig S Anderson in International Journal of Stroke

Supplemental meterial, sj-pdf-1-eso-10.1177_23969873221078136 for Pressor therapy in acute ischaemic stroke: an updated systematic review by Torbj��rn Austveg Str��msnes, Truls J��rgen Kaugerud Hagen, Menglu Ouyang, Xia Wang, Chen Chen, Silje-Emilie Rygg, David Hewson FRCA, Rob Lenthall, Norman McConachie, Wazim Izzath, Philip M Bath, Permesh Singh Dhillon, Anna Podlasek, Timothy England, Nikola Sprigg, Thompson G Robinson, Rajiv Advani, Hege Ihle-Hansen, Else Charlotte Sandset and Kailash Krishnan in European Stroke Journal

Sex is a key biological variable in traumatic brain injury (TBI) and plays a significant role in neuroinflammatory responses. However, the molecular mechanisms contributing to this sexually dimorphic neuroinflammatory response remain elusive. Here we describe a significant and previously unreported tissue enrichment and sex specific alteration of a set of inflammatory microRNAs (miRNAs) in CD11b + cells of brain and bone marrow isolated from naïve mice as well as mice subjected to TBI. Our data from naïve mice demonstrated that expression levels of miR-146a-5p and miR-150-5p were relatively higher in brain CD11b + cells, and that miR-155-5p and miR-223-3p were highly enriched in bone marrow CD11b + cells. Furthermore, while miR-150-5p and miR-155-5p levels were higher in male brain CD11b + cells, no significant sexual difference was observed for miR-146a-5p and miR-223-3p. However, TBI resulted in sex specific differential responses of these miRNAs in brain CD11b + cells. Specifically, miR-223 levels in brain CD11b + cells were markedly elevated in both sexes in response to TBI at 3 and 24 hr, with levels in females being significantly higher than males at 24 hr. We then focused on analyzing several miR-223-3p targets and inflammation-related marker genes following injury. Corresponding to the greater elevation of miR-223-3p in females, the miR-223-3p targets, TRAF6 and FBXW7 were significantly reduced in females compared to males. Interestingly, anti-inflammatory genes ARG1 and IL4 were higher in females after TBI than in males. These observations suggest miR-223-3p and other inflammatory responsive miRNAs may play a key role in sex-specific neuroinflammatory response following TBI.

We found evidence of late-onset Alzheimer disease (LOAD)-associated genetic polymorphism within an exon of Mucin 6 (MUC6) and immediately downstream from another gene: Adaptor Related Protein Complex 2 Subunit Alpha 2 (AP2A2). PCR analyses on genomic DNA samples confirmed that the size of the MUC6 variable number tandem repeat (VNTR) region was highly polymorphic. In a cohort of autopsied subjects with quantitative digital pathology data (n = 119), the size of the polymorphic region was associated with the severity of pTau pathology in neocortex. In a separate replication cohort of autopsied subjects (n = 173), more pTau pathology was again observed in subjects with longer VNTR regions (p = 0.031). Unlike MUC6, AP2A2 is highly expressed in human brain. AP2A2 expression was lower in a subset analysis of brain samples from persons with longer versus shorter VNTR regions (p = 0.014 normalizing with AP2B1 expression). Double-label immunofluorescence studies showed that AP2A2 protein often colocalized with neurofibrillary tangles in LOAD but was not colocalized with pTau proteinopathy in progressive supranuclear palsy, or with TDP-43 proteinopathy. In summary, polymorphism in a repeat-rich region near AP2A2 was associated with neocortical pTau proteinopathy (because of the unique repeats, prior genome-wide association studies were probably unable to detect this association), and AP2A2 was often colocalized with neurofibrillary tangles in LOAD.

Antibiotics are the front-line treatment against many bacterial infectious diseases in human. The excessive and long-term use of antibiotics in human cause several side effects. It is important to understand the underlying molecular mechanisms of action of antibiotics in the host cell to avoid the side effects due to the prevalent uses. In the current study, we investigated the crosstalk between mitochondria and lysosomes in the presence of widely used antibiotics: erythromycin (ERM) and clindamycin (CLDM), which target the 50S subunit of bacterial ribosomes. We report here that both ERM and CLDM induced caspase activation and cell death in several different human cell lines. The activity of the mitochondrial respiratory chain was compromised in the presence of ERM and CLDM leading to bioenergetic crisis and generation of reactive oxygen species. Antibiotics treatment impaired autophagy flux and lysosome numbers, resulting in decreased removal of damaged mitochondria through mitophagy, hence accumulation of defective mitochondria. We further show that over-expression of transcription factor EB (TFEB) increased the lysosome number, restored mitochondrial function and rescued ERM- and CLDM-induced cell death. These studies indicate that antibiotics alter mitochondria and lysosome interactions leading to apoptotsis and may develop a novel approach for targeting inter-organelle crosstalk to limit deleterious antibiotic-induced side effects.

In order to reduce the weight of the lithium-ion battery and increase its capacity, the copper foil as a conventional current collector is completely abandoned, and a novel ultralight negative electrode prepared by freeze-drying technology and carboxymethyl cellulose (CMC) has a 3D sponge-like structure. Further, graphite is employed as an electrode material. X-ray diffraction and Raman spectroscopy show no damage to the graphite structure during the formation of the carbon sponge. The thin layer of acetylene black deposit acts as a current collector and allows graphite to maximize contact with the electrolyte. In the half-cell experiment, this new 3D CMC spongy ultralight collector-free electrode achieves considerable cyclical stability. This paper describes innovative and fairly simple techniques to fully realize 3D CMC sponge-like current collector applied in lithium-ion battery, rather than relatively heavy and expensive copper foil, thereby improving the weight and volumetric energy density of such advanced batteries.

Approximately one-third of aneurysmal subarachnoid hemorrhage (aSAH) patients develop delayed cerebral vasospasm (DCV) 3–10 days after aneurysm rupture resulting in additional, permanent neurologic disability. Currently, no validated biomarker is available to determine the risk of DCV in aSAH patients. MicroRNAs (miRNAs) have been implicated in virtually all human diseases, including aSAH, and are found in extracellular biofluids including plasma and cerebrospinal fluid (CSF). We used a custom designed TaqMan Low Density Array miRNA panel to examine the levels of 47 selected brain and vasculature injury related miRNAs in CSF and plasma specimens collected from 31 patients with or without DCV at 3 and 7 days after aSAH, as well as from eight healthy controls. The analysis of the first 18-patient cohort revealed a striking differential expression pattern of the selected miRNAs in CSF and plasma of aSAH patients with DCV from those without DCV. Importantly, this differential expression was observed at the early time point (3 days after aSAH), before DCV event occurs. Seven miRNAs were identified as reliable DCV risk predictors along with a prediction model constructed based on an array of additional 19 miRNAs on the panel. These chosen miRNAs were then used to predict the risk of DCV in a separate, testing cohort of 15 patients. The accuracy of DCV risk prediction in the testing cohort reached 87%. The study demonstrates that our novel designed miRNA panel is an effective predictor of DCV risk and has strong applications in clinical management of aSAH patients.

Supplemental material, sj-pdf-1-wso-10.1177_17474930211025436 for Thrombolysis outcomes according to arterial characteristics of acute ischemic stroke by alteplase dose and blood pressure target by Zien Zhou, Chao Xia, Grant Mair, Candice Delcourt, Sohei Yoshimura, Xiaosheng Liu, Zengai Chen, Alejandra Malavera, Cheryl Carcel, Xiaoying Chen, Xia Wang, Rustam Al-Shahi Salman, Thompson G Robinson, Richard I Lindley, John Chalmers, Joanna M Wardlaw, Mark W Parsons, Andrew M Demchuk and Craig S Anderson in International Journal of Stroke

It is well-established that lysine-specific demethylase 1 (LSD1) is the first identified histone demethylase. Based on its demethylase enzymatic activity, LSD1 plays a pivotal role in vast range of cellular processes and cancers, but the understanding of its effects on inflammation is relatively limited. Using in vivo models of lipopolysaccharide (LPS)-induced inflammation and in vitro assays in mouse mammary epithelial cells, we identified the novel regulatory roles and underlying mechanisms of LSD1 on LPS-induced mastitis. Mammary gland and cells were collected for the following experiments after treatment. Histological changes were determined by H&E. Western blot analysis was used to detect the protein expression. ELISA and real-time PCR were used to evaluate protein and mRNA expression of inflammatory genes. Our results showed that LPS treatment resulted in a significant increase in LSD1 protein expression. GSK-LSD1 is a selective inhibitor of LSD1 enzyme activity. Treatment of mice with GSK-LSD1 inhibited LSD1 activity, reduced inflammatory cells recruitment to tissues and attenuated LPS-induced damage in mammary gland. Mechanistic investigations suggested that LSD1 inhibition led to the increase of histone H3K4me2 and H3K9me2. Furthermore, GSK-LSD1 inhibition of LSD1 further inhibited nuclear factor κ-B (NF-κB) signaling cascades, and subsequently inhibited the production of cytokines (TNF-α, IL-6 and IL-1β) in mammary gland. Taken together, our data reveal LSD1 as a potential regulator of inflammation and improve our understanding of epigenetic control on inflammation.

Supplemental material, WSO908140 Supplemental material for Prognostic significance of early urinary catheterization after acute stroke: Secondary analyses of the international HeadPoST trial by Menglu Ouyang, Laurent Billot, Lili Song, Xia Wang, Christine Roffe, Hisatomi Arima, Pablo M Lavados, Maree L Hackett, Verónica V Olavarría, Paula Muñoz-Venturelli, Sandy Middleton, Octavio M Pontes-Neto, Tsong-Hai Lee, Caroline L Watkins, Thompson G Robinson and Craig S Anderson in International Journal of Stroke

Supplemental material, sj-pdf-1-wso-10.1177_1747493020938307 for Worse prognosis in women, compared with men, after thrombolysis: An individual patient data pooling study of Asian acute stroke registries by Xia Wang, Cheryl Carcel, Ruigang Wang, Jingwei Li, Hee-Joon Bae, Yilong Wang, Anxin Wang, Yongjun Wang, Kazunori Toyoda, Yi Sui, Tsong-Hai Lee, Jose C Navarro, Mu-Chien Sun, Craig S Anderson, Vijay Sharma, Else C Sandset and Mark Woodward: INDAGA Cardiologists Investigators in International Journal of Stroke

The novel coronavirus (2019‐nCoV) was first detected in patients with pneumonia of an unknown cause in Wuhan, China in December 2019. It has since been confirmed as the pathogen for the new coronavirus pneumonia, recently named “coronavirus disease 2019” (COVID‐19) by the World Health Organization. Although the general population is commonly susceptible to the disease, infected elderly people show fast progression and severe manifestations with a high proportion in critical condition as a result of compromised immunity and underlying diseases. In order to improve the quality of nursing, reduce complications, and decrease mortality of critically ill elderly patients, we assembled a national expert group with expertise in critical nursing to write this consensus, based on a literature review and a subsequent panel discussion. The consensus covers the assessment, clinical nursing, discharge care, and other aspects of care for critically ill elderly patients with COVID‐19, aiming to share insights and provide guidance for clinical practice.

Supplemental material, WSO897858 Supplemental material1 for Validation of the simplified modified Rankin scale for stroke trials: Experience from the ENCHANTED alteplase-dose arm by Xiaoying Chen, Jingwei Li, Craig S Anderson, Richard I Lindley, Maree L Hackett, Thompson Robinson, Pablo M Lavados, Xia Wang, Hisatomi Arima, John Chalmers, Candice Delcourt and for the ENCHANTED Investigators in International Journal of Stroke

Supplemental material, WSO904913 Supplemental Material1 for Sleep duration and risk of cardiovascular events: The SAVE study by Jingwei Li, Danni Zheng, Kelly A Loffler, Xia Wang, R Doug McEvoy, Richard J Woodman, Yuanming Luo, Geraldo Lorenzi-Filho, Ferran Barbe, Manjari Tripathi, Craig S Anderson and for the SAVE Investigators in International Journal of Stroke

Supplemental material, sj-pdf-1-eso-10.1177_2396987320957513 for Sex differences in treatment, radiological features and outcome after intracerebral haemorrhage: Pooled analysis of Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage trials 1 and 2 by Else Charlotte Sandset, Xia Wang, Cheryl Carcel, Shoichiro Sato, Candice Delcourt, Hisatomi Arima, Christian Stapf, Thompson Robinson, Pablo Lavados, John Chalmers, Mark Woodward and Craig S Anderson in European Stroke Journal

In this paper, the optical forces of particles in optical tweezers under non-ideal conditions are investigated. The calculation of optical forces are carried out by combining three dimensional finite-difference time-domain (FDTD) method and Maxwell stress Tensor (MST). Numerical results show the changes of trapping stiffness and equilibrium position induced by several common seen non-ideal conditions in experiment. This study is expected to estimate the error of optical force in real situation and that is of great use to further optimize the performance of optical tweezers.

Alzheimer’s disease (AD) and type-2 diabetes mellitus (T2DM) are highly prevalent aging-related diseases associated with significant morbidity and mortality. Some findings in human and animal models have linked T2DM to AD-type dementia. Despite epidemiological associations between the T2DM and cognitive impairment, the inter-relational mechanisms are unclear. The preponderance of evidence in longitudinal studies with autopsy confirmation have indicated that vascular mechanisms, rather than classic AD-type pathologies, underlie the cognitive decline often seen in self-reported T2DM. T2DM is a known risk factor for cardiovascular and cerebrovascular disease (CVD), including increased risk of infarcts and small vessel disease in the brain and other organs. Furthermore, neuropathological examinations of post-mortem brains demonstrated evidence of cerebrovascular disease and little to no correlation between T2DM and β-amyloid deposits or neurofibrillary tangles. Nevertheless, the mechanisms upstream of early AD-specific pathology remain obscure. In this regard, there may indeed be overlap between the pathologic mechanisms of T2DM/”metabolic syndrome”, and AD. More specifically, cerebral insulin processing, glucose metabolism, mitochondrial function, and/or lipid metabolism could be altered in patients in early AD and directly influence symptomatology and/or neuropathology.

Mastitis is an inflammation of mammary gland, which directly affects the milk production performance and causes huge economic losses in the dairy industry. During mastitis, the blood-milk barrier (BMB) loses its integrity and aggravates the severity of mastitis. Exogenous DNase I has been exerted protective effects in different model of tissue injury. Here, we designed a study to investigate the effects of DNase I on inflammation and BMB in a mice model of Staphylococcus aureus-induced mastitis. In the model, we found that DNase I treatment significantly alleviated the inflammatory response through decrease of inflammatory cells in mammary alveoli, MPO activity and cytokines in mammary gland. Furthermore, immunofluorescent staining and western blotting demonstrated that exogenous DNase I obviously reduced BMB permeability and changed the expression of tight junction proteins to support the re-establishment of the barrier integrity. Mechanismly, DNase I treatment inhibited NF-κB and enhanced AKT signaling pathways. Therefore, our results indicate that DNase I may be an effective treatment for attenuating mastitis.

Aneurysmal subarachnoid hemorrhage (aSAH) is a high mortality hemorrhagic stroke that affects nearly 30,000 patients annually in the United States. Approximately 30% of aSAH patients die during initial hospitalization and those who survive often carry poor prognosis with one in five having permanent physical and/or cognitive disabilities. The poor outcome of aSAH can be the result of the initial catastrophic event or due to the many acute or delayed neurological complications, such as cerebral ischemia, hydrocephalus, and re-bleeding. Unfortunately, no effective biomarker exists to predict or diagnose these complications at a clinically relevant time point when neurologic injury can be effectively treated and managed. Recently, a number of studies have demonstrated that microRNAs (miRNAs) in extracellular biofluids are highly associated with aSAH and complications. Here we provide an overview of the current research on relevant human studies examining the correlation between miRNAs and aSAH complications and discuss the potential application of using miRNAs as biomarkers in aSAH management.

Traumatic brain injury (TBI) is a leading cause of long-term impairments in higher cognitive functioning, including deficits in attention and memory. It is well known that some of these persistent deficits are related, in part, to ongoing secondary injury events characterized by pervasive biochemical and pathophysiological stressors, including a rapid and sustained phase of mitochondrial dysfunction. A loss of mitochondrial function impacts a number of important cellular events and we have begun to investigate the novel hypothesis that mitochondria play a critical role in regulating the cellular activity of specific microRNAs in response to cellular demands and stressors. In this special issue report, we summarize briefly the rationale for investigating the crosstalk between mitochondria and microRNA, and provide recent preliminary data suggesting that mitochondria-microRNA interactions are modified in response to TBI-related cellular stressors. We postulate that this interaction is critical for regulating appropriate cellular microRNA responses, which opens up opportunities for therapeutic interventions targeting both mitochondrial function and microRNA activity.

ObjectiveThis study aimed to evaluate the therapeutic effect of caffeine citrate on early premature infants with apnea of prematurity (AOP), and the impact on movement and neurobehavioral development in their early lives.Study designAmongst 397 premature infants whose gestational age (GA) were less than 32 weeks, 172 premature infants were eligible for this study from January 2014 to May 2017. 94 infants received caffeine citrate intervention, 20 infants were given aminophyline and the rest 58 infants didn't received any methylxanthines. According to the incidence of apnea, caffeine using was divided into two situations of therapeutic and preventive administration. The primary clinical outcomes were recorded which included length of stay (LOS), duration of mechanical ventilation, the incidence of complications and outcomes.Results62 cases (66%) were assigned to receive caffeine within 3 days after birth, and 69 cases (74%) received caffeine less than one month. Caffeine could reduce LOS, duration of MV and nasal continues positive airway pressure (nCPAP), the incidence of nosocomial infection and bronchial pulmonary dysplasia (BPD) (p0.05). Caffeine showed different effects on clinical outcomes in early premature infants based on their GAs, and premature infants with larger GA could benefit more from the intervention (p

The surface bioinspired modification of particles and films is a mainstream direction in biomaterial design and application. The interfacial coating of extracellular-matrix-like hydrogel can endow functional inorganic nanoparticles high circulation stability and biocompatibility but remains challenging due to large surface tension difference between organic gelators and solid nanosurfaces. Herein, the supramolecular hydrogel of NapGdFdFdK around gold nanorods (Au NRs-Gel) has been constructed by the amidation-grafting modification and the protonation-induced interface-assistant assembly of peptide precursors. As a proof of concept study, the acoustic cavitation experiments and in vitro ultrasound imaging have proved that the abundant hydrophobic microdomains as well as the water-rich network in the supramolecular hydrogel can serve as valid sites to efficiently generate and stabilize nanobubbles as cavitation seeds to realize bubble-free ultrasound imaging. In vivo augmented ultrasound imaging and imaging-guided high intensity focused ultrasound (HIFU) therapy based on the Balb/c mice bearing HeLa tumor model have been conducted. As the first example of using nanosurface hydrogelation to endow nanoparticles with bubble-free ultrasound theranostic ability, this work offers a simple approach to design multifunctional nanovehicles for ultrasound-guided drug/protein/gene delivery.

TDP-43 proteinopathy is very prevalent among the elderly (affecting at least 25% of individuals over 85 years of age) and is associated with substantial cognitive impairment. Risk factors implicated in age-related TDP-43 proteinopathy include commonly inherited gene variants, comorbid Alzheimer's disease pathology, and thyroid hormone dysfunction. To test parameters that are associated with aging-related TDP-43 pathology, we performed exploratory analyses of pathologic, genetic, and biochemical data derived from research volunteers in the University of Kentucky Alzheimer's Disease Center autopsy cohort (n = 136 subjects). Digital pathologic methods were used to discriminate and quantify both neuritic and intracytoplasmic TDP-43 pathology in the hippocampal formation. Overall, 46.4% of the cases were positive for TDP-43 intracellular inclusions, which is consistent with results in other prior community-based cohorts. The pathologies were correlated with hippocampal sclerosis of aging (HS-Aging) linked genotypes. We also assayed brain parenchymal thyroid hormone (triiodothyronine [T3] and thyroxine [T4]) levels. In cases with SLCO1A2/IAPP or ABCC9 risk associated genotypes, the T3/T4 ratio tended to be reduced (p = .051 using 2-tailed statistical test), and in cases with low T3/T4 ratios (bottom quintile), there was a higher likelihood of HS-Aging pathology (p = .025 using 2-tailed statistical test). This is intriguing because the SLCO1A2/IAPP and ABCC9 risk associated genotypes have been associated with altered expression of the astrocytic thyroid hormone receptor (protein product of the nearby gene SLCO1C1). These data indicate that dysregulation of thyroid hormone signaling may play a role in age-related TDP-43 proteinopathy.

Supplemental Material for Applicability of ENCHANTED trial results to current acute ischemic stroke patients eligible for intravenous thrombolysis in England and Wales: Comparison with the Sentinel Stroke National Audit Programme registry by Thompson G Robinson, Benjamin D Bray, Lizz Paley, Nikola Sprigg, Xia Wang, Hisatomi Arima, Philip M Bath, Joseph P Broderick, Alice C Durham, Jong S Kim, Pablo M Lavados, Tsong-Hai Lee, Sheila Martins, Thang H Nguyen, Jeyaraj D Pandian, Mark W Parsons, Octavio M Pontes-Neto, Stefano Ricci, Vijay K Sharma, Jiguang Wang, Mark Woodward, Anthony G Rudd, John Chalmers, Craig S Anderson and for the ENCHANTED Investigators and the SSNAP Collaboration in International Journal of Stroke

Supplemental Material for Low-dose versus standard-dose alteplase in acute ischemic stroke in Asian stroke registries: an individual patient data pooling study by Xia Wang, Jingwei Li, Tom J Moullaali, Keon-Joo Lee, Beom Joon Kim, Hee-Joon Bae, Anxin Wang, Yilong Wang, David Z Wang, Yongjun Wang, Masaya Kumamoto, Kazunori Toyoda, Masatoshi Koga, Shoichiro Sato, Sohei Yoshimura, Yi Sui, Bing Xu, Ying Xiao, Tsong-Hai Lee, Chia-Wei Liou, Jiann-Der Lee, Tsung-I Peng, Yen-Chu Huang, Prakash R Paliwal, Manasi Sharma, Cyrus Escabillas, Jose C Navarro, Mu-Chien Sun, Yi Dong, Qiang Dong, Craig S Anderson and Vijay K Sharma: for the ENCHANTED Investigators in International Journal of Stroke

Supplemental Material for Oedema extension distance in intracerebral haemorrhage: Association with baseline characteristics and long-term outcome by Robert Hurford, Andy Vail, Calvin Heal, Wendy C Ziai, Jesse Dawson, Santosh B Murthy, Xia Wang, Craig S Anderson, Daniel F Hanley, Adrian R Parry-Jones and on behalf of the VISTA-ICH Collaborators: the STRONG STAR Consortium in European Stroke Journal

Supplemental Material for Who will benefit more from low-dose alteplase in acute ischemic stroke? by Xia Wang, Keon-Joo Lee, Tom J Moullaali, Beom Joon Kim, Qiang Li, Hee-Joon Bae, Cheryl Carcel, Candice Delcourt, Hisatomi Arima, Shoichiro Sato, Thompson G Robinson, Lili Song, Guofang Chen, Jie Yang, John Chalmers, Craig S Anderson, Richard Lindley, Mark Woodward and for the ENCHANTED Investigators in International Journal of Stroke

The pathology-based classification of Alzheimer’s disease (AD) and other neurodegenerative diseases is a work in progress that is important for both clinicians and basic scientists. Analyses of large autopsy series, biomarker studies, and genomics analyses have provided important insights about AD and shed light on previously unrecognized conditions, enabling a deeper understanding of neurodegenerative diseases in general. After demonstrating the importance of correct disease classification for AD and primary age-related tauopathy, we emphasize the public health impact of an underappreciated AD “mimic,” which has been termed “hippocampal sclerosis of aging” or “hippocampal sclerosis dementia.” This pathology affects >20% of individuals older than 85 years and is strongly associated with cognitive impairment. In this review, we provide an overview of current hypotheses about how genetic risk factors ( GRN , TMEM106B , ABCC9 , and KCNMB2 ), and other pathogenetic influences contribute to TDP-43 pathology and hippocampal sclerosis. Because hippocampal sclerosis of aging affects the “oldest-old” with arteriolosclerosis and TDP-43 pathologies that extend well beyond the hippocampus, more appropriate terminology for this disease is required. We recommend “cerebral age-related TDP-43 and sclerosis” (CARTS). A detailed case report is presented, which includes neuroimaging and longitudinal neurocognitive data. Finally, we suggest a neuropathology-based diagnostic rubric for CARTS.

BACKGROUND Our goals were to screen newborns and characterize the occurrence of glucose-6-phosphate dehydrogenase (G6PD) deficiency in southwestern China. Meanwhile, we would like to analyze the factors that might affect the results of neonatal dried blood spots for glucose-6-phosphate dehydrogenase screening test, to improve the clinical quality control level, effectively reduce the external factors in the process of detection. METHODS This study involved an evaluation of G6PD data for 20,644 newborns from a universal newborn screening program. Heel prick blood specimens were collected around 72 hours after birth and were dried on filter papers. For G6PD deficiency the fluorescent spot test was employed. We studied the association between incidence of G6PD deficiency and influence factors. RESULTS This study involved an evaluation of G6PD data for 20,644 neonatal heel prick blood samples from 10,984 males and 9,660 females. There were 503 positive results for G6PD deficiency (299 males and 204 females), and the G6PD deficiency-positive rate was estimated to be around 2.4%. The gender-specific prevalence for males was 2.7%, and for females 2.1%. Multiple factors may influence the result of the G6PD test, such as season, temperature, and specimen of indwelling time. CONCLUSIONS This study analyzed the prevalence of G6PD deficiency in Sichuan, China. Accelerating the speed of sample delivery and ensuring availability of screening results can aid the screening and diagnosis.

Made available in DSpace on 2018-12-11T17:19:48Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-07-01 National Natural Science Foundation of China Objectives: The water-associated attributes of resin-dentin interfaces created by contemporary adhesives are important determinants of bond integrity and stability. In the present work, these attributes were estimated from the perspectives of causality, to examine the behavior of the first and most-recently launched versions of universal adhesives when applied in either the etch-and-rinse mode or the self-etch mode. Methods: The immediate cause of interfacial permeability and the time-dependent cause of water sorption were investigated in conjunction with the intermediate effect of interface degradation and the more long-term effect of loss of mechanical strength, before and after thermomechanical cycling. The results were compared with control etch-and-rinse and self-etch adhesives. Results: Although the introduction of this new class of universal adhesives has brought forth significant changes to the dental adhesion arena, including more application options, reduced bonding armamentarium and increased user friendliness, the water-associated attributes that are critical for making resin-dentin bonds more durable to environmental challenges and less susceptible to degradation have remained unchanged at large, when compared with benchmarks established by former classes of adhesives. Conclusion: It appears that the current trend of adhesive development has brought forth significant changes but lacks the vigor that demarcates progress and technological sublimity. Clinical significance: The advent of the user friendly universal adhesives has brought forth significant changes to the dental adhesion arena. However, the elements that are critical for making resin-dentin bonds more durable to environmental challenges and less susceptible to degradation have remained unchanged at large. Department of Restorative Dentistry Institute of Science and Technology São Paulo State University UNESP São Jose dos Campos Department of Operative Dentistry and Endodontics Guanghua School of Stomatology & Guangdong Provincial Key Laboratory of Stomatology Sun Yat-sen University State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology School of Stomatology The Fourth Military Medical University Department of Endodontics The Dental College of Georgia Augusta University Department of Biomedical and Neuromotor Sciences DIBINEM University of Bologna – Alma Mater Studiorum The Third Affiliated Hospital of Xinxiang Medical University Department of Restorative Dentistry Institute of Science and Technology São Paulo State University UNESP São Jose dos Campos National Natural Science Foundation of China: 81720108011 National Natural Science Foundation of China: 81722015

Supplemental material for Statistical analysis plan for evaluating different intensities of blood pressure control in the ENhanced Control of Hypertension And Thrombolysis strokE stuDy by Craig S Anderson, Mark Woodward, Hisatomi Arima, Xiaoying Chen, Richard I Lindley, Xia Wang, John Chalmers and Thompson G Robinson in International Journal of Stroke

Supplemental Material for Statistical analysis plan for pooled individual patient data from two landmark randomized trials (INTERACT2 and ATACH-II) of intensive blood pressure lowering treatment in acute intracerebral hemorrhage by Tom J Moullaali, Xia Wang, Renee' H Martin, Virginia B Shipes, Adnan I Qureshi, Craig S Anderson and Yuko Y Palesch in International Journal of Stroke

HLA-B*40:317 differs from HLA-A*40:06:01:01 by one nucleotide exchange at position 344(G>T) with an amino exchange.

The ABCC9 gene and its polypeptide product, SUR2, are increasingly implicated in human neurologic disease, including prevalent diseases of the aged brain. SUR2 proteins are a component of the ATP-sensitive potassium ("KATP") channel, a metabolic sensor for stress and/or hypoxia that has been shown to change in aging. The KATP channel also helps regulate the neurovascular unit. Most brain cell types express SUR2, including neurons, astrocytes, oligodendrocytes, microglia, vascular smooth muscle, pericytes, and endothelial cells. Thus it is not surprising that ABCC9 gene variants are associated with risk for human brain diseases. For example, Cantu syndrome is a result of ABCC9 mutations; we discuss neurologic manifestations of this genetic syndrome. More common brain disorders linked to ABCC9 gene variants include hippocampal sclerosis of aging (HS-Aging), sleep disorders, and depression. HS-Aging is a prevalent neurological disease with pathologic features of both neurodegenerative (aberrant TDP-43) and cerebrovascular (arteriolosclerosis) disease. As to potential therapeutic intervention, the human pharmacopeia features both SUR2 agonists and antagonists, so ABCC9/SUR2 may provide a "druggable target", relevant perhaps to both HS-Aging and Alzheimer's disease. We conclude that more work is required to better understand the roles of ABCC9/SUR2 in the human brain during health and disease conditions.

Prophenoloxidase (PPO) is an essential enzyme in insect innate immunity because of its role in humoral defense. In this study, we have cloned a full-length cDNA of Antheraea pernyi prophenoloxidase (ApPPO) with an open-reading frame encoding 683 amino acids, and the deduced amino acid sequence of ApPPO exhibited a high similarity with those of lepidoptera. The expression of ApPPO was inducible so that the mRNA level was significantly upregulated in the microbial challenged tissues, including fat body, hemocytes, and midgut. To better investigate the enzymatic and immunological properties of ApPPO, recombinant ApPPO (rApPPO) was produced in Escherichia coli. Several functional verification experiments were performed after studying the enzymatic properties. It was found that rApPPO could be stimulated by the microbial challenged larvae hemolymph and then killed bacteria in the radial diffusion assay. Furthermore, rApPPO also induced the transcription of cecropins after injected into the larvae 24 h later.

Misfolded protein in the amygdala is a neuropathologic feature of Alzheimer disease and many other neurodegenerative disorders. We examined extracts from human amygdala (snap-frozen at autopsy) to investigate whether novel and as yet uncharacterized misfolded proteins would be detectable. Polypeptides from the detergent-insoluble, urea-soluble protein fractions of amygdala were interrogated using liquid chromatography-electrospray ionization-tandem mass spectrometry. Among the detergent-insoluble proteins identified in amygdala of demented subjects but not controls were Tau, TDP-43, Aβ, α-synuclein, and ApoE. Additional detergent-insoluble proteins from demented subjects in the high-molecular weight portion of SDS gels included NNT, TNIK, PRKDC (DNA-PK, or DNA-PKcs), ferritin light chain (FTL), AIFM1, SYT11, STX1B, EAA1, COL25A1, M4K4, CLH1, SQSTM, SYNJ1, C3, and C4. In follow-up immunohistochemical experiments, NNT, TNIK, PRKDC, AIFM1, and FTL were observed in inclusion body-like structures in cognitively impaired subjects' amygdalae. Double-label immunofluorescence revealed that FTL and phospho-PRKDC immunoreactivity colocalized partially with TDP-43 and/or Tau inclusion bodies. Western blots showed high-molecular weight "smears", particularly for NNT and PRKDC. A preliminary genetic association study indicated that rare NNT, TNIK, and PRKDC gene variants had nominally significant association with Alzheimer-type dementia risk. In summary, novel detergent-insoluble proteins, with evidence of proteinaceous deposits, were found in amygdalae of elderly, cognitively impaired subjects.