Abstract P732: Genetic Ablation of Endothelial C3a-Receptor Confers Cerebrovascular Protection Independent of the Dynamics of Reperfusion in Stroke

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Adam Kindelin ◽  
Sara Bowen ◽  
Saif Ahmad ◽  
Michael F Waters ◽  
Nasrul Hoda ◽  
...  
Keyword(s):  
Infarct Volume ◽  
Critical Role ◽  
Behavioral Outcomes ◽  
Intravenous Thrombolysis ◽  
Similar Degree ◽  
Genetic Ablation ◽  
Neurovascular Injury ◽  
Volume Blood ◽  
Inflammatory Effect

Background: Stroke enhances endothelial C3a Receptor (C3aR End ) expression and humoral levels of C3a which is further exacerbated by intravenous thrombolysis (IVT). Therefore, it is critical to investigate the role of C3aR End in post-stroke neurovascular injury. Hypothesis: Genetic depletion of C3aR is vasculoprotective in stroke. Methods: Using a loxP - Cre approach (C3aR Flox/Flox xCdh5 Cre ), we generated mice conditionally deficient or sufficient in C3aR End (C3aR End-/- or C3aR End+/+ ), and subjected males (6±0.5-mo old) to thrombotic stroke (TS). Cerebral blood flow (CBF), behavioral outcomes, infarct volume, blood brain barrier (BBB) leakage, brain hemoglobin (Hb) content, brain tissue oxygen (PbtO 2 ) , neutrophil polarization ( Proinflammatory N1: Li6G + CD206 - vs. Antiinflammatory N2: Li6G + CD206 + ) and their brain infiltration were analyzed. P<0.05 was considered statistically significant. Results: TS resulted in similar degree of cerebral ischemia in both groups (N=10/gp); however, CBF, behavior, and infarct volume were significantly improved in C3aR End-/- vs. C3aR End+/+ mice at 72h post-TS. BBB-leakage and brain-Hb at 72h were less in C3aR End-/- vs. C3aR End+/+ mice but this did not meet significance (N=5/gp). Interestingly, C3a infusion 3h post-TS significantly enhanced BBB-leakage and brain-Hb in C3aR End+/+ but not in C3aR End-/- mice at 72h (N=5/gp), demonstrating that C3a in conjunction with C3aR End exacerbates neurovascular injury in TS. Moreover, late-IVT at 4h post-TS (2 mg/kgbwt; N=8/gp) significantly enhanced PbtO 2 in C3aR End-/- vs. C3aR End+/+ mice when assessed at 6h. Finally, C3aR deficiency significantly enhanced the N2/N1 ratio relative to the C3aR sufficient group at 24h post-TS (N=3/gp); thus inducing an anti-inflammatory effect and reduced neutrophil brain infiltration. Conclusion: C3aR End plays a critical role in stroke injury. Future studies targeting brain specific C3aR End are warranted.

scholarly journals EPC1/TIP60-Mediated Histone Acetylation Facilitates Spermiogenesis in Mice

2017 ◽  
Vol 37 (19) ◽  
Author(s):  
Yixin Dong ◽  
Kyo-ichi Isono ◽  
Kazuyuki Ohbo ◽  
Takaho A. Endo ◽  
Osamu Ohara ◽  
...  
Keyword(s):  
Histone Acetylation ◽  
Germ Cells ◽  
Essential Role ◽  
Critical Role ◽  
Male Germ Cells ◽  
Genetic Ablation ◽  
Histone Hyperacetylation ◽  
Critical Components ◽  
Underlying Mechanisms

ABSTRACT Global histone hyperacetylation is suggested to play a critical role for replacement of histones by transition proteins and protamines to compact the genome during spermiogenesis. However, the underlying mechanisms for hyperacetylation-mediated histone replacement remains poorly understood. Here, we report that EPC1 and TIP60, two critical components of the mammalian nucleosome acetyltransferase of H4 (NuA4) complexes, are coexpressed in male germ cells. Strikingly, genetic ablation of either Epc1 or Tip60 disrupts hyperacetylation and impairs histone replacement, in turn causing aberrant spermatid development. Taking these observations together, we reveal an essential role of the NuA4 complexes for histone hyperacetylation and subsequent compaction of the spermatid genome.

scholarly journals Hypoxic mitophagy regulates mitochondrial quality and platelet activation and determines severity of I/R heart injury

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Weilin Zhang ◽  
He Ren ◽  
Chunling Xu ◽  
Chongzhuo Zhu ◽  
Hao Wu ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Acute Ischemia ◽  
Dependent Manner ◽  
Genetic Ablation ◽  
A Cell ◽  
Novel Strategy

Mitochondrial dysfunction underlies many prevalent diseases including heart disease arising from acute ischemia/reperfusion (I/R) injury. Here, we demonstrate that mitophagy, which selectively removes damaged or unwanted mitochondria, regulated mitochondrial quality and quantity in vivo. Hypoxia induced extensive mitochondrial degradation in a FUNDC1-dependent manner in platelets, and this was blocked by in vivo administration of a cell-penetrating peptide encompassing the LIR motif of FUNDC1 only in wild-type mice. Genetic ablation of Fundc1 impaired mitochondrial quality and increased mitochondrial mass in platelets and rendered the platelets insensitive to hypoxia and the peptide. Moreover, hypoxic mitophagy in platelets protected the heart from worsening of I/R injury. This represents a new mechanism of the hypoxic preconditioning effect which reduces I/R injury. Our results demonstrate a critical role of mitophagy in mitochondrial quality control and platelet activation, and suggest that manipulation of mitophagy by hypoxia or pharmacological approaches may be a novel strategy for cardioprotection.

scholarly journals The MNK1/2-eIF4E axis drives melanoma plasticity, progression, and resistance to immunotherapy

2020 ◽  
Author(s):  
Fan Huang ◽  
Christophe Gonçalves ◽  
Margarita Bartish ◽  
Joelle Rémy-Sarrazin ◽  
Qianyu Guo ◽  
...  
Keyword(s):  
Mouse Model ◽  
Critical Role ◽  
Inflammatory Factors ◽  
Genetic Ablation ◽  
Immune Exhaustion ◽  
New Strategy ◽  
Phenotype Switch ◽  
Phenotype Switching ◽  
Immunosuppressive Microenvironment

AbstractMelanomas commonly undergo a phenotype switch, from a proliferative to an invasive state. Melanoma plasticity exhibited as phenotype switching contributes to immunotherapy resistance, however the mechanisms are not completely understood and thus therapeutically unexploited. Here, using a transgenic melanoma mouse model, we demonstrated a critical role of the MNK1/2-eIF4E axis in melanoma plasticity and resistance to immunotherapy. We showed that phospho-eIF4E deficient murine melanomas express high levels of melanocytic antigens, with similar results verified in patient melanomas. Mechanistically, we identified that phospho-eIF4E controls the translation of NGFR, a critical effector of phenotype switching. In patients with melanoma, the expression of MKNK1, the kinase for eIF4E, positively correlated with markers of immune exhaustion. Genetic ablation of phospho-eIF4E reprogrammed the immunosuppressive microenvironment, exemplified by lowered production of inflammatory factors and increased CD8+ T cell infiltrates. Blocking phospho-eIF4E, using MNK1/2 inhibitors, offers a new strategy to inhibit melanoma plasticity and improve the survival response to anti-PD-1 immunotherapy.

scholarly journals Development of opioid-induced hyperalgesia depends on reactive astrocytes controlled by Wnt5a signaling

2021 ◽  
Author(s):  
XIN LIU ◽  
Chilman Bae ◽  
Bolong Liu ◽  
Yongmei Zhang ◽  
Xiangfu Zhou ◽  
...  
Keyword(s):  
Neural Circuit ◽  
Critical Role ◽  
Wnt Signaling Pathway ◽  
Opioid Analgesics ◽  
Reactive Astrocytes ◽  
Opioid Overdose ◽  
Knock Out ◽  
Genetic Ablation ◽  
Opioid Induced Hyperalgesia

Opioid analgesics are the frontline pain medicine for managing various types of pain. Paradoxically, repeated use of opioid analgesics may cause an exacerbated pain state known as opioid-induced hyperalgesia (OIH). OIH significantly contributes to dose escalation and consequently opioid overdose. In addition to neuronal malplasticity, emerging evidence suggests a critical role of reactive glia in OIH development. A potential astrocytic underpinning of OIH pathogenesis is indicated by their prominently activation in OIH animal models. However, this hypothesis has not been conclusively tested and the mechanism underlying the astrocyte activation remains unclear. Here, we show that reactive astrocytes (a.k.a. astrogliosis) are critical for OIH development in mice. Genetic ablation of astrogliosis inhibited the expression of OIH and morphine-induced neural circuit polarization (NCP) in the spinal dorsal horn (SDH). We also found that Wnt5a is a neuron-to-astrocyte signal that is required for morphine-induced astrogliosis. Conditional knock-out of Wnt5a in neurons or its co-receptor ROR2 in astrocytes blocked not only morphine-induced astrogliosis but also OIH and NCP. Furthermore, we showed that the Wnt5a-ROR2 signaling-dependent astrogliosis contributes to OIH via inflammasome-regulated IL-1β. Our results reveal an important role of morphine-induced astrogliosis in OIH pathogenesis and elucidate a neuron-to-astrocyte intercellular Wnt signaling pathway that controls the astrogliosis.

scholarly journals Kinin B1 Receptor Is Important in the Pathogenesis of Myeloperoxidase-Specific ANCA GN

2019 ◽  
Vol 31 (2) ◽  
pp. 297-307 ◽  
Author(s):  
Peiqi Hu ◽  
Hua Su ◽  
Hong Xiao ◽  
Shen-Ju Gou ◽  
Carolina A. Herrera ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Kidney Diseases ◽  
Surface Display ◽  
Critical Role ◽  
Neutrophil Activation ◽  
Cell Trafficking ◽  
Genetic Ablation ◽  
Activated Neutrophils

BackgroundMyeloperoxidase-specific ANCA (MPO-ANCA) are implicated in the pathogenesis of vasculitis and GN. Kinins play a major role during acute inflammation by regulating vasodilatation and vascular permeability and by modulating adhesion and migration of leukocytes. Kinin system activation occurs in patients with ANCA vasculitis. Previous studies in animal models of GN and sclerosing kidney diseases have demonstrated protective effects of bradykinin receptor 1 (B1R) blockade via interference with myeloid cell trafficking.MethodsTo investigate the role of B1R in a murine model of MPO-ANCA GN, we evaluated effects of B1R genetic ablation and pharmacologic blockade. We used bone marrow chimeric mice to determine the role of B1R in bone marrow–derived cells (leukocytes) versus nonbone marrow–derived cells. We elucidated mechanisms of B1R effects using in vitro assays for MPO-ANCA–induced neutrophil activation, endothelial adherence, endothelial transmigration, and neutrophil adhesion molecule surface display.ResultsB1R deficiency or blockade prevented or markedly reduced ANCA-induced glomerular crescents, necrosis, and leukocyte influx in mice. B1R was not required for in vitro MPO-ANCA–induced neutrophil activation. Leukocyte B1R deficiency, but not endothelial B1R deficiency, decreased glomerular neutrophil infiltration induced by MPO-ANCA in vivo. B1R enhanced ANCA-induced neutrophil endothelial adhesion and transmigration in vitro. ANCA-activated neutrophils exhibited changes in Mac-1 and LFA-1, important regulators of neutrophil endothelial adhesion and transmigration: ANCA-activated neutrophils increased surface expression of Mac-1 and increased shedding of LFA-1, whereas B1R blockade reduced these effects.ConclusionsThe leukocyte B1R plays a critical role in the pathogenesis of MPO-ANCA–induced GN in a mouse model by modulating neutrophil–endothelial interaction. B1R blockade may have potential as a therapy for ANCA GN and vasculitis.

scholarly journals Anterior cingulate cortex encoding of effortful behavior

2019 ◽  
Vol 121 (2) ◽  
pp. 701-714 ◽  
Author(s):  
Blake S. Porter ◽  
Kristin L. Hillman ◽  
David K. Bilkey
Keyword(s):  
Firing Rate ◽  
Anterior Cingulate Cortex ◽  
Energy Use ◽  
Critical Role ◽  
Behavioral Outcomes ◽  
Cingulate Cortex ◽  
Anterior Cingulate ◽  
Relative Value ◽  
Multiple Behaviors

An animal’s ability to assess the value of their behaviors to minimize energy use while maximizing goal achievement is critical to its survival. The anterior cingulate cortex (ACC) has been previously shown to play a critical role in this behavioral optimization process, especially when animals are faced with effortful behaviors. In the present study, we designed a novel task to investigate the role of the ACC in evaluating behaviors that varied in effort but all resulted in the same outcome. We recorded single unit activity from the ACC as rats ran back and forth in a shuttle box that could be tilted to different tilt angles (0, 15, and 25°) to manipulate effort. Overall, a majority of ACC neurons showed selective firing to specific effort conditions. During effort expenditure, ACC units showed a consistent firing rate bias toward the downhill route compared with the more difficult uphill route, regardless of the tilt angle of the apparatus. Once rats completed a run and received their fixed reward, ACC units also showed a clear firing rate preference for the single condition with the highest relative value (25° downhill). To assess effort preferences, we used a choice version of our task and confirmed that rats prefer downhill routes to uphill routes when given the choice. Overall, these results help to elucidate the functional role of the ACC in monitoring and evaluating effortful behaviors that may then bias decision-making toward behaviors with the highest utility. NEW & NOTEWORTHY We developed a novel effort paradigm to investigate how the anterior cingulate cortex (ACC) responds to behaviors with varied degrees of physical effort and how changes in effort influence the ACC’s evaluation of behavioral outcomes. Our results provide evidence for a wider role of the ACC in its ability to motivate effortful behaviors and evaluate the outcome of multiple behaviors within an environment.

Distinct Roles of Integrins α6 and α4 in Fetal Liver Hematopoietic Stem and Progenitor Cell Homing.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 353-353
Author(s):  
Hong Qian ◽  
Elisabeth Georges-Labouesse ◽  
Alexander Nyström ◽  
Anna Domogatskaya ◽  
Karl Tryggvason ◽  
...  
Keyword(s):  
Fetal Liver ◽  
Critical Role ◽  
Liver Cells ◽  
Hematopoietic Stem ◽  
Knockout Mouse Model ◽  
Genetic Ablation ◽  
Integrin Α4 ◽  
Fetal Liver Cells

Abstract During development and after transplantation, intravenously injected hematopoietic stem and progenitor cells (HSPCs) selectively transmigrate through the sinusoidal walls into the bone marrow (BM) niches to engraft and reconstitute hematopoiesis. The rate of reconstitution following transplantation varies depending on the source of hematopoietic stem cells (HSCs) (To, et al 1992). However, the molecular pathways that control the homing of HSCs, in particular, of fetal HSCs are still not well understood. In the present study we studied the contribution of α6 and α4 integrins in homing of fetal liver HSPCs into adult BM by using function-blocking antibodies and an integrin α6 knockout mouse model. We found an ubiquitous expression of both integrin α6 and α4 receptors on fetal liver Lin−Sca-1+c-kit+ (LSK) HSPCs. Genetic ablation of integrin α6 resulted in reduced homing of fetal liver progenitors (HPCs) to BM of lethally irradiated adult recipients. In agreement with this, the integrin α6 antibody inhibited homing of fetal liver HPCs into BM and spleen. The role of integrin a6 in homing and engraftment of fetal liver HSCs was studied by a competitive repopulation assay by using integrin α6−/− or α6+/+ fetal liver cells. Absence of α6 integrin in fetal liver cells did not cause any engraftment defect or mobilization hypersensitivity as compared to wild-type cells. In agreement with this, anti-integrin α6 antibody did not either inhibit BM homing of short-term or long-term HSCs. In contrast, homing of fetal liver HSCs and HPCs to BM was virtually abrogated after treatment with integrin α4 antibody. Our results show that the α6 integrin receptors are functional during homing of fetal liver HPCs, but not multilineage repopulating HSC in vivo. Furthermore, we show the critical role of integrin α4 receptor for homing of both fetal liver HPCs and multilineage repopulating HSCs to BM, indicating distinct developmentally regulated functions for integrin α6 and α4 receptors during fetal hematopoiesis

scholarly journals Critical Role of Calbindin-D28k in Calcium Homeostasis Revealed by Mice Lacking Both Vitamin D Receptor and Calbindin-D28k

2004 ◽  
Vol 279 (50) ◽  
pp. 52406-52413 ◽  
Author(s):  
Wei Zheng ◽  
Yixia Xie ◽  
Gang Li ◽  
Juan Kong ◽  
Jian Q. Feng ◽  
...  
Keyword(s):  
Vitamin D ◽  
Secondary Hyperparathyroidism ◽  
Vitamin D Receptor ◽  
Calcium Homeostasis ◽  
Critical Role ◽  
Mineral Density ◽  
Genetic Ablation ◽  
High Calcium ◽  
Calbindin D28k

Calbindin (CaBP)-D28k and CaBP-D9k are cytosolic vitamin D-dependent calcium-binding proteins long thought to play an important role in transepithelial calcium transport. However, recent genetic studies suggest that CaBP-D28k is not essential for calcium metabolism. Genetic ablation of this gene in mice leads to no calcemic abnormalities. Genetic inactivation of the vitamin D receptor (VDR) gene leads to hypocalcemia, secondary hyperparathyroidism, rickets, and osteomalacia, accompanied by 90% reduction in renal CaBP-D9k expression but little change in CaBP-D28k. To address whether the role of CaBP-D28k in calcium homeostasis is compensated by CaBP-D9k, we generated VDR/CaBP-D28k double knockout (KO) mice, which expressed no CaBP-D28k and only 10% of CaBP-D9k in the kidney. On a regular diet, the double KO mice were more growth-retarded and 42% smaller in body weight than VDRKO mice and died prematurely at 2.5–3 months of age. Compared with VDRKO mice, the double KO mice had higher urinary calcium excretion and developed more severe secondary hyperparathyroidism and rachitic skeletal phenotype, which were manifested by larger parathyroid glands, higher serum parathyroid hormone levels, much lower bone mineral density, and more distorted growth plate with more osteoid formation in the trabecular region. On high calcium, high lactose diet, blood-ionized calcium levels were normalized in both VDRKO and the double KO mice; however, in contrast to VDRKO mice, the skeletal abnormalities were not completely corrected in the double KO mice. These results directly demonstrate that CaBP-D28k plays a critical role in maintaining calcium homeostasis and skeletal mineralization and suggest that its calcemic role can be mostly compensated by CaBP-D9k.

scholarly journals HDAC1 deregulation promotes neuronal loss and deficit of motor function in stroke pathogenesis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jui-Sheng Chen ◽  
Hao-Kuang Wang ◽  
Chien-Yu Hsu ◽  
Yu-Ting Su ◽  
Jia-Shing Chen ◽  
...  
Keyword(s):  
Dna Damage ◽  
Infarct Volume ◽  
Behavioral Outcomes ◽  
Neuronal Loss ◽  
Ischemic Insult ◽  
Stroke Incidence ◽  
Histone Deacetylase 1 ◽  
Damage Repair ◽  
The Brain

AbstractStroke is a common cause of death worldwide and leads to disability and cognitive dysfunction. Ischemic stroke and hemorrhagic stroke are major categories of stroke, accounting for 68% and 32% of strokes, respectively. Each year, 15 million people experience stroke worldwide, and the stroke incidence is rising. Epigenetic modifications regulate gene transcription and play a major role in stroke. Accordingly, histone deacetylase 1 (HDAC1) participates in DNA damage repair and cell survival. However, the mechanisms underlying the role of HDAC1 in stroke pathogenesis are still controversial. Therefore, we investigated the role of HDAC1 in stroke by using a rat model of endothelin-1-induced brain ischemia. Our results revealed that HDAC1 was deregulated following stroke, and its expressional level and enzymatic activity were decreased. We also used MS-275 to inhibit HDAC1 function in rats exposed to ischemic insult. We found that HDAC1 inhibition promoted the infarct volume, neuronal loss, DNA damage, neuronal apoptosis after stroke, and levels of reactive oxygen species and inflammation cytokines. Additionally, HDAC1 inhibition deteriorated the behavioral outcomes of rats with ischemic insult. Overall, our findings demonstrate that HDAC1 participates in ischemic pathogenesis in the brain and possesses potential for use as a therapeutic target.

The Role of the SLP in Autism Spectrum Disorder Screening and Assessment

2008 ◽  
Vol 15 (2) ◽  
pp. 50-59 ◽  
Author(s):  
Amy Philofsky
Keyword(s):  
Language Development ◽  
Critical Role ◽  
Children With Autism ◽  
Autism Spectrum ◽  
Children With Asd ◽  
Prevalence Estimates ◽  
Notable Increase ◽  
Screening Assessment ◽  
Critical Components

AbstractRecent prevalence estimates for autism have been alarming as a function of the notable increase. Speech-language pathologists play a critical role in screening, assessment and intervention for children with autism. This article reviews signs that may be indicative of autism at different stages of language development, and discusses the importance of several psychometric properties—sensitivity and specificity—in utilizing screening measures for children with autism. Critical components of assessment for children with autism are reviewed. This article concludes with examples of intervention targets for children with ASD at various levels of language development.

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