Critical Evaluation of Mouse Models Used to Study Pain and Loss of Pain Perception in Diabetic Neuropathy

2012 ◽  
Vol 120 (04) ◽  
pp. 188-190 ◽  
Author(s):  
A. Bierhaus ◽  
P. Nawroth
Keyword(s):  
Diabetic Neuropathy ◽  
Mouse Models ◽  
Molecular Mechanisms ◽  
Pain Perception ◽  
Critical Evaluation ◽  
Knock Out ◽  
Background Strain ◽  
And Gender ◽  
To Receive ◽  
Diabetes Induction

AbstractA number of studies have addressed diabetic neuropathy (DN) in transgenic and knock out mouse models to unravel the molecular mechanisms underlying metabolic pain and loss of pain perception. However, it is difficult to compare these studies with each other or even with human DN due to experimental differences including the type of diabetes, the background strain of the respective mouse model, the methods of diabetes induction and the duration of diabetes, animal age and gender. To receive useful information for DN from genetically modified mice, it is therefore mandatory to first define the appropriate model and – if necessary – to backcross transgenic strains into the respective background to allow a reliable (and at least in part translatable to human DN) interpretation of the results.

Referral Patterns for Youths Identified at Risk for Suicide by Trained Gatekeepers

Crisis ◽  
2012 ◽  
Vol 33 (2) ◽  
pp. 113-119 ◽  
Author(s):  
Michael S. Rodi ◽  
Lucas Godoy Garraza ◽  
Christine Walrath ◽  
Robert L. Stephens ◽  
D. Susanne Condron ◽  
...  
Keyword(s):  
Suicide Prevention ◽  
Demographic Characteristics ◽  
Service Access ◽  
Referral Patterns ◽  
Race And Gender ◽  
Lee Smith ◽  
Prevention Behavior ◽  
Key Variables ◽  
And Gender ◽  
To Receive

Background: In order to better understand the posttraining suicide prevention behavior of gatekeeper trainees, the present article examines the referral and service receipt patterns among gatekeeper-identified youths. Methods: Data for this study were drawn from 26 Garrett Lee Smith grantees funded between October 2005 and October 2009 who submitted data about the number, characteristics, and service access of identified youths. Results: The demographic characteristics of identified youths are not related to referral type or receipt. Furthermore, referral setting does not seem to be predictive of the type of referral. Demographic as well as other (nonrisk) characteristics of the youths are not key variables in determining identification or service receipt. Limitations: These data are not necessarily representative of all youths identified by gatekeepers represented in the dataset. The prevalence of risk among all members of the communities from which these data are drawn is unknown. Furthermore, these data likely disproportionately represent gatekeepers associated with systems that effectively track gatekeepers and youths. Conclusions: Gatekeepers appear to be identifying youth across settings, and those youths are being referred for services without regard for race and gender or the settings in which they are identified. Furthermore, youths that may be at highest risk may be more likely to receive those services.

Grading Teachers: Race and Gender Differences in Low Evaluation Ratings and Teacher Employment Outcomes

2019 ◽  
Vol 56 (5) ◽  
pp. 1800-1833 ◽  
Author(s):  
Steven Drake ◽  
Amy Auletto ◽  
Joshua M. Cowen
Keyword(s):  
Charter Schools ◽  
Evaluation System ◽  
Employment Outcomes ◽  
Teachers Of Color ◽  
High Stakes ◽  
Teacher Labor Market ◽  
Race And Gender ◽  
And Gender ◽  
To Receive ◽  
The Relationship

In July 2011, the State of Michigan adopted a broad set of teacher labor market reforms, including a high-stakes evaluation system designed in part to remove low-performing teachers. We examine the characteristics of teachers rated as “minimally effective” and “ineffective,” as well as their schools, and the relationship between low effectiveness ratings and later employment outcomes. Results suggest teachers of color across traditional and charter schools are more likely to receive low effectiveness ratings than their within-school peers. These low rating risks are higher for teachers of color working in comparatively White-faculty contexts. Male and novice teachers are also rated low more frequently, and important differences appear to exist in the usage of low ratings by traditional public and charter schools.

scholarly journals Neurogranin Regulates Adult-Born Olfactory Granule Cell Spine Density and Odor-Reward Associative Memory in Mice

2021 ◽  
Vol 22 (8) ◽  
pp. 4269
Author(s):  
Simona Gribaudo ◽  
Daniele Saraulli ◽  
Giulia Nato ◽  
Sara Bonzano ◽  
Giovanna Gambarotta ◽  
...  
Keyword(s):  
Associative Memory ◽  
Molecular Mechanisms ◽  
Granule Cells ◽  
Large Population ◽  
Adult Life ◽  
Long Term Potentiation ◽  
Spine Density ◽  
Knock Out ◽  
Memory Impairments ◽  
Dependent Learning

Neurogranin (Ng) is a brain-specific postsynaptic protein, whose role in modulating Ca2+/calmodulin signaling in glutamatergic neurons has been linked to enhancement in synaptic plasticity and cognitive functions. Accordingly, Ng knock-out (Ng-ko) mice display hippocampal-dependent learning and memory impairments associated with a deficit in long-term potentiation induction. In the adult olfactory bulb (OB), Ng is expressed by a large population of GABAergic granule cells (GCs) that are continuously generated during adult life, undergo high synaptic remodeling in response to the sensory context, and play a key role in odor processing. However, the possible implication of Ng in OB plasticity and function is yet to be investigated. Here, we show that Ng expression in the OB is associated with the mature state of adult-born GCs, where its active-phosphorylated form is concentrated at post-synaptic sites. Constitutive loss of Ng in Ng-ko mice resulted in defective spine density in adult-born GCs, while their survival remained unaltered. Moreover, Ng-ko mice show an impaired odor-reward associative memory coupled with reduced expression of the activity-dependent transcription factor Zif268 in olfactory GCs. Overall, our data support a role for Ng in the molecular mechanisms underlying GC plasticity and the formation of olfactory associative memory.

scholarly journals Early alterations of neurovascular unit in the retina in mouse models of tauopathy

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Fan Xia ◽  
Yonju Ha ◽  
Shuizhen Shi ◽  
Yi Li ◽  
Shengguo Li ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Mouse Models ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Leukocyte Adhesion ◽  
Neurovascular Unit ◽  
Integrated Analysis ◽  
Therapeutic Effects ◽  
Retinal Ganglion ◽  
Potential Biomarker

AbstractThe retina, as the only visually accessible tissue in the central nervous system, has attracted significant attention for evaluating it as a biomarker for neurodegenerative diseases. Yet, most of studies focus on characterizing the loss of retinal ganglion cells (RGCs) and degeneration of their axons. There is no integrated analysis addressing temporal alterations of different retinal cells in the neurovascular unit (NVU) in particular retinal vessels. Here we assessed NVU changes in two mouse models of tauopathy, P301S and P301L transgenic mice overexpressing the human tau mutated gene, and evaluated the therapeutic effects of a tau oligomer monoclonal antibody (TOMA). We found that retinal edema and breakdown of blood–retina barrier were observed at the very early stage of tauopathy. Leukocyte adhesion/infiltration, and microglial recruitment/activation were constantly increased in the retinal ganglion cell layer of tau transgenic mice at different ages, while Müller cell gliosis was only detected in relatively older tau mice. Concomitantly, the number and function of RGCs progressively decreased during aging although they were not considerably altered in the very early stage of tauopathy. Moreover, intrinsically photosensitive RGCs appeared more sensitive to tauopathy. Remarkably, TOMA treatment in young tau transgenic mice significantly attenuated vascular leakage, inflammation and RGC loss. Our data provide compelling evidence that abnormal tau accumulation can lead to pathology in the retinal NVU, and vascular alterations occur more manifest and earlier than neurodegeneration in the retina. Oligomeric tau-targeted immunotherapy has the potential to treat tau-induced retinopathies. These data suggest that retinal NVU may serve as a potential biomarker for diagnosis and staging of tauopathy as well as a platform to study the molecular mechanisms of neurodegeneration.

scholarly journals Will Universal Jurisdiction Advance Accountability for Sexualized and Gender-based Crimes? A View from Within on Progress and Challenges in Germany

2021 ◽  
Vol 22 (5) ◽  
pp. 894-913
Author(s):  
Silke Studzinsky ◽  
Alexandra Lily Kather
Keyword(s):  
International Law ◽  
Critical Evaluation ◽  
Federal Court ◽  
Universal Jurisdiction ◽  
Professional Experiences ◽  
Sexualized Violence ◽  
Gender Based ◽  
And Gender ◽  
Trial Monitoring ◽  
Federal Prosecutor

AbstractThis Article is based on the professional experiences of the authors working as lawyers and activists towards accountability for sexualized and gender-based crimes under international law. It provides a critical evaluation of universal jurisdiction cases in Germany addressing conflict-related sexualized violence. In particular, the article looks deeper into the Office of the German Federal Prosecutor General of the Federal Court of Justice’s (GBA) approach to gender while taking note of the barriers in the way of investigating and adjudicating crimes under international law. Both authors have been following universal jurisdiction developments in Germany closely, particularly in relation to the investigation and prosecution of sexual and gender-based crimes. With regard to the proceedings against two high-rank representatives of the armed rebel group Forces Démocratiques de liberation du Rwanda (FDLR), the findings in this article are informed by trial monitoring reports organized and conducted by a group of organisations and institutions, namely Medica Mondiale, the European Center for Constitutional and Human Rights (ECCHR), and the Hamburger Institut für Sozialforschung. In light of the fact that German trial records are absent of publicly accessible records of what was said in the court room, the consortium of groups co-monitored the FLDR trial.

scholarly journals Deficiency of the onco-miRNA cluster, miR-106b∼25, causes oligozoospermia and the cooperative action of miR-106b∼25 and miR-17∼92 is required to maintain male fertility

2020 ◽  
Vol 26 (6) ◽  
pp. 389-401
Author(s):  
Alicia Hurtado ◽  
Rogelio Palomino ◽  
Ina Georg ◽  
Miguel Lao ◽  
Francisca M Real ◽  
...  
Keyword(s):  
Male Fertility ◽  
Molecular Mechanisms ◽  
Mirna Cluster ◽  
Knock Out ◽  
Cooperative Action ◽  
Mouse Mutants ◽  
New Genes ◽  
Mirna Clusters ◽  
Testicular Histology ◽  
And Function

Abstract The identification of new genes involved in sexual development and gonadal function as potential candidates causing male infertility is important for both diagnostic and therapeutic purposes. Deficiency of the onco-miRNA cluster miR-17∼92 has been shown to disrupt spermatogenesis, whereas mutations in its paralog cluster, miR-106b∼25, that is expressed in the same cells, were reported to have no effect on testis development and function. The aim of this work is to determine the role of these two miRNA clusters in spermatogenesis and male fertility. For this, we analyzed miR-106b∼25 and miR-17∼92 single and double mouse mutants and compared them to control mice. We found that miR-106b∼25 knock out testes show reduced size, oligozoospermia and altered spermatogenesis. Transcriptomic analysis showed that multiple molecular pathways are deregulated in these mutant testes. Nevertheless, mutant males conserved normal fertility even when early spermatogenesis and other functions were disrupted. In contrast, miR-17∼92+/−; miR-106b∼25−/− double mutants showed severely disrupted testicular histology and significantly reduced fertility. Our results indicate that miR-106b∼25 and miR-17∼92 ensure accurate gene expression levels in the adult testis, keeping them within the required thresholds. They play a crucial role in testis homeostasis and are required to maintain male fertility. Hence, we have identified new candidate genetic factors to be screened in the molecular diagnosis of human males with reproductive disorders. Finally, considering the well-known oncogenic nature of these two clusters and the fact that patients with reduced fertility are more prone to testicular cancer, our results might also help to elucidate the molecular mechanisms linking both pathologies.

scholarly journals Moving toward molecular mechanisms for chemotaxis in eukaryotic cells

2019 ◽  
Vol 30 (23) ◽  
pp. 2873-2877
Author(s):  
Peter Devreotes
Keyword(s):  
Molecular Mechanisms ◽  
Eukaryotic Cells ◽  
To Receive

It is a tremendous honor to receive the 2019 E.B. Wilson Award and be recognized for my work on chemotaxis in eukaryotic cells. In writing this essay, I hope to achieve three aims: 1) to tell the story of how people in my group made discoveries over the years; 2) to outline key principles we have learned about chemotaxis; and 3) to point to the most important outstanding questions.

Airway Compliance Measurements in Mouse Models of Respiratory Diseases

2021 ◽  
Author(s):  
Annette Robichaud ◽  
Liah Fereydoonzad ◽  
Samuel L Collins ◽  
Jeffrey Martin Loube ◽  
Yumiko Ishii ◽  
...  
Keyword(s):  
Mouse Models ◽  
Genetic Model ◽  
Airway Remodeling ◽  
Work Of Breathing ◽  
Full Range ◽  
Disease Models ◽  
Study Objective ◽  
Knock Out ◽  
Airway Tree ◽  
Leukotriene C4 Synthase

The quantification of airway compliance (Caw) is essential to the study of airway alterations in disease models. However, the required measurements of airway pressure and volume are difficult to acquire in mice. We hypothesized that the inflation limb of full-range pressure-volume (PV) curves could be used to quantify Caw, as it contains a segment where only the airway tree is distended. The study objective was to assess the feasibility of the approach by analysis of full-range PV curves previously collected in three mouse models: an elastase model of emphysema, a genetic model spontaneously developing emphysema (leukotriene C4 synthase knock-out; LTC4S-KO) and a bleomycin model of lung fibrosis. Attempts to validate results included Caw change relative to respiratory system compliance (ΔCaw/ΔC), the minute work of breathing (mWOB) and the elastance at 20.5 Hz (Ers_20.5) from prior respiratory mechanics measurements in the same subjects. Caw was estimated at 3% of total compliance in healthy mice or 2.3 ± 1 μL/cmH2O (n=17). The technique detected changes in models of respiratory obstructive and restrictive diseases relative to control mice as well as differences in the two emphysema models studied. The changes in Caw were consistent with those seen in ΔCaw/ΔC, mWOB or Ers_20.5, with some variations according to the model, as well as with results reported in the literature in humans and mice. Direct Caw measurements in subjects as small as mice could prove useful to further characterize other respiratory disease models associated with airway remodeling or to assess treatment effects.

PRDM16 Is a Compact Myocardium-Enriched Transcription Factor Required to Maintain Compact Myocardial Cardiomyocyte Identity in Left Ventricle

Circulation ◽  
2021 ◽  
Author(s):  
Tongbin Wu ◽  
Zhengyu Liang ◽  
Zengming Zhang ◽  
Canzhao Liu ◽  
Lunfeng Zhang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Single Cell ◽  
Rna Sequencing ◽  
Mouse Models ◽  
Molecular Mechanisms ◽  
Left Ventricular ◽  
Ventricular Noncompaction ◽  
Chip Sequencing ◽  
Transcriptional Signature ◽  
Underlying Mechanisms

Background: Left ventricular noncompaction cardiomyopathy (LVNC) was discovered half a century ago as a cardiomyopathy with excessive trabeculation and a thin ventricular wall. In the decades since, numerous studies have demonstrated that LVNC primarily impacts left ventricles (LVs), and is often associated with LV dilation and dysfunction. However, owing in part to the lack of suitable mouse models that faithfully mirror the selective LV vulnerability in patients, mechanisms underlying susceptibility of LV to dilation and dysfunction in LVNC remain unknown. Genetic studies have revealed that deletions and mutations in PRDM16 cause LVNC, but previous conditional Prdm16 knockout mouse models do not mirror the LVNC phenotype in patients, and importantly, the underlying molecular mechanisms by which PRDM16 deficiency causes LVNC are still unclear. Methods: Prdm16 cardiomyocyte (CM)-specific knockout ( Prdm16 cKO ) mice were generated and analyzed for cardiac phenotypes. RNA sequencing and ChIP sequencing were performed to identify direct transcriptional targets of PRDM16 in CMs. Single cell RNA sequencing in combination with Spatial Transcriptomics were employed to determine CM identity at single cell level. Results: CM-specific ablation of Prdm16 in mice caused LV-specific dilation and dysfunction, as well as biventricular noncompaction, which fully recapitulated LVNC in patients. Mechanistically, PRDM16 functioned as a compact myocardium-enriched transcription factor, which activated compact myocardial genes while repressing trabecular myocardial genes in LV compact myocardium. Consequently, Prdm16 cKO LV compact myocardial CMs shifted from their normal transcriptomic identity to a transcriptional signature resembling trabecular myocardial CMs and/or neurons. Chamber-specific transcriptional regulation by PRDM16 was in part due to its cooperation with LV-enriched transcription factors Tbx5 and Hand1. Conclusions: These results demonstrate that disruption of proper specification of compact CM may play a key role in the pathogenesis of LVNC. They also shed light on underlying mechanisms of LV-restricted transcriptional program governing LV chamber growth and maturation, providing a tangible explanation for the susceptibility of LV in a subset of LVNC cardiomyopathies.

scholarly journals Immunomodulatory Effects of Polysaccharide from Marine FungusPhoma herbarumYS4108 on T Cells and Dendritic Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Song Chen ◽  
Ran Ding ◽  
Yan Zhou ◽  
Xian Zhang ◽  
Rui Zhu ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Interleukin 12 ◽  
Related Factors ◽  
Knock Out ◽  
Specific Immunity

YCP, as a kind of natural polysaccharides from the mycelium of marine filamentous fungusPhoma herbarumYS4108, has great antitumor potentialviaenhancement of host immune response, but little is known about the molecular mechanisms. In the present study, we mainly focused on the effects and mechanisms of YCP on the specific immunity mediated by dendritic cells (DCs) and T cells. T cell /DC activation-related factors including interferon- (IFN-)γ, interleukin-12 (IL-12), and IL-4 were examined with ELISA. Receptor knock-out mice and fluorescence-activated cell sorting are used to analyze the YCP-binding receptor of T cells and DCs. RT-PCR is utilized to measure MAGE-A3 for analyzing the tumor-specific killing effect. In our study, we demonstrated YCP can provide the second signal for T cell activation, proliferation, and IFN-γproduction through binding to toll-like receptor- (TLR-) 2 and TLR-4. YCP could effectively promote IL-12 secretion and expression of markers (CD80, CD86, and MHC II)viaTLR-4 on DCs. Antigen-specific immunity against mouse melanoma cells was strengthened through the activation of T cells and the enhancement of capacity of DCs by YCP. The data supported that YCP can exhibit specific immunomodulatory capacity mediated by T cells and DCs.

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