scholarly journals Neuropeptide S-Mediated Modulation of Prepulse Inhibition Depends on Age, Gender, Stimulus-Timing, and Attention

2021 ◽  
Vol 14 (5) ◽  
pp. 489
Author(s):  
Wei Si ◽  
Xiaobin Liu ◽  
Hans-Christian Pape ◽  
Rainer K. Reinscheid
Keyword(s):  
Prepulse Inhibition ◽  
Knockout Mice ◽  
Young Male ◽  
Careful Examination ◽  
Neuropeptide S ◽  
Compensatory Mechanisms ◽  
Attentional Processes ◽  
Attentional Deficits ◽  
Knockout Animals

Conflicting reports about the role of neuropeptide S (NPS) in animal models of psychotic-like behavior and inconsistent results from human genetic studies seeking potential associations with schizophrenia prompted us to reevaluate the effects of NPS in the prepulse inhibition (PPI) paradigm in mice. Careful examination of NPS receptor (NPSR1) knockout mice at different ages revealed that PPI deficits are only expressed in young male knockout animals (<12 weeks of age), that can be replicated in NPS precursor knockout mice and appear strain-independent, but are absent in female mice. PPI deficits can be aggravated by MK-801 and alleviated by clozapine. Importantly, treatment of wildtype mice with a centrally-active NPSR1 antagonist was able to mimic PPI deficits. PPI impairment in young male NPSR1 and NPS knockout mice may be caused by attentional deficits that are enhanced by increasing interstimulus intervals. Our data reveal a substantial NPS-dependent developmental influence on PPI performance and confirm a significant role of attentional processes for sensory-motor gating. Through its influence on attention and arousal, NPS appears to positively modulate PPI in young animals, whereas compensatory mechanisms may alleviate NPS-dependent deficits in older mice.

scholarly journals Review of rationale and progress toward targeting cyclin-dependent kinase 2 (CDK2) for male contraception†

2020 ◽  
Vol 103 (2) ◽  
pp. 357-367
Author(s):  
Erik B Faber ◽  
Nan Wang ◽  
Gunda I Georg
Keyword(s):  
Cell Cycle ◽  
Binding Site ◽  
Knockout Mice ◽  
Male Contraception ◽  
Cyclin Dependent Kinase ◽  
Compensatory Mechanisms ◽  
Binding Partner ◽  
Male Contraceptive ◽  
Clinical Stages

Abstract Cyclin-dependent kinase 2 (CDK2) is a member of the larger cell cycle regulating CDK family of kinases, activated by binding partner cyclins as its name suggests. Despite its canonical role in mitosis, CDK2 knockout mice are viable but sterile, suggesting compensatory mechanisms for loss of CDK2 in mitosis but not meiosis. Here, we review the literature surrounding the role of CDK2 in meiosis, particularly a cyclin-independent role in complex with another activator, Speedy 1 (SPY1). From this evidence, we suggest that CDK2 could be a viable nonhormonal male contraceptive target. Finally, we review the literature of pertinent CDK2 inhibitors from the preclinical to clinical stages, mostly developed to treat various cancers. To date, there is no potent yet selective CDK2 inhibitor that could be repurposed as a contraceptive without appreciable off-target toxicity. To achieve selectivity for CDK2 over closely related kinases, developing compounds that bind outside the conserved adenosine triphosphate-binding site may be necessary.

scholarly journals Polyamine homeostasis in arginase knockout mice

2007 ◽  
Vol 293 (4) ◽  
pp. C1296-C1301 ◽  
Author(s):  
Joshua L. Deignan ◽  
Justin C. Livesay ◽  
Lisa M. Shantz ◽  
Anthony E. Pegg ◽  
William E. O'Brien ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Polyamine Metabolism ◽  
Mrna Levels ◽  
Ornithine Aminotransferase ◽  
Double Knockout ◽  
Mammalian Tissues ◽  
Knockout Animals ◽  
Regulatory Functions ◽  
Arginase I

The role of ornithine decarboxylase (ODC) in polyamine metabolism has long been established, but the exact source of ornithine has always been unclear. The arginase enzymes are capable of producing ornithine for the production of polyamines and may hold important regulatory functions in the maintenance of this pathway. Utilizing our unique set of arginase single and double knockout mice, we analyzed polyamine levels in the livers, brains, kidneys, and small intestines of the mice at 2 wk of age, the latest timepoint at which all of them are still alive, to determine whether tissue polyamine levels were altered in response to a disruption of arginase I (AI) and II (AII) enzymatic activity. Whereas putrescine was minimally increased in the liver and kidneys from the AII knockout mice, spermidine and spermine were maintained. ODC activity was not greatly altered in the knockout animals and did not correlate with the fluctuations in putrescine. mRNA levels of ornithine aminotransferase (OAT), antizyme 1 (AZ1), and spermidine/spermine- N1-acetyltransferase (SSAT) were also measured and only minor alterations were seen, most notably an increase in OAT expression seen in the liver of AI knockout and double knockout mice. It appears that putrescine catabolism may be affected in the liver when AI is disrupted and ornithine levels are highly reduced. These results suggest that endogenous arginase-derived ornithine may not directly contribute to polyamine homeostasis in mice. Alternate sources such as diet may provide sufficient polyamines for maintenance in mammalian tissues.

scholarly journals CD8 Knockout Mice Are Protected from Challenge by Vaccination with WR201, a Live Attenuated Mutant ofBrucella melitensis

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Samuel L. Yingst ◽  
Mina Izadjoo ◽  
David L. Hoover
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Cd8 T Cells ◽  
Knockout Mice ◽  
Present Report ◽  
Serum Antibody ◽  
Cytotoxic Cells ◽  
Knockout Animals ◽  
Deficient Mice

CD8+ T cells have been reported to play an important role in defense againstB. abortusinfection in mouse models. In the present report, we use CD8 knockout mice to further elucidate the role of these cells in protection fromB. melitensisinfection. Mice were immunized orally by administration ofB. melitensisWR201, a purine auxotrophic attenuated vaccine strain, then challenged intranasally withB. melitensis16M. In some experiments, persistence of WR201 in the spleens of CD8 knockout mice was slightly longer than that in the spleens of normal mice. However, development of anti-LPS serum antibody, antigen-induced production ofγ-interferon (IFN-γ) by immune splenic lymphocytes, protection against intranasal challenge, and recovery of nonimmunized animals from intranasal challenge were similar between normal and knockout animals. Further, primaryBrucellainfection was not exacerbated in perforin knockout and Fas-deficient mice and these animals’ anti-Brucellaimmune responses were indistinguishable from those of normal mice. These results indicate that CD8+ T cells do not play an essential role as either cytotoxic cells or IFN-γproducers, yet they do participate in a specific immune response to immunization and challenge in this murine model ofB. melitensisinfection.

Young Male with Bilateral ICA Dissection: Beyond CADISS Trial

2021 ◽  
pp. 251660852098428
Author(s):  
Vikas Bhatia ◽  
Chirag Jain ◽  
Sucharita Ray ◽  
jay Kumar
Keyword(s):  
Management Strategies ◽  
Young Male ◽  
Acute Onset ◽  
The Body ◽  
Artery Dissection ◽  
Cervical Artery Dissection ◽  
Stroke Study ◽  
History Of

Objective: To report a case of young male with stroke and bilateral internal carotid artery (ICA) dissection. Background: Cervical Artery Dissection in Stroke Study trial has provided some insight on management of patients with ICA dissection. However, there is a need to modify the management strategies as per specific clinical scenario. Design/Methods: Case report and literature review. Results: A 45-year-old male presented with 1 month old history of acute onset numbness of right half of the body with slurring of speech. Computed tomography angiography showed complete occlusion of left cervical ICA just beyond origin with presence of fusiform dilatation and spiral flap in right extracranial cervical ICA. The patient was started on antiplatelets and taken for endovascular procedure using 2-mesh-based carotid stents. Patient was discharged after 3 days on antiplatelet therapy. At 1-year follow-up, there were no fresh symptoms. Conclusion: This case emphasizes the role of successful endovascular management of carotid dissection in a young male. These clinical situations may not be fully represented in trials, and a case-based approach is required.

scholarly journals Minireview: Thyroid Hormone Transporters: The Knowns and the Unknowns

2011 ◽  
Vol 25 (1) ◽  
pp. 1-14 ◽  
Author(s):  
W. Edward Visser ◽  
Edith C. H. Friesema ◽  
Theo J. Visser
Keyword(s):  
Thyroid Hormone ◽  
Organic Anion ◽  
Psychomotor Retardation ◽  
Cellular Level ◽  
Monocarboxylate Transporter ◽  
Causative Role ◽  
Organic Anion Transporting Polypeptide ◽  
Neurological Abnormalities ◽  
Knockout Animals

The effects of thyroid hormone (TH) on development and metabolism are exerted at the cellular level. Metabolism and action of TH take place intracellularly, which require transport of the hormone across the plasma membrane. This process is mediated by TH transporter proteins. Many TH transporters have been identified at the molecular level, although a few are classified as specific TH transporters, including monocarboxylate transporter (MCT)8, MCT10, and organic anion-transporting polypeptide 1C1. The importance of TH transporters for physiology has been illustrated dramatically by the causative role of MCT8 mutations in males with psychomotor retardation and abnormal serum TH concentrations. Although Mct8 knockout animals have provided insight in the mechanisms underlying parts of the endocrine phenotype, they lack obvious neurological abnormalities. Thus, the pathogenesis of the neurological abnormalities in males with MCT8 mutations is not fully understood. The prospects of identifying other transporters and transporter-based syndromes promise an exciting future in the TH transporter field.

Pathogenic and Compensatory Mechanisms in Epidermis of Sphingomyelin Synthase 2-Deficient Mice

2021 ◽  
pp. 1-7
Author(s):  
Shota Sakai ◽  
Asami Makino ◽  
Akihito Nishi ◽  
Takeshi Ichikawa ◽  
Tadashi Yamashita ◽  
...  
Keyword(s):  
Plasma Membranes ◽  
Lamellar Body ◽  
Lipid Mediator ◽  
Permeability Barrier ◽  
Compensatory Mechanisms ◽  
Terrestrial Environment ◽  
Sphingomyelin Synthase ◽  
Epidermal Permeability Barrier ◽  
Deficient Mice

Sphingomyelin (SM) is a constituent of cellular membranes, while ceramides (Cer) produced from SM on plasma membranes serve as a lipid mediator that regulates cell proliferation, differentiation, and apoptosis. In the skin, SM also is a precursor of Cer, an important constituent of epidermal permeability barrier. We investigated the role of epidermal SM synthase (SMS)2, an isoform of SMS, which modulates SM and Cer levels on plasma membranes. Although SMS2-knockout (SMS2-KO) mice were not neonatal lethal, an ichthyotic phenotype with epidermal hyperplasia and hyperkeratosis was evident at birth, which persisted until 2 weeks of age. These mice showed abnormal lamellar body morphology and secretion, and abnormal extracellular lamellar membranes in the stratum corneum. These abnormalities were no longer evident by 4 weeks of age in SMS2-KO mice. Our study suggests that (1) exposure to a dry terrestrial environment initiates compensatory responses, thereby normalizing epidermal ichthyotic abnormalities and (2) that a nonlethal gene abnormality can cause an ichthyotic skin phenotype.

Who Are the Stalking Victims? Exploring the Victimization Experiences and Psychosocial Characteristics of Young Male and Female Adults in Hong Kong

2019 ◽  
pp. 088626051988993 ◽  
Author(s):  
Heng Choon (Oliver) Chan ◽  
Lorraine Sheridan
Keyword(s):  
Hong Kong ◽  
Young Male ◽  
Limited Information ◽  
Psychosocial Characteristics ◽  
Male And Female ◽  
Lifetime Prevalence Rate ◽  
Victimization Experience ◽  
Stalking Victims ◽  
Stalking Victimization

Most stalking studies are conducted in the West. Limited information is available on victims of stalking from the Asian continent. This study specifically explored the victimization experiences of young male and female adults in Hong Kong. Using a large sample of university students ( N = 2,496) aged between 18 and 40 years, the gender distribution of stalking incident characteristics was examined, along with prevalence of various stalking behaviors, and victim–offender relationships by types of stalking behaviors. The differential role of demographic and psychosocial characteristics in stalking victimization experience was also explored. The lifetime prevalence rate of stalking victimization was 8.2%, with a higher estimate in females than males (11.6% vs. 3.8%). The sample analyzed in this study was 196 stalking victims. Although surveillance-oriented behaviors were most frequently reported by both males and females, significant gender differences in types of stalking behaviors were noted. Multivariate analyses indicated that increases in age and levels of self-esteem were correlated with an increased probability of experiencing stalking victimization, while being a male and higher levels of life satisfaction were related to a lower likelihood of falling prey to stalking victimization. This study concludes with a call for anti-stalking legislation in Hong Kong given the devastating nature and consequences of stalking victimization.

scholarly journals The (Patho)Biology of SRC Kinase in Platelets and Megakaryocytes

Medicina ◽  
2020 ◽  
Vol 56 (12) ◽  
pp. 633
Author(s):  
Lore De Kock ◽  
Kathleen Freson
Keyword(s):  
Platelet Activation ◽  
Knockout Mice ◽  
Missense Variant ◽  
Surface Receptors ◽  
Src Signaling ◽  
Normal Platelet ◽  
Fibrinogen Binding ◽  
Cellular Environment ◽  
Proplatelet Formation

Proto-oncogene tyrosine-protein kinase SRC (SRC), as other members of the SRC family kinases (SFK), plays an important role in regulating signal transduction by different cell surface receptors after changes in the cellular environment. Here, we reviewed the role of SRC in platelets and megakaryocytes (MK). In platelets, inactive closed SRC is coupled to the β subunit of integrin αIIbβ3 while upon fibrinogen binding during platelet activation, αIIbβ3-mediated outside-in signaling is initiated by activation of SRC. Active open SRC now further stimulates many downstream effectors via tyrosine phosphorylation of enzymes, adaptors, and especially cytoskeletal components. Functional platelet studies using SRC knockout mice or broad spectrum SFK inhibitors pointed out that SRC mediates their spreading on fibrinogen. On the other hand, an activating pathological SRC missense variant E527K in humans that causes bleeding inhibits collagen-induced platelet activation while stimulating platelet spreading. The role of SRC in megakaryopoiesis is much less studied. SRC knockout mice have a normal platelet count though studies with SFK inhibitors point out that SRC could interfere with MK polyploidization and proplatelet formation but these inhibitors are not specific. Patients with the SRC E527K variant have thrombocytopenia due to hyperactive SRC that inhibits proplatelet formation after increased spreading of MK on fibrinogen and enhanced formation of podosomes. Studies in humans have contributed significantly to our understanding of SRC signaling in platelets and MK.

Sign in / Sign up

Export Citation Format

Share Document