Calcium/calmodulin-dependent serine protein kinase (CASK) is a membrane-associated guanylate kinase (MAGUK) protein that is associated with neurodevelopmental disorders. CASK is thought to have both ...pre- and postsynaptic functions, but the mechanism and consequences of its functions in the brain have yet to be elucidated, because homozygous CASK-knockout (CASK-KO) mice die before brain maturation. Taking advantage of the X-chromosome inactivation (XCI) mechanism, here we examined the synaptic functions of CASK-KO neurons in acute brain slices of heterozygous CASK-KO female mice. We also analyzed CASK-knockdown (KD) neurons in acute brain slices generated by in utero electroporation. Both CASK-KO and CASK-KD neurons showed a disruption of the excitatory and inhibitory (E/I) balance. We further found that the expression level of the N-methyl-D-aspartate receptor subunit GluN2B was decreased in CASK-KD neurons and that overexpressing GluN2B rescued the disrupted E/I balance in CASK-KD neurons. These results suggest that the down-regulation of GluN2B may be involved in the mechanism of the disruption of synaptic E/I balance in CASK-deficient neurons.
Zinc nanoparticles are documented to be harmful to fish because their accumulation in fish bring about many irreversible changes in their health. Nigella sativa and its oil have been endorsed in ...aquaculture to improve fish health.
Two hundred seventy experimental fish (113 ± 5 g body weight) were divided into 6 groups G1–6; control fish fed a diet without any treatment (G1), 0.3% of NSO (G2), 0.5% of NSO (G3), ZnO NPs (40 mg/kg diet) (G4), 0.3% of NSO and ZnO NPs (40 mg/kg diet) (G5), 0.5% of NSO and ZnO NPs (40 mg/kg diet) (G6), the trial lasted for six weeks.
Growth performance was enhanced in fish received diets containing NSO, final weight (FW), weight gain (WG), daily weight gain (DWG), and relative growth rate (RGR) were significantly increased with lower food conversion ratios (FCR) compared to the control. The hepatic glutathione peroxidase (GPx), catalase (CAT), and metallothionein (MT) were increased in response to ZnO NPs stress and only 0.5% NSO supplementation could ameliorate such increment. The immune-related genes interleukin1-beta (IL-1β), tumor necrosis factor-beta (TNF-β), transforming growth factor-beta 2 (TGF-β2) and C-type lysozyme as well as growth-related gene insulin-like growth factor 1 (IGF1) in liver showed an upregulation in fish fed with NSO diets. Administration of ZnO NPs lowered the resistance of Oreochromis niloticus against bacterial infection with Aeromonas hydrophila and NSO could enhance the immunity in the highest tested concentration (0.5%) (G6).
The obtained results implied that NSO could enhance the oxidative and immune status of O. niloticus which could compensate ZnO NPs stress as well as experimental infection of a virulent strain of A. hydrophila. Our results revealed that NSO might increase fish growth and immunity only at a high dose (0.5%).
•Zinc nanoparticles could suppress Nile tilapia immunity.•Nigella sativa oil could ameliorate nanoparticles withdrawals.•Cytokines expressions affected by Zinc nanoparticles and Nigella sativa oil supplementation.
Background
Pollution with heavy metals (HMs) is time- and concentration-dependent. Lead and zinc pollute the aquatic environment, causing severe health issues in aquatic animals.
Materials and ...methods
Nile tilapia, the predominant cultured fish in Egypt, were experimentally exposed to 10% of LC
50
of lead nitrate (PbNO
3
) and zinc sulfate (ZnSO
4
). Samples were collected in three different periods, 4, 6, and 8 weeks, in addition to a trial to treat the experimental fish infected with
Aeromonas hydrophila
, with an antibiotic (florfenicol).
Results
Liver enzymes were linearly upsurged in a time-dependent manner in response to HMs exposure. ALT was 92.1 IU/l and AST was 82.53 IU/l after eight weeks. In the eighth week of the HMs exposure, in the hepatic tissue, the levels of glutathione peroxidase (GPx), catalase (CAT), and metallothionein (MT) were increased to 117.8 U/mg prot, 72.2 U/mg prot, and 154.5 U/mg prot, respectively. On exposure to HMs, gene expressions of some cytokines were linearly downregulated in a time-dependent manner compared to the control. After four weeks of exposure to the HMs, the oxidative burst activity (OBA) of immune cells was decreased compared to the control 9.33 and 10.3 cells, respectively. Meanwhile, the serum bactericidal activity (SBA) significantly declined to 18.5% compared to the control 32.6% after eight weeks of exposure. Clinical signs of
A. hydrophila
infection were exaggerated in polluted fish, with a mortality rate (MR) of 100%. The re-isolation rate of
A. hydrophila
was decreased in fish treated with florfenicol regardless of the pollution impacts after eight weeks of HMs exposure.
Conclusion
It could be concluded that the immune suppression and oxidative stress resulting from exposure to HMs are time-dependent. Clinical signs and post-mortem lesions in polluted fish infected with
A. hydrophila
were prominent. Infected-Nile tilapia had weak responses to florfenicol treatment due to HMs exposure.
The strictly aquatic breathing Nile tilapia, Oreochromis niloticus is an extremely hypoxia-tolerant fish. To augment our understanding of the effects of hypoxia on anaerobic glycolysis in the Nile ...tilapia, we studied the effect of short-term for 1 day (trial 1) and long-term for 30 days (trial 2) hypoxia on a selected glycolytic enzymes activity and mRNA expression in liver and white muscle. The hypoxic oxygen concentrations used in the two trials were 2, 1, and 0.5 mg O ₂ L ⁻¹ for comparison with a control normoxic group 8 mg O ₂ L ⁻¹. The activity of phosphofructokinase (PFK), pyruvate kinase (PK), and lactate dehydrogenase (LDH) in liver and white muscle except liver LDH decreased in trial 1 and increased in trial 2. Assessments of mRNA levels in trial 1 revealed that PFK was downregulated and LDH was upregulated in liver and white muscle, while PK fluctuated between upregulation in liver and downregulation in white muscle. Meanwhile, PK and LDH were upregulated while PFK was similar to control values in both tissues in trial 2. Comet assay results demonstrated an increase in DNA damage that was directly proportional to increasing hypoxic concentrations. This damage was more pronounced in trial 1. This suggests that the Nile tilapia cope better with long-term hypoxic conditions, possibly as an adaptive response.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
This article was originally published under standard licence, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the paper have been modified accordingly.
•Neurexins (NRXNs) have been implicated in wide variety of neuropsychiatric disorders.•Bi-allelic NRXN1 deficiency causes developmental disorders phenotypically resembling Pitt-Hopkins ...syndrome.•Rodent Nrxn mutant models exhibit behavioral abnormalities reminiscent of neuropsychiatric disorders.
Neurexins are a family of presynaptic single-pass transmembrane proteins that act as synaptic organizers in mammals. The neurexins consist of three genes (NRXN1, NRXN2, and NRXN3), each of which produces a longer α- and shorter β-form. Genomic alterations in NRXN genes have been identified in a wide variety of neuropsychiatric disorders, including autism spectrum disorders (ASD), schizophrenia, intellectual disability (ID), and addiction. Remarkably, a bi-allelic deficiency of NRXN1 was recently linked to Pitt-Hopkins syndrome. The fact that some mono-allelic functional variants of NRXNs are also found in healthy controls indicates that other genetic or environmental factors affect the penetrance of NRXN deficiency. In this review, we summarize the common research methods and representative results of human genetic studies that have implicated NRXN variants in various neuropsychiatric disorders. We also summarize studies of rodent models with NRXN deficiencies that complement our knowledge of human genetics.
Increasing interest has been focused on lncRNAs as potential markers in the pathogenesis and progression of numerous diseases.
We aimed to investigate the expression pattern and role of cell-free ...lncRNAs (GAS5, HCG27_201 and LY86-AS1) in pre-diabetic, diabetic and T2DM groups.
Quantification of the expression level of cell-free lncRNAs (GAS5, HCG27_201 and LY86-AS1) was performed by real-time PCR in 210 individuals classified in diabetic (T2DM), pre-diabetic and control groups.
Significant differences were observed in the relative expression level of lncRNAs (GAS5, LY86-AS1 and HCG27_201) among the three studied groups. The LncRNA expression levels decreased gradually from the control to the pre-diabetic group and reached the lowest values in the T2DM group. The A receiver operating characteristic curve (ROC) was applied to identify a cut-off value for each of the three genes among our groups. The three lncRNAs showed promising results in discriminating between the diabetic patients and controls, with HCG27_201 gene expression having the best performance. Furthermore, lncRNA expression was able to predict the future development of DM in the pre-diabetics because ROC analysis among diabetics and pre-diabetics revealed considerable results. GAS5 gene expression showed the best performance. Additionally, HCG27_201 expression was the most valuable biomarker for differentiating between pre-diabetics and controls and presented a sensitivity of 91% and specificity of 64%.
We concluded that cell free lncRNAs (GAS5, LY86-AS1 and HCG27_201) could be considered promising diagnostic and predictive biomarkers for DM and that HCG27_201 could act as a potential diagnostic biomarker for pre-diabetes.
•lncRNAs are involved in T2DM pathological process.•lncRNA showed ability to predict development of DM.•GAS5, LY86-AS1 and HCG27_201 could be considered as diagnostic biomarkers for DM.•The three studied lncRNA could also be considered as predictive biomarkers for DM.•HCG27_201 could act as a potential diagnostic biomarker for pre-diabetes.
IQSEC3, a gephyrin-binding GABAergic (gamma-aminobutyric acidergic) synapse-specific guanine nucleotide exchange factor, was recently reported to regulate activity-dependent GABAergic synapse ...maturation, but the underlying signaling mechanisms remain incompletely understood.
We generated mice with conditional knockout (cKO) of Iqsec3 to examine whether altered synaptic inhibition influences hippocampus-dependent fear memory formation. In addition, electrophysiological recordings, immunohistochemistry, and behavioral assays were used to address our question.
We found that Iqsec3-cKO induces a specific reduction in GABAergic synapse density, GABAergic synaptic transmission, and maintenance of long-term potentiation in the hippocampal CA1 region. In addition, Iqsec3-cKO mice exhibited impaired fear memory formation. Strikingly, Iqsec3-cKO caused abnormally enhanced activation of ribosomal P70-S6K1–mediated signaling in the hippocampus but not in the cortex. Furthermore, inhibiting upregulated S6K1 signaling by expressing dominant-negative S6K1 in the hippocampal CA1 of Iqsec3-cKO mice completely rescued impaired fear learning and inhibitory synapse density but not deficits in long-term potentiation maintenance. Finally, upregulated S6K1 signaling was rescued by IQSEC3 wild-type, but not by an ARF-GEF (adenosine diphosphate ribosylation factor–guanine nucleotide exchange factor) inactive IQSEC3 mutant.
Our results suggest that IQSEC3-mediated balanced synaptic inhibition in hippocampal CA1 is critical for the proper formation of hippocampus-dependent fear memory.
Immunotherapy becomes a promising line of treatment for breast cancer (BC) however, its success rate is still limited.
The study was designed to optimize the condition for producing an effective ...dendritic cell (DCs) based immunotherapy by using DCs and T lymphocytes together with tumor-infiltrating lymphocytes (TILs) and tumor-infiltrating DCs (TIDCs), treated with anti-PD1 and anti-CTLA4 monoclonal antibodies. This mixture of immune cells was co-cultured with autologous breast cancer cells (BCCs) isolated from 26 BC females.
There was a significant upregulation of CD86 and CD83 on DCs (
= 0.001 and 0.017, respectively), similarly upregulation of CD8, CD4 and CD103 on T cells (
= 0.031, 0.027, and 0.011, respectively). While there was a significant downregulation of FOXP3 and combined CD25.CD8 expression on regulatory T cells (
= 0.014 for both). Increased CD8/Foxp3 ratio (
< 0.001) was also observed. CD133, CD34 and CD44 were downregulated on BCCs (
= 0.01, 0.021, and 0.015, respectively). There was a significant increase in interferon-γ (IFN-γ,
< 0.001), lactate dehydrogenase (LDH,
= 0.02), and a significant decrease in vascular endothelial growth factor (VEGF,
< 0.001) protein levels. Gene expression of FOXP3 and Programmed cell death ligand 1 (PDL-1) were downregulated in BCCs (
< 0.001, for both), similarly cytotoxic T lymphocyte antigen-4 (CTLA4,
= 0.02), Programmed cell death 1 (PD-1,
< 0.001) and FOXP3 (
< 0.001) were significantly downregulated in T cells.
activation of immune cells (DCs, T cells, TIDCs, and TILs) with immune checkpoint inhibitors could produce a potent and effective BC immunotherapy. However, these data should be validated on an experimental animal model to be transferred to the clinical setting.
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