Investigating brain alterations in the Dp1Tyb mouse model of Down syndrome

Down syndrome (DS) is one of the most common birth defects and the most prevalent genetic form of intellectual disability. DS arises from trisomy of chromosome 21, but its molecular and pathological consequences are not fully understood. In this study, we compared Dp1Tyb mice, a DS model, against their wild-type (WT) littermates of both sexes to investigate the impact of DS-related genetic abnormalities on the brain phenotype. We performed in vivo whole brain magnetic resonance imaging (MRI) and hippocampal 1H magnetic resonance spectroscopy (MRS) on the animals at 3 months of age. Subsequently, ex vivo MRI scans and histological analyses were conducted post-mortem. Our findings unveiled the following neuroanatomical and biochemical alterations in the Dp1Tyb brains: a smaller surface area and a rounder shape compared to WT brains, with DS males also presenting smaller global brain volume compared with the counterpart WT. Regional volumetric analysis revealed significant changes in 26 out of 72 examined brain regions, including the medial prefrontal cortex and dorsal hippocampus. These alterations were consistently observed in both in vivo and ex vivo imaging data. Additionally, high-resolution ex vivo imaging enabled us to investigate cerebellar layers and hippocampal subregions, revealing selective areas of decrease and remodelling in these structures. An analysis of hippocampal metabolites revealed an elevation in glutamine and the glutamine/glutamate ratio in the Dp1Tyb mice compared to controls, suggesting a possible imbalance in the excitation/inhibition ratio. This was accompanied by the decreased levels of taurine. Histological analysis revealed fewer neurons in the hippocampal CA3 and DG layers, along with an increase in astrocytes and microglia. These findings recapitulate multiple neuroanatomical and biochemical features associated with DS, enriching our understanding of the potential connection between chromosome 21 trisomy and the resultant phenotype

Intravenous vitamin C in the treatment of post-laser hyperpigmentation for melasma: A short report

Melasma is difficult to treat. Vitamin C, topical and by iontophoresis, has been shown to be useful. When lasers are used, there is a significant incidence of post-laser hyperpigmentation. There is no single established treatment for the latter. The case history of a 51-year-old Chinese woman is presented. Intravenous vitamin C appears to be useful in treating this complication

FPGA technology in process tomography

The aims of this paper are to provide a review of the process tomography applications employing field programmable gate arrays (FPGA) and to understand current FPGA related researches, in order to seek for the possibility to applied FPGA technology in an ultrasonic process tomography system. FPGA allows users to implement complete systems on a programmable chip, meanwhile, five main benefits of applying the FPGA technology are performance, time to market, cost, reliability, and long-term maintenance. These advantages definitely could help in the revolution of process tomography, especially for ultrasonic process tomography and electrical process tomography. Future work is focused on the ultrasonic process tomography for chemical process column investigation using FPGA for the aspects of low cost, high speed and reconstructed image quality

Intratumoral IL-12 delivery empowers CAR-T cell immunotherapy in a pre-clinical model of glioblastoma

Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain cancer, for which effective therapies are urgently needed. Chimeric antigen receptor (CAR)-based immunotherapy represents a promising therapeutic approach, but it is often impeded by highly immunosuppressive tumor microenvironments (TME). Here, in an immunocompetent, orthotopic GBM mouse model, we show that CAR-T cells targeting tumor-specific epidermal growth factor receptor variant III (EGFRvIII) alone fail to control fully established tumors but, when combined with a single, locally delivered dose of IL-12, achieve durable anti-tumor responses. IL-12 not only boosts cytotoxicity of CAR-T cells, but also reshapes the TME, driving increased infiltration of proinflammatory CD4+ T cells, decreased numbers of regulatory T cells (Treg), and activation of the myeloid compartment. Importantly, the immunotherapy-enabling benefits of IL-12 are achieved with minimal systemic effects. Our findings thus show that local delivery of IL-12 may be an effective adjuvant for CAR-T cell therapy for GBM

No Origin, No Problem for Yeast DNA Replication

Eukaryotic DNA replication initiates from multiple sites on each chromosome called replication origins (origins). In the budding yeast Saccharomyces cerevisiae, origins are defined at discrete sites. Regular spacing and diverse firing characteristics of origins are thought to be required for efficient completion of replication, especially in the presence of replication stress. However, a S. cerevisiae chromosome III harboring multiple origin deletions has been reported to replicate relatively normally, and yet how an origin-deficient chromosome could accomplish successful replication remains unknown. To address this issue, we deleted seven well-characterized origins from chromosome VI, and found that these deletions do not cause gross growth defects even in the presence of replication inhibitors. We demonstrated that the origin deletions do cause a strong decrease in the binding of the origin recognition complex. Unexpectedly, replication profiling of this chromosome showed that DNA replication initiates from non-canonical loci around deleted origins in yeast. These results suggest that replication initiation can be unexpectedly flexible in this organism

Association of Methylentetraydrofolate Reductase (MTHFR) 677 C > T gene polymorphism and homocysteine levels in psoriasis vulgaris patients from Malaysia: a case-control study

<p>Abstract</p> <p>Background</p> <p>The methylenetetrahydrofolate reductase (MTHFR) enzyme catalyzes the reduction of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate and methyl donors. The methyl donors are required for the conversion of homocysteine to methionine. Mutation of MTHFR 677 C > T disrupts its thermostability therefore leads to defective enzyme activities and dysregulation of homocysteine levels.</p> <p>Methods</p> <p>This case-control study (n = 367) was conducted to investigate the correlation of the MTHFR gene polymorphism [NM_005957] and psoriasis vulgaris amongst the Malaysian population. Overnight fasting blood samples were collected from a subgroup of consented psoriasis vulgaris patients and matched controls (n = 84) for the quantification of homocysteine, vitamin B₁₂and folic acid levels.</p> <p>Results</p> <p>There was no significant increase of the MTHFR 677 C > T mutation in patients with psoriasis vulgaris compared with controls (<it>χ</it>²= 0.733, p = 0.392). No significant association between homocysteine levels and MTHFR gene polymorphism in cases and controls were observed (F = 0.91, df = 3, 80, p = 0.44). However, homocysteine levels in cases were negatively correlated with vitamin B₁₂(r = -0.173) and folic acid (r = -0.345) levels. Vitamin B₁₂and folic acid levels in cases were also negatively correlated (r = -0.164).</p> <p>Conclusions</p> <p>Our results indicate that there was no significant association between the MTHFR gene polymorphism and psoriasis vulgaris in the Malaysian population. There was no significant increase of the plasma homocysteine level in the psoriasis patients compared to the controls.</p

Perception of improvement after orthognathic surgery: the important variables affecting patient satisfaction

PURPOSE: We evaluated which factors affect patient satisfaction and if patient expectations were fulfilled after orthognathic surgery. METHODS: Questionnaires consisting of 14 questions were given 1 year after bimaxillary osteotomy for class-III correction to subjects. Six questions were answered using an 11-point rating scale based on a visual analog scale (VAS; 0 = poor; 10 = excellent). Also included were seven closed-form questions with yes/no answers, as well as one open question for 'further remarks'. Sagittal and vertical cephalometric parameters were determined on postoperative cephalograms. RESULTS: Seventy-seven patients (37 females, 40 males; mean age, 23.4 +/- 4.9 (SD) years) responded. The intention to undergo surgery only for aesthetic improvement was noted in 11.9% of patients; only improvement of chewing function in 15.5%; both in 71.4%; and none/don't know in 2.6%. Postoperative satisfaction was rated (in means) with 8.13 +/- 1.97 on VAS and correlated significantly with the opinions of friends and relatives. Facial aesthetics was rated 5.6 +/- 1.2 before surgery and 8.1 +/- 1.5 after surgery (p = 0.04). Preoperative chewing function was rated 5.65 +/- 1.8 and 8.03 +/- 1.51 after surgery (p = 0.014). TMJ disorders or hypoesthesia had no negative impacts. Cephalometric analyses revealed a significantly lower SNB (75.3 degrees +/- 2.7 degrees ; p = 0.033) in patients rating lower than grade 7 for overall satisfaction. For SNA and ArGoMe, no significant differences were observed. CONCLUSION: The most distinctive factors for patient satisfaction after orthognathic surgery were chewing function and facial aesthetics with respect to the lower face. Function, aesthetics, and even psychological aspects should be considered equally when planning surgery

P2Y2 receptor activation regulates the expression of acetylcholinesterase and acetylcholine receptor genes at vertebrate neuromuscular junctions

ABSTRACT At the vertebrate neuromuscular junction (nmj), ATP is known to be coreleased with acetylcholine from the synaptic vesicles. We have previously shown that the P2Y 1 receptor is localized at the nmj. Here, we extend the findings to show that another nucleotide receptor, P2Y 2 , is also localized there and with P2Y 1 jointly mediates trophic responses to ATP. The P2Y 2 receptor mRNA in rat muscle increased during development and peaked in adulthood. The P2Y 2 receptor protein was shown to become restricted to the nmjs during embryonic development, in chick and in rat. In both rat and chick myotubes, P2Y 1 and P2Y 2 are expressed, increasing with differentiation, but P2Y 4 is absent. The P2Y 2 agonist UTP stimulated there inositol trisphosphate production and phosphorylation of extracellular signal-regulated kinases, in a dose-dependent manner. These UTP-induced responses were insensitive to the P2Y 1 -specific antagonist MRS 2179 (2Ј-deoxy-N 6 -methyl adenosine 3Ј,5Ј-diphosphate diammonium salt). In differentiated myotubes, P2Y 2 activation induced expression of acetylcholinesterase (AChE) protein (but not control ␣-tubulin). This was shown to arise from AChE promoter activation, mediated by activation of the transcription factor Elk-1. Two Elk-1-responsive elements, located in intron-1 of the AChE promoter, were found by mutation to act in this gene activation initiated at the P2Y 2 receptor and also in that initiated at the P2Y 1 receptor. Furthermore, the promoters of different acetylcholine receptor subunits were also stimulated by application of UTP to myotubes. These results indicate that ATP regulates postsynaptic gene expressions via a common pathway triggered by the activation of P2Y 1 and P2Y 2 receptors at the nmjs

Intracranial injection of dengue virus induces interferon stimulated genes and CD8(+) T cell infiltration by sphingosine kinase 1 independent pathways

We have previously reported that the absence of sphingosine kinase 1 (SK1) affects both dengue virus (DENV) infection and innate immune responses in vitro. Here we aimed to define SK1-dependancy of DENV-induced disease and the associated innate responses in vivo. The lack of a reliable mouse model with a fully competent interferon response for DENV infection is a challenge, and here we use an experimental model of DENV infection in the brain of immunocompetent mice. Intracranial injection of DENV-2 into C57BL/6 mice induced body weight loss and neurological symptoms which was associated with a high level of DENV RNA in the brain. Body weight loss and DENV RNA level tended to be greater in SK1-/- compared with wildtype (WT) mice. Brain infection with DENV-2 is associated with the induction of interferon-β (IFN-β) and IFN-stimulated gene (ISG) expression including viperin, Ifi27l2a, IRF7, and CXCL10 without any significant differences between WT and SK1-/- mice. The SK2 and sphingosine-1-phosphate (S1P) levels in the brain were unchanged by DENV infection or the lack of SK1. Histological analysis demonstrated the presence of a cellular infiltrate in DENV-infected brain with a significant increase in mRNA for CD8 but not CD4 suggesting this infiltrate is likely CD8+ but not CD4+ T-lymphocytes. This increase in T-cell infiltration was not affected by the lack of SK1. Overall, DENV-infection in the brain induces IFN and T-cell responses but does not influence the SK/S1P axis. In contrast to our observations in vitro, SK1 has no major influence on these responses following DENV-infection in the mouse brain.Wisam H. Al-Shujairi, Jennifer N. Clarke, Lorena T. Davies, Mohammed Alsharifi, Stuart M. Pitson, Jillian M. Car