Polymorphisms in the bradykinin B2 receptor gene and childhood asthma

Bradykinin has been suggested as one of the key mediators of bronchial asthma. Polymorphisms with a potential functional relevance have been described in the B2 bradykinin receptor gene. Study of these polymorphisms in 77 children with asthma and 73 controls revealed no association. However, when comparing the asthmatics according to their age at onset (before and after age 4), the exon 1 allele BE1-2G was significantly associated with late-onset asthma (p <0.05). Since BE1-2G has previously been shown to lead to a higher transcription rate of the B2 receptor, this result warrants further investigation of the role of bradykinin in conferring susceptibility to pediatric asthma

Can Artificial Noise Boost Further the Secrecy of Dual-hop RIS-aided Networks?

In this paper, we quantify the physical layer security of a dual-hop regenerative relaying-based wireless communication system assisted by reconfigurable intelligent surfaces (RISs). In particular, the setup consists of a source node communicating with a destination node via a regenerative relay. In this setup, a RIS is installed in each hop to increase the source-relay and relay-destination communications reliability, where the RISs' phase shifts are subject to quantization errors. The legitimate transmission is performed under the presence of a malicious eavesdropper attempting to compromise the legitimate transmissions by overhearing the broadcasted signal from the relay. To overcome this problem, we incorporate a jammer to increase the system's secrecy by disrupting the eavesdropper through a broadcasted jamming signal. Leveraging the well-adopted Gamma and Exponential distributions approximations, the system's secrecy level is quantified by deriving approximate and asymptotic expressions of the secrecy intercept probability (IP) metric in terms of the main network parameters. The results show that the secrecy is enhanced significantly by increasing the jamming power and/or the number of reflective elements (REs). In particular, an IP of approximately $10^{-4}$ can be reached with $40$ REs and $10$ dB of jamming power-to-noise ratio even when the legitimate links' average signal-to-noise ratios are $10$-dB less than the eavesdropper's one. We show that cooperative jamming is very helpful in strong eavesdropping scenarios with a fixed number of REs, and the number of quantization bits does not influence the secrecy when exceeding $3$ bits. All the analytical results are endorsed by Monte Carlo simulations

Response of Auxins and Cytokinins on Citrus suhuiensis Adventitious Shoot Culture Initiation and Growth

Bacterial and viral diseases are the common problems hampering vast majority of citrus plant which resulted in the decrease of citrus trees development and production yield. While the usage of chemicals to eliminate internal pathogens is harmful to the ecosystem, plant tissue culture is another alternative to develop disease-free plants based on the defined physical and chemical conditions under aseptic environment. This study aimed to initiate Citrus suhuiensis (C. suhuiensis) adventitious shoot culture specifically in response towards different types of plant growth regulators (PGRs). The effect of explants and PGRs were evaluated on the shoot growth within 35 days. C. suhuiensis shoot cultures were induced from three different explants which are leaf, callus and seeds on the solid Murashige and Skoog (MS) medium containing different combinations of PGR which are auxins i.e. 1-naphthylacetic acid (NAA) or indole butyric acid (IBA) at 0.5 mg/L, respectively with cytokinins i.e. 6-benzylaminopurine (BAP) or kinetin (KN) at various concentrations (0.5 - 4.0 mg/L). Based on the results, the earliest shoot emergence from the cotyledon can be observed after 8th day of inoculation for PGRs combination of 0.5 mg/L IBA with 2.0 mg/L, 3.0 mg/L KN and 3.0 mg/L BAP, respectively. Meanwhile, based on the ANOVA analysis (p-value < 0.05), the most significant PGRs combination for the establishment of C. suhuiensis shoot culture is IBA and KN followed by the treatment of NAA and KN. The findings of this study can serve as a basis for future investigation of micropropagation of shoot culture and cultivation of C. suhuiensis plant

Optimization of plant growth regulators for Citrus suhuiensis callus induction

Correct types and concentration of plant growth regulators (PGRs) will enhance and optimize the growth of callus cultures. This paper reported the effects of several types of cytokinins (2,4-dichlorophenoxyacetic acid (2,4-D) and 1-naphthalene acetic acid (NAA)) and auxins (6–Benzylaminopurine (BAP) and kinetin) on the callus induction of C. suhuiensis. The cotyledons from C. suhuiensis seeds were excised as the explant and cultured on Murashige and Skoog (MS) media, 3% (w/v) sugar, 0.05% (w/v) malt extract and 0.25% (w/v) agar under the continuous dark condition supplemented with the chosen PGRs at the concentration range of 0.5, 1.0, 2.0, 3.0 and 4.0 mg/L. The growth of callus at each treatment was measured as gram (g) of fresh weight and percentage of callus induction. The results showed that 1.0 mg/L 2,4-D gave the highest growth of callus (0.15 g and 100% callus percentage). After identifying the effective PGRs, Central Composite Design (CCD) from the Design Expert® software version 9.0 was used to obtain the optimum concentration of cytokinin and auxin on C. suhuiensis callus cultures. It was observed that the highest amount of callus culture induced was 0.218 g when the media was supplemented with 1.0 mg/L 2,4-D and 1.0 mg/L kinetin

Cancer and systemic inflammation: treat the tumour and treat the host

Determinants of cancer progression and survival are multifactorial and host responses are increasingly appreciated to have a major role. Indeed, the development and maintenance of a systemic inflammatory response has been consistently observed to confer poorer outcome, in both early and advanced stage disease. For patients, cancer-associated symptoms are of particular importance resulting in a marked impact on day-to-day quality of life and are also associated with poorer outcome. These symptoms are now recognised to cluster with one another with anorexia, weight loss and physical function forming a recognised cluster whereas fatigue, pain and depression forming another. Importantly, it has become apparent that these symptom clusters are associated with presence of a systemic inflammatory response in the patient with cancer. Given the understanding of the above, there is now a need to intervene to moderate systemic inflammatory responses, where present. In this context the rationale for therapeutic intervention using nonselective anti-inflammatory agents is clear and compelling and likely to become a part of routine clinical practice in the near future. The published literature on therapeutic intervention using anti-inflammatory agents for cancer-associated symptoms was reviewed. There are important parallels with the development of useful treatments for the systemic inflammatory response in patients with rheumatological disease and cardiovascular disease

Early age exposure to moisture damage and systemic inflammation at the age of 6 years

Cross-sectional studies have shown that exposure to indoor moisture damage and mold may be associated with subclinical inflammation. Our aim was to determine whether early age exposure to moisture damage or mold is prospectively associated with subclinical systemic inflammation or with immune responsiveness in later childhood. Home inspections were performed in children's homes in the first year of life. At age 6 years, subclinical systemic inflammation was measured by serum C-reactive protein(CRP) and blood leucocytes and immune responsiveness by ex vivo production of interleukin 1-beta(IL-1beta), IL-6 and tumor necrosis factor-alpha(TNF-alpha) in whole blood cultures without stimulation or after 24h stimulation with phorbol 12-myristate 13-acetate and ionomycin(PI), lipopolysaccharide(LPS) or peptidoglycan(PPG) in 251 to 270 children. Moisture damage in child's main living areas in infancy was not significantly associated with elevated levels of CRP or leucocytes at 6 years. In contrast, there was some suggestion for an effect on immune responsiveness, as moisture damage with visible mold was positively associated with LPS-stimulated production of TNF-alpha and minor moisture damage was inversely associated with PI-stimulated IL-1beta. While early life exposure to mold damage may have some influence on later immune responsiveness, it does not seem to increase subclinical systemic inflammation in later life. This article is protected by copyright. All rights reserved

TPH1A218C polymorphism and temperament in major depression

BACKGROUND: In major depression, one of the candidate genes possibly affecting the risk and severity of symptoms has been found to be tryptophan hydroxylase (TPH1). Variation in treatment response to antidepressive agents according to TPH1 genotype has also been found in several studies. However, the relationship between temperament and TPH1 genotype in major depression is poorly understood, as only one study has been published so far. There are no earlier studies on the interaction between temperament traits, antidepressive medication response and TPH1 genotype. This interaction was studied in 97 subjects with major depression treated for six weeks with selective serotonine reuptake inhibitors. METHODS: Temperament dimensions Harm Avoidance (HA), Novelty Seeking (NS), Reward Dependence (RD) and Persistence (P) scores at baseline (1) and endpoint (2) were rated with the Temperament and Character Inventory (TCI) and compared between TPH1 A218C genotypes. Multivariate analysis of co-variance (MANCOVA) was used to analyze the interaction between the TPH1 genotype, treatment response and the different temperament dimensions at baseline and endpoint. In the analysis model, treatment response was used as a covariate and TPH1 genotype as a factor. A post hoc analysis for an interaction between remission status and TPH1 A218C genotype at endpoint HA level was also performed. RESULTS: The number of TPH1 A-alleles was associated with increasing levels in NS1 and NS2 scores and decreasing levels in HA1 and HA2 scores between TPH1 A218C genotypes. In the MANCOVA model, TPH1 genotype and treatment response had an interactive effect on both HA1 and HA2 scores, and to a lesser degree on NS2 scores. Additionally, an interaction between remission status and TPH1 A218C genotype was found to be associated with endpoint HA score, with a more marked effect of the interaction between CC genotype and remission status compared to A-allele carriers. CONCLUSIONS: Our results suggest that in acute depression TPH1 A218C polymorphism and specifically the CC genotype together with the information on remission or treatment response differentiates between different temperament profiles and their changes

Myc and Omomyc functionally associate with the Protein Arginine Methyltransferase 5 (PRMT5) in glioblastoma cells

The c-Myc protein is dysregulated in many human cancers and its function has not been fully elucitated yet. The c-Myc inhibitor Omomyc displays potent anticancer properties in animal models. It perturbs the c-Myc protein network, impairs c-Myc binding to the E-boxes, retaining transrepressive properties and inducing histone deacetylation. Here we have employed Omomyc to further analyse c-Myc activity at the epigenetic level. We show that both Myc and Omomyc stimulate histone H4 symmetric dimethylation of arginine (R) 3 (H4R3me2s), in human glioblastoma and HEK293T cells. Consistently, both associated with protein Arginine Methyltransferase 5 (PRMT5)-the catalyst of the reaction-and its co-factor Methylosome Protein 50 (MEP50). Confocal experiments showed that Omomyc co-localized with c-Myc, PRMT5 and H4R3me2s-enriched chromatin domains. Finally, interfering with PRMT5 activity impaired target gene activation by Myc whereas it restrained Omomyc-dependent repression. The identification of a histone-modifying complex associated with Omomyc represents the first demonstration of an active role of this miniprotein in modifying chromatin structure and adds new information regarding its action on c-Myc targets. More importantly, the observation that c-Myc may recruit PRMT5-MEP50, inducing H4R3 symmetric di-methylation, suggests previously unpredictable roles for c-Myc in gene expression regulation and new potential targets for therapy

Agenesis of the putamen and globus pallidus caused by recessive mutations in the homeobox gene GSX2

Basal ganglia are subcortical grey nuclei that play essential roles in controlling voluntary movements, cognition and emotion. While basal ganglia dysfunction is observed in many neurodegenerative or metabolic disorders, congenital malformations are rare. In particular, dysplastic basal ganglia are part of the malformative spectrum of tubulinopathies and X-linked lissencephaly with abnormal genitalia, but neurodevelopmental syndromes characterized by basal ganglia agenesis are not known to date. We ascertained two unrelated children (both female) presenting with spastic tetraparesis, severe generalized dystonia and intellectual impairment, sharing a unique brain malformation characterized by agenesis of putamina and globi pallidi, dysgenesis of the caudate nuclei, olfactory bulbs hypoplasia, and anomaly of the diencephalic-mesencephalic junction with abnormal corticospinal tract course. Whole-exome sequencing identified two novel homozygous variants, c.26C>A; p.(S9*) and c.752A>G; p.(Q251R) in the GSX2 gene, a member of the family of homeobox transcription factors, which are key regulators of embryonic development. GSX2 is highly expressed in neural progenitors of the lateral and median ganglionic eminences, two protrusions of the ventral telencephalon from which the basal ganglia and olfactory tubercles originate, where it promotes neurogenesis while negatively regulating oligodendrogenesis. The truncating variant resulted in complete loss of protein expression, while the missense variant affected a highly conserved residue of the homeobox domain, was consistently predicted as pathogenic by bioinformatic tools, resulted in reduced protein expression and caused impaired structural stability of the homeobox domain and weaker interaction with DNA according to molecular dynamic simulations. Moreover, the nuclear localization of the mutant protein in transfected cells was significantly reduced compared to the wild-type protein. Expression studies on both patients' fibroblasts demonstrated reduced expression of GSX2 itself, likely due to altered transcriptional self-regulation, as well as significant expression changes of related genes such as ASCL1 and PAX6. Whole transcriptome analysis revealed a global deregulation in genes implicated in apoptosis and immunity, two broad pathways known to be involved in brain development. This is the first report of the clinical phenotype and molecular basis associated to basal ganglia agenesis in humans

Continuous Rather Than Solely Early Farm Exposure Protects From Hay Fever Development

BACKGROUND: An important window of opportunity for early-life exposures has been proposed for the development of atopic eczema and asthma.OBJECTIVE: However, it is unknown whether hay fever with a peak incidence around late school age to adolescence is similarly determined very early in life.METHODS: In the Protection against Allergy-Study in Rural Environments (PASTURE) birth cohort potentially relevant exposures such as farm milk consumption and exposure to animal sheds were assessed at multiple time points from infancy to age 10.5 years and classified by repeated measure latent class analyses (n [ 769). Fecal samples at ages 2 and 12 months were sequenced by 16S rRNA. Hay fever was defined by parent -reported symptoms and/or physician's diagnosis of hay fever in the last 12 months using questionnaires at 10.5 years.RESULTS: Farm children had half the risk of hay fever at 10.5 years (adjusted odds ratio [aOR] 0.50; 95% CI 0.31-0.79) than that of nonfarm children. Whereas early life events such as gut microbiome richness at 12 months (aOR 0.66; 95% CI 0.46-0.96) and exposure to animal sheds in the first 3 years of life (aOR 0.26; 95% CI 0.06-1.15) were determinants of hay fever, the continuous consumption of farm milk from infancy up to school age was necessary to exert the protective effect (aOR 0.35; 95% CI 0.17-0.72).CONCLUSIONS: While early life events determine the risk of subsequent hay fever, continuous exposure is necessary to achieve protection. These findings argue against the notion that only early life exposures set long-lasting trajectories. (c) 2022 The Authors. Published by Elsevier IncPeer reviewe