We aimed to elucidate the underlying disease in a Hungarian family, with only one affected family member, a 16-year-old male Hungarian patient, who developed global developmental delay, cognitive ...impairment, behavioral problems, short stature, intermittent headaches, recurrent dizziness, strabismus, hypermetropia, complex movement disorder and partial pituitary dysfunction. After years of detailed clinical investigations and careful pediatric care, the exact diagnosis of the patient and the cause of the disease was still unknown.
We aimed to perform whole exome sequencing (WES) in order to investigate whether the affected patient is suffering from a rare monogenic disease.
Using WES, we identified a novel, de novo frameshift variant (c.1902dupG, p.Ala636SerfsTer12) of the catenin beta-1 (CTNNB1) gene. Assessment of the novel CTNNB1 variant suggested that it is a likely pathogenic one and raised the diagnosis of CTNNB1 neurodevelopmental disorder (OMIM 615,075).
Our manuscript may contribute to the better understanding of the genetic background of the recently discovered CTNNB1 neurodevelopmental disorder and raise awareness among clinicians and geneticists. The affected Hungarian family demonstrates that based on the results of the clinical workup is difficult to establish the diagnosis and high-throughput genetic screening may help to solve these complex cases.
Optical antennas have generated much interest in recent years due to their ability to focus optical energy beyond the diffraction limit, benefiting a broad range of applications such as sensitive ...photodetection, magnetic storage, and surface-enhanced Raman spectroscopy. To achieve the maximum field enhancement for an optical antenna, parameters such as the antenna dimensions, loading conditions, and coupling efficiency have been previously studied. Here, we present a framework, based on coupled-mode theory, to achieve maximum field enhancement in optical antennas through optimization of optical antennas’ radiation characteristics. We demonstrate that the optimum condition is achieved when the radiation quality factor (Q rad) of optical antennas is matched to their absorption quality factor (Q abs). We achieve this condition experimentally by fabricating the optical antennas on a dielectric (SiO2) coated ground plane (metal substrate) and controlling the antenna radiation through optimizing the dielectric thickness. The dielectric thickness at which the matching condition occurs is approximately half of the quarter-wavelength thickness, typically used to achieve constructive interference, and leads to ∼20% higher field enhancement relative to a quarter-wavelength thick dielectric layer.
•The pedigree quality of the autochthonous Blonde, Sallow Belly and Red Mangalica pig breeds were sufficiently long and complete to make analyses reliable.•Although conventional inbreeding of all ...breeds continuously increased the new inbreeding decreased in all cased during the last decade.•Based on the estimated parameters the remained genetic diversity on the predicted future inbreeding the conducted gene conservation programs of the Mangalica breed were efficient.•Nevertheless, close monitoring is necessary especially for the Red Mangalica breed.
The maintenance of genetic diversity (GD) and low rate of inbreeding are two main goals for any conservation programs, especially in a small, closed population which is likely to violate these conservation targets in a long run. Among the conservation programs in Hungary probably the most characterizing is that of the Mangalica pigs, which is an autochthonous Hungarian pig breed group that has been preserved for biological diversity since 1973. The current study aimed to expose the evolution of population structure, GD and inbreeding coefficient with different approaches by analysing the pedigree of these breeds in the context of the conservation program. Genealogy analysis used the data of 12,808, 2393 and 3963 Blonde, Swallow-Belly and Red breeding animals born between 1980 and 2021, respectively. The reference populations (REF2021) were defined as breeding animals born between 2016 and 2021. Pedigree completeness was more than 90% in the fifth generation and the complete generation equivalent ranged from 4.29 to 7.08 and from 6.87 to 9.73 for the whole and the reference populations (REF2021), respectively. Generation interval on average was vary from 3.06 to 3.45 years with the longer pathways to the son. Most of different estimated inbreeding coefficient showed increased trends through pedigrees except for the Kalinowski new inbreeding coefficient (FNew) which decreased in all breeds in the last decade. The mean Wright inbreeding coefficient (Fw) was low, being 5.50%, 4.30% and 7.54% for the Blonde, Swallow-Belly, and Red reference populations (REF2021), respectively. Fw showed strong correlation with FNew but low correlation with FBal while the two types of ancestral inbreeding coefficients (FBal and FKal) were ranging from moderate strong to strong correlation in every breed. Effective population size of the reference populations (REF2021) was 85.57, 76.91, and 57.56, respectively. Based on the predicted future inbreeding for the next 25 years only the Red Mangalica breed was predicted to be “Transitional” in the endangerment categories. The GD loss in these three breeds was 5.6%, 5.7% and 8.7%, respectively, in which the loss due to genetic drift was decisive compared to the unequal founder contributions. In conclusion, the three populations at the present and in the next few generations are having optimistic perspective in terms of GD. These populations should be focused on reducing new inbreeding in mating plans and the Red population need to be monitored more carefully because of its current highest GD loss, smallest effective population size and highest inbreeding coefficient.
This paper is concerned with the design and the analysis of a semi-active suspension controller. In the recent years different kinds of semi-active control strategies, like two-state Skyhook, ...LQ-clipped or model-predictive control, have already been developed in the literature. In this paper, a new semi-active suspension control strategy that a priori satisfies the principal limitations of a semi-active suspension actuator (dissipative constraint and force bounds) is introduced using the tools of the linear parameter varying (LPV) theory. This new approach exhibits some interesting advantages (implementation, performance flexibility, robustness, etc.) compared to already existing methods. Both industrial criterion based evaluation and simulations on a nonlinear quarter vehicle model are performed to show the efficiency of the method and to validate the theoretical approach.
In conserving the genetic diversity of domestic animal breeds, strategies that emphasise between-breed diversity may not be optimal, as they neglect within-breed variation. The aim of the present ...study was to assess the extent of population subdivision in three Mangalica pig breeds and the contribution of migration to their substructure. Wright's
coefficient was calculated based on genealogical data with breeding animals born between 1981 and 2023, with three colour variants (Blonde, Swallow-Belly and Red). These Wright's
coefficients were analysed using multidimensional scaling to reveal the population substructure. The average
coefficient was 0.04 for the Blonde breed and 0.047 for the Swallow-Belly and Red Mangalica breeds, while these parameters were lower in the active herds at 0.03 and 0.04, respectively. The migration of individuals between herds was 61.63% for the Blonde breed and 75.53% and 63.64% for the Swallow-Belly and Red Magalica breeds, respectively. No population substructure was observed in any of the Mangalica breeds, which can be explained by the extensive migration between herds.
The toxicity of and resistance to platinum complexes as cisplatin, oxaliplatin or carboplatin calls for the replacement of these therapeutic agents in clinical settings. We have previously identified ...a set of half sandwich-type osmium, ruthenium and iridium complexes with bidentate glycosyl heterocyclic ligands exerting specific cytostatic activity on cancer cells but not on non-transformed primary cells. The apolar nature of the complexes, conferred by large, apolar benzoyl protective groups on the hydroxyl groups of the carbohydrate moiety, was the main molecular feature to induce cytostasis. We exchanged the benzoyl protective groups to straight chain alkanoyl groups with varying length (3 to 7 carbon units) that increased the IC
value as compared to the benzoyl-protected complexes and rendered the complexes toxic. These results suggest a need for aromatic groups in the molecule. The pyridine moiety of the bidentate ligand was exchanged for a quinoline group to enlarge the apolar surface of the molecule. This modification decreased the IC
value of the complexes. The complexes containing (η
-
-cymene)Ru(II), (η
-
-cymene)Os(II) or (η
-Cp*)Ir(III) were biologically active unlike the complex containing (η
-Cp*)Rh(III). The complexes with cytostatic activity were active on ovarian cancer (A2780, ID8), pancreatic adenocarcinoma (Capan2), sarcoma (Saos) and lymphoma cell lines (L428), but not on primary dermal fibroblasts and their activity was dependent on reactive oxygen species production. Importantly, these complexes were cytostatic on cisplatin-resistant A2780 ovarian cancer cells with similar IC
values as on cisplatin-sensitive A2780 cells. In addition, the quinoline-containing Ru and Os complexes and the short chain alkanoyl-modified complexes (C3 and C4) proved to be bacteriostatic in multiresistant Gram-positive
and
isolates. Hereby, we identified a set of complexes with submicromolar to low micromolar inhibitory constants against a wide range of cancer cells, including platinum resistant cells and against multiresistant Gram-positive bacteria.
We show that a class of optimal input design problems have only discrete spectral measures as solutions. If we fix any finite set of possible frequencies then a randomized version of the resulting ...convex problem has a unique (sparse) solution with probability 1. We also propose a data-driven approach to optimal input design via virtual off-line estimators that coincide with the optimized PE estimator modulo a negligible error, both for open loop and closed loop systems.
Genetic variability in the FADS1-FADS2 gene cluster encoding delta-5 (D5D) and delta-6 (D6D) desaturases has been associated with plasma long-chain PUFA (LCPUFA) and lipid levels in adults. To better ...understand these relationships, we further characterized the association between FADS1-FADS2 genetic variability and D5D and D6D activities in adolescents. Thirteen single nucleotide polymorphisms (SNPs) were genotyped in 1,144 European adolescents (mean ± SD age: 14.7 ± 1.4 y). Serum phospholipid fatty acid levels were analyzed using gas chromatography. D5D and D6D activities were estimated from the C20:4n-6/C20:3n-6 and C20:3n-6/C18:2n-6 ratios, respectively. Minor alleles of nine SNPs were associated with higher 18:2n-6 levels (1.9E-18 ≤ P ≤ 6.1E-5), lower C20:4n-6 levels (7.1E-69 ≤ P ≤ 1.2E-12), and lower D5D activity (7.2E-44 ≤ P ≤ 4.4E-5). All haplotypes carrying the rs174546 minor allele were associated with lower D5D activity, suggesting that this SNP is in linkage disequilibrium with a functional SNP within FADS1. In contrast, only the rs968567 minor allele was associated with higher D6D activity (P = 1.5E-6). This finding agrees with an earlier in vitro study showing that the minor allele of rs968567 is associated with a higher FADS2 promoter activity. These results suggest that rare alleles of several SNPs in the FADS gene cluster are associated with higher D6D activity and lower D5D activity in European adolescents.
Ketamine Bokor, Gyula; Anderson, Peter D.
Journal of pharmacy practice,
12/2014, Volume:
27, Issue:
6
Journal Article
Peer reviewed
Ketamine is a dissociative anesthetic and substance of abuse. Numerous effects can result from the abuse of ketamine. Death from acute direct toxicity is rare. Ketamine can alter numerous functions ...in the brain including color perception, memory, attention, cognition, reaction time, and sense of time and can produce psychological addiction. Chronic ketamine abuse can produce toxicity to the gastrointestinal and urinary tract. Gastrointestinal changes include epigastric pain, hepatic dysfunction, and impaired gallbladder activity. The most common urological condition from ketamine is cystitis but renal failure has been reported.
Background and Purpose
Glycogen phosphorylase (GP) is the key enzyme for glycogen degradation. GP inhibitors (GPi‐s) are glucose lowering agents that cause the accumulation of glucose in the liver as ...glycogen. Glycogen metabolism has implications in beta cell function. Glycogen degradation can maintain cellular glucose levels, which feeds into catabolism to maintain insulin secretion, and elevated glycogen degradation levels contribute to glucotoxicity. The purpose of this study was to assess whether influencing glycogen metabolism in beta cells by GPi‐s affects the function of these cells.
Experimental Approach
The effects of structurally different GPi‐s were investigated on MIN6 insulinoma cells and in a mouse model of diabetes.
Key Results
GPi treatment increased glycogen content and, consequently, the surface area of glycogen in MIN6 cells. Furthermore, GPi treatment induced insulin receptor β (InsRβ), Akt and p70S6K phosphorylation, as well as pancreatic and duodenal homeobox 1(PDX1) and insulin expression. In line with these findings, GPi‐s enhanced non‐stimulated and glucose‐stimulated insulin secretion in MIN6 cells. The InsRβ was shown to co‐localize with glycogen particles as confirmed by in silico screening, where components of InsR signalling were identified as glycogen‐bound proteins. GPi‐s also activated the pathway of insulin secretion, indicated by enhanced glycolysis, mitochondrial oxidation and calcium signalling. Finally, GPi‐s increased the size of islets of Langerhans and improved glucose‐induced insulin release in mice.
Conclusion and Implications
These data suggest that GPi‐s also target beta cells and can be repurposed as agents to preserve beta cell function or even ameliorate beta cell dysfunction in different forms of diabetes.
Linked Articles
This article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc
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