714 research outputs found

    Hemizygous variants in protein phosphatase 1 regulatory subunit 3F (PPP1R3F) are associated with a neurodevelopmental disorder characterized by developmental delay, intellectual disability and autistic features

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    Protein phosphatase 1 regulatory subunit 3F (PPP1R3F) is a member of the glycogen targeting subunits (GTSs), which belong to the large group of regulatory subunits of protein phosphatase 1 (PP1), a major eukaryotic serine/threonine protein phosphatase that regulates diverse cellular processes. Here, we describe the identification of hemizygous variants in PPP1R3F associated with a novel X-linked recessive neurodevelopmental disorder in 13 unrelated individuals. This disorder is characterized by developmental delay, mild intellectual disability, neurobehavioral issues such as autism spectrum disorder, seizures and other neurological findings including tone, gait and cerebellar abnormalities. PPP1R3F variants segregated with disease in affected hemizygous males that inherited the variants from their heterozygous carrier mothers. We show that PPP1R3F is predominantly expressed in brain astrocytes and localizes to the endoplasmic reticulum in cells. Glycogen content in PPP1R3F knockout astrocytoma cells appears to be more sensitive to fluxes in extracellular glucose levels than in wild-type cells, suggesting that PPP1R3F functions in maintaining steady brain glycogen levels under changing glucose conditions. We performed functional studies on nine of the identified variants and observed defects in PP1 binding, protein stability, subcellular localization and regulation of glycogen metabolism in most of them. Collectively, the genetic and molecular data indicate that deleterious variants in PPP1R3F are associated with a new X-linked disorder of glycogen metabolism, highlighting the critical role of GTSs in neurological development. This research expands our understanding of neurodevelopmental disorders and the role of PP1 in brain development and proper function

    Bisphenol A adsorption using modified aloe vera leaf-wastes derived bio-sorbents from aqueous solution: kinetic, isotherm, and thermodynamic studies

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    Reactive-oxygen-species are produced more often in the body when bisphenol A (BPA), an endocrine-disrupting-substance, is present. In this investigation, bio-sorbents from an aqueous solution adapted from Aloe-vera were used to survey BPA removal. Aloe-vera leaf wastes were used to create activated carbon, which was then analyzed using Fourier transform infrared (FTIR), Field emission scanning electron microscopy (FESEM), X-ray diffraction (XRD), Thermogravimetric analysis (TGA), Zeta potential, and Brunauer-Emmett-Teller (BET) techniques. It was revealed that the adsorption process adheres to the Freundlich isotherm model with R-2>0.96 and the pseudo-second-order kinetic model with R-2>0.99 under ideal conditions (pH = 3, contact time = 45 min, concentration of BPA = 20 mg.L-1, and concentration of the adsorbent = 2 g.L-1). After five-cycle, the efficacy of removal was greater than 70. The removal of phenolic-chemicals from industrial-effluent can be accomplished with the assistance of this adsorbent in a cost-effective and effective-approach

    Modelling of the multi-transition periodic flaring in G9.62+0.20E

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    We present detailed modeling of periodic flaring events in the 6.7 GHz and 12.2 GHz methanol lines as well as the OH 1665 MHz and 1667 MHz transitions observed in the G9.62+0.20E star-forming region. Our analysis is performed within the framework of the one-dimensional Maxwell-Bloch equations, which intrinsically cover the complementary quasi-steady state maser and transient superradiance regimes. We find that the variations in flaring time-scales measured for the different species/transitions, and sometimes even for a single spectral line, are manifestations of and are best modeled with Dicke's superradiance, which naturally accounts for a modulation in the duration of flares through corresponding changes in the inversion pump. In particular, it can explain the peculiar behaviour observed for some features, such as the previously published result for the OH 1667 MHz transition at vlsr=+1.7v_\mathrm{lsr}=+1.7 km s1^{-1} as well as the methanol 6.7 GHz line at vlsr=1.8v_\mathrm{lsr}=-1.8 km s1^{-1}, through a partial quenching of the population inversion during flaring events.Comment: 13 pages, 13 figures, accepted MNRA

    Super-radiance from a relativistic source

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    Cooperative super-radiant emission from a highly relativistic multi-particle source is modeled and solved for the simple case of two particles. An existing model of a single relativistic two-level particle is used to construct a Hamiltonian describing relativistic velocity dependent multi-particle super-radiance. The standard diagrammatic framework is applied to the calculation of time evolution and density operators from this Hamiltonian, demonstrating during the process a departure from standard results and calculation methods. In particular, the so-called vertical photon result of the literature is shown to be modified by the relativistic Lorentz factor of the sample; additionally, a set of coupled differential equations describing certain propagators in the velocity-dependent small sample framework are introduced and solved numerically via a hybrid fourth order Runge–Kutta and convolution approach. The model is applied to the simple case of two highly relativistic particles travelling with slightly differing velocities simulated at varying relativistic mean sample β factors, and velocity coherence requirements for a sample to demonstrate enhanced super-radiant emission in the observer frame are evaluated. These coherence requirements are found to become increasingly restrictive at higher β factors, even in the context of standard results of relativistic velocity differential transformations

    Genomic mutation landscape of skin cancers from DNA repair-deficient xeroderma pigmentosum patients

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    Abstract Xeroderma pigmentosum (XP) is a genetic disorder caused by mutations in genes of the Nucleotide Excision Repair (NER) pathway (groups A-G) or in Translesion Synthesis DNA polymerase η (V). XP is associated with an increased skin cancer risk, reaching, for some groups, several thousand-fold compared to the general population. Here, we analyze 38 skin cancer genomes from five XP groups. We find that the activity of NER determines heterogeneity of the mutation rates across skin cancer genomes and that transcription-coupled NER extends beyond the gene boundaries reducing the intergenic mutation rate. Mutational profile in XP-V tumors and experiments with POLH knockout cell line reveal the role of polymerase η in the error-free bypass of (i) rare TpG and TpA DNA lesions, (ii) 3’ nucleotides in pyrimidine dimers, and (iii) TpT photodimers. Our study unravels the genetic basis of skin cancer risk in XP and provides insights into the mechanisms reducing UV-induced mutagenesis in the general population

    Antibacterial Activity and Cell Responses of Vancomycin-Loaded Alginate Coating on ZSM-5 Scaffold for Bone Tissue Engineering Applications

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    Despite the significant advancement in bone tissue engineering, it is still challenging to find a desired scaffold with suitable mechanical and biological properties, efficient bone formation in the defect area, and antibacterial resistivity. In this study, the zeolite (ZSM-5) scaffold was developed using the space holder method, and a novel vancomycin-loaded alginate coating was developed on it to promote their characteristics. Our results demonstrated the importance of alginate coating on the microstructure, mechanical, and cellular properties of the ZSM-5 scaffold. For instance, a three-fold increase in the compressive strength of coated scaffolds was observed compared to the uncoated ZSM-5. After the incorporation of vancomycin into the alginate coating, the scaffold revealed significant antibacterial activity against Staphylococcus aureus (S. aureus). The inhibition zone increased to 35 mm. Resets also demonstrated 74 ± 2.5% porosity, 4.3 ± 0.07 MPa strength in compressive conditions, acceptable cellular properties (72.3 ± 0.2 (%control) cell viability) after 7 days, good cell attachment, and calcium deposition. Overall, the results revealed that this scaffold could be a great candidate for bone tissue engineering

    Major Thalassemia, Screening or Treatment: An Economic Evaluation Study in Iran

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    Background: Beta-thalassemia minor and thalassemia major are an autosomal recessive disease with hypochromic, microcytic anemia, and morbidities, Today, therapeutic advances have significantly improved the life expectancy of thalassemia major patients, but at the cost of financial toxicity. The present study aimed to investigate the possibility of increasing the funding for thalassemia screening programs and comparing the cost-effectiveness of screening for thalassemia in the treatment of the patients. Methods: In this study, screening for thalassemia minor was compared with the treatment of thalassemia major patients. A decision tree model was used for analysis. A hospital database, supplemented with a review of published literature, was used to derive input parameters for the model. A lifetime study horizon was used and future costs and consequences were discounted at 3. The approach of purchases of services was used to evaluate the screening test costs for patients with thalassemia major. Also, a bottom-up method was applied to estimate other screening and treatment costs. All the costs were calculated over one year. The number of gained quality-adjusted life years (QALYs) was calculated using the EQ-5D questionnaire in the evaluated patients. Results: In this study, 26.97 births of patients with thalassemia major were prevented by screening techniques. On the other hand, total screening costs for patients with thalassemia major were estimated equal to US 879 879, while the costs of preventing the birth of each thalassaemia major patient was US 32 624 by screening techniques. In comparison, the cost of managing a patient with thalassemia major is about US 136 532 per year. The life time QALYs for this is 11.8 QALYs. Results are presented using a societal perspective. Incremental cost per QALY gained with screening as compared with managing thalassaemia major was US 11 571. Conclusion: Screening is a long-term value for money intervention that is highly cost effective and its long-term clinical and economic benefits outweigh those of managing thalassaemia major patients. © 2022 The Author(s); Published by Kerman University of Medical Sciences

    Antibacterial activity of recently approved antibiotics against methicillin-resistant Staphylococcus aureus (MRSA) strains: A systematic review and meta-analysis

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    Background: Methicillin-resistant Staphylococcus aureus (MRSA) infections are considered an important public health problem, and treatment options are limited. Accordingly, in this meta-analysis, we analyzed published studies to survey in vitro activity of recently approved antibiotics against MRSA isolates. Methods: We searched electronic databases; PubMed, Scopus, and Web of Science to identify relevant studies (until November 30, 2020) that have focused on the in vitro activity of telavancin, dalbavancin, oritavancin, and tedizolid against MRSA isolates. Statistical analyses were conducted using STATA software (version 14.0). Results: Thirty-eight studies were included in this meta-analysis. Overall in vitro activity of tedizolid on 12,204 MRSA isolates was 0.250 and 0.5 µg/mL for MIC50 and MIC90, (minimum inhibitory concentration at which 50 and 90 of isolates were inhibited, respectively), respectively. The overall antibacterial activity of dalbavancin on 28539 MRSA isolates was 0.060 and 0.120 µg/mL for MIC50 and MIC90, respectively. The overall antibacterial activity of oritavancin on 420 MRSA isolates was 0.045 and 0.120 µg/mL for MIC50 and MIC90, respectively. The overall antibacterial activity of telavancin on 7353 MRSA isolates was 0.032 and 0.060 µg/mL for MIC50 and MIC90, respectively. The pooled prevalence of tedizolid, telavancin, and dalbavancin susceptibility was 100 (95 CI: 100�100). Conclusion: Telavancin, dalbavancin, oritavancin, and tedizolid had potent in vitro activity against MRSA isolates. The low MICs and high susceptibility rates of these antibiotics recommend a hopeful direction to introduce useful antibiotics in treating MRSA infections in the future. © 2022, The Author(s)

    Rare pathogenic variants in WNK3 cause X-linked intellectual disability

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    This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordData availability: All data are available upon request. The sequence variants in WNK3 (NM_004656.3) reported in the paper have been deposited in ClinVar database. Their respective accession numbers (SCV002107163 to SCV002107168) are indicated in Tables 1 and S1.Purpose WNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown. Method We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID). Results We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.Pro204Arg, p.Leu300Ser, p.Glu607Val) in WNK3 in 14 male individuals from 6 unrelated families. Affected individuals had identifier with variable presence of epilepsy and structural brain defects. WNK3 variants cosegregated with the disease in 3 different families with multiple affected individuals. This included 1 large family previously diagnosed with X-linked Prieto syndrome. WNK3 pathogenic missense variants localize to the catalytic domain and impede the inhibitory phosphorylation of the neuronal-specific chloride cotransporter KCC2 at threonine 1007, a site critically regulated during the development of synaptic inhibition. Conclusion Pathogenic WNK3 variants cause a rare form of human X-linked identifier with variable epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism.Estonian Research CouncilNational Natural Science Foundation of ChinaRoyal SocietySouth Carolina Department of Disabilities and Special Needs (SCDDSN)National Institute of Neurological Disorders and Stroke (NINDS