Defect In Synthesis Research Articles

Neonatal screening for primary and central congenital hypothyroidism: is it time to go Dutch?

Thyroid hormone (TH) is indispensable for brain development in utero and during the first two to three years of life, and the negative effects of TH deficiency on brain development are irreversible. Detection of TH deficiency early in life by neonatal screening allows early treatment, thereby preventing brain damage. Inborn shortage of TH, also named congenital hypothyroidism (CH), can be the result of defective thyroid gland development or TH synthesis (primary or thyroidal CH (CH-T)). Primary CH is characterized by low blood TH and elevated thyroid-stimulating hormone (TSH) concentrations. Less frequently, CH is due to insufficient stimulation of the thyroid gland because of disturbed hypothalamic or pituitary function (central CH). Central CH is characterised by low TH concentrations while TSH is normal, low or slightly elevated. Most newborn screening (NBS) programs for CH are primarily TSH-based thereby do not detect central CH. Only a few NBS programs worldwide aim to detect both forms of CH by different strategies. In the Netherlands, we have a unique T4-TSH-thyroxine-binding globulin (TBG) NBS algorithm for CH which enables detection of primary and central CH. Although the necessity of central CH detection by NBS is still under debate, it has been shown that most central CH patients have moderate-to-severe hypothyroidism instead of mild, and that early detection of central CH by NBS problably improves its clinical outcome and clinical care for central CH patients with multiple pituitary hormone deficiency. We are therefore convinced that detection of central CH by NBS is of utmost importance.

Synthesis of an efficient Mn4+-doped fluoride red phosphor with excellent fluorescence stability by green synthesis method for warm WLED

Currently, Mn4+-doped fluoride phosphors have become a research hotspot, which can help compensate for the missing red component in cold white light-emitting diodes (WLEDs). However, significant synthesis defects limit the development of such fluorescent powders due to the use of highly toxic solvent HF. To improve this situation, a simple green synthesis method should be explored to synthesize Mn4+-activated fluoride phosphor. In this study, a series of red-emitting Mn4+-activated BaTiF6 phosphors are successfully synthesized via the non-toxic reaction system (HNO3/HCl + NH4F). Its crystal structure, morphology, optical characteristics and thermal stability are systematically evaluated. Under blue light excitation, BaTiF6:Mn4+ exhibits a bright narrow-band red emission with exceptional correlated color temperature (3909 K) and color purity (90%). Additionally, the critical concentration of Mn4+ is determined to be 0.03 and the concentration quenching mechanism is also systematically discussed. By calculating the crystal field strength (Dq), Racah parameters (B and C) and nephelauxetic effect ratio parameter β1, it is confirmed that BaTiF6 host can provide a strong crystal field environment for Mn4+. Moreover, these results are compared with other matrix materials. Intriguingly, the optimal sample exists satisfactory thermal stability, whose fluorescence intensity at 423 K retains 49% of that at 298 K and the activation energy reaches up to 0.925 eV. In addition, the chromaticity shift and chromaticity coordinate variation are calculated as 17 × 10−3 and (−0.0063, 0.0063), respectively. Meanwhile, the feasibility of the as-fabricated WLEDs for interior illumination is examined. A high-performance warm WLED with low correlated color temperature (CCT = 4470 K) and high color rendering index (Ra = 88.3) is achieved by using BaTiF6:Mn4+ as a red-emitting material, moreover, WLED exhibits strong output stability under high driving current. The findings of this work provide a comprehensive understanding for rational design of high-performance Mn4+-activated fluoride red phosphors through a simple green synthesis method.

Hypocalcemia in thalassemia major patients requires an extra-careful approach

Thalassemia is a hematological disorder caused by a gene mutation that leads to defective synthesis of hemoglobin complex. One of the complications of thalassemia is hypocalcemia which is presented with paresthesia, muscle spasm, low-serum calcium, and intracranial calcification. Hypocalcemia can affect thalassemic patients via various mechanisms. Blood transfusion-related and transfusion-independent iron overload, drug side effects, vitamin D3 deficiency, and genetic disorders and polymorphisms are among the etiologies of hypocalcemia in major thalassemia. A careful approach to the differential etiology of this phenomenon is crucial for a resultful treatment.

Asfotase alfa improved skeletal mineralization and fracture healing in a child with MCAHS.

Tissue non-specific alkaline phosphatase (TNSALP) is an enzyme that is tethered to the cell membrane by glycosylphosphatidylinositol (GPI) and converts inorganic pyrophosphate to inorganic phosphate. Inorganic phosphate combines with calcium to form hydroxyapatite, the main mineral in the skeleton. When TNSALP is defective, conversion of inorganic pyrophosphate to inorganic phosphate is impaired and the skeleton is at risk of under-mineralization. Phosphatidylinositol glycan anchor biosynthesis class N (PIGN) is one of more than 20 genes in the GPI-biosynthesis family. Pathogenic variants in PIGN have been identified in multiple congenital anomalies-hypotonia-seizures syndrome (OMIM 614080), although a metabolic bone disease or skeletal fragility phenotype has not been reported. We describe a female child with multiple congenital anomalies-hypotonia-seizures syndrome due to a compound heterozygous pathogenic variant in PIGN who sustained a low-trauma distal femur fracture at age 7.4years. We hypothesized that the GPI synthesis defect may result in metabolic bone disease from inadequate anchoring of TNSALP in bone and initiated asfotase alfa, a human bone-targeted recombinant TNSALP-Fc-deca-aspartate peptide, as it could bypass the PIGN genetic defect that possibly caused her skeletal fragility. Asfotase alfa was begun at 8.5years. Baseline X-rays revealed mild rachitic findings of wrists and knees, which resolved by 5months of treatment. Bone mineral density (BMD) assessed by dual-energy X-ray absorptiometry (DXA) showed mild improvement in spine, hip and total body less head after 16months of treatment, while radius declined. She sustained additional low trauma fractures at right tibia and left humeral neck at 11 and 15months into treatment, which healed quickly. Calcium, phosphorus, and parathyroid hormone levels have remained within the normal range over the 18months of treatment. For adverse effect, she experienced a rash and discomfort in the first week of treatment which resolved with ibuprofen and diphenhydramine. She also developed subcutaneous fat atrophy. Overall, in this child with a compound pathogenic variant in PIGN, off-label use of asfotase alfa has been generally well tolerated with minimal side effects and resolution of rickets, but she continues to remain skeletally fragile.

Phenotypic signs of connective tissue dysplasia in adolescents

Introduction. Connective tissue dysplasia (СTD) is a group of polymorphic pathological conditions caused by hereditary or congenital defects in collagen synthesis and accompanied by a violation of the functions of the musculoskeletal system and internal organs, which is considered as a factor in the development of pathology of the maxillofacial region in children: dystrophic forms of periodontal diseases; anomalies of shape, size, teething; pathology of the temporomandibularthe mandibular joint. There are diffi culties in determining the pathogenetic relationship between CTD and individual nosological forms of dental diseases, which is important for determining the prognosis of their course and the choice of methods of rehabilitation of children. It is important to improve the methodology of preventive examinations in relation to the early detection of phenotypic signs of CTD, including in the maxillofacial region. Substantiation of the connection of CTD with dental diseases will make it possible to develop examination and medical examination schemes, increase the effectiveness of comprehensive prevention of dental diseases and rehabilitation of adolescents with combined pathology.The aim is to study the incidence of CTD in adolescents and its relationship with dental diseases in order to develop a scheme of examinations and medical examinations, increase the effectiveness of comprehensive prevention of dental diseases and rehabilitation of adolescents with combined pathology.Materials and methods. A survey of 140 male adolescents aged 15–18 years, students of schools in Smolensk was conducted. When examining the somatic status, generally accepted markers of CTD were taken into account: bone (asthenic type of constitution, scoliotic deformity of the spine, hallux valgus, chest deformities), skin (increased skin extensibility of more than 3 cm), articular (hypermobility of joints) and visceral (changes from the cardiovascular system — prolapses of the heart valves, abnormally located chords; changes from the respiratory organs — polycystic lung disease, trachiobronchial dyskinesia; changes from the urinary system — nephroptosis, kidney doubling; changes from the gastrointestinal tract — visceroptosis, gallbladder anomaly; changes from the blood system — thrombocytopathy, hemoglobinopathy). When examining the dental status, the following generally accepted markers of CTD were taken into account: malocclusion (prognathia, deep bite, their combination), narrowing of the dentition, anomalies of the position of individual teeth, anomalies of soft tissue attachment, gum recession, chronic gingivitis. The diagnosis of CTD and the health group was established by a pediatrician on the basis of clinical recommendations and the order of the Ministry of Health of the Russian Federation № 621 dated 30.12.2003 «On a comprehensive assessment of the health status of children». Factor analysis was used to form a set of signs combining signs of CTD and dental diseases.Results. Of the phenotypic signs of СTD, bone and joint changes were diagnosed in 79,3 % (95 % CI 72,6– 86) of adolescents. In second place in frequency 35 % (95 % CI 27,1–42,9) were signs of СTD of the cardiovascular system and the organ of vision (myopia). 40 % (95 % CI 31,9–48,1) of the examined adolescents were diagnosed with chronic gingivitis, gum recession. Deep bite and prognathia were more common than other malocclusions: in 40,7 % (95 % CI 32,6–48,9) and 17,1 % (95 % CI 10,9–23,4), respectively. The use of factor analysis allowed us to identify four most informative factors (the fi rst of them is the most signifi cant) to characterize the relationship between the signs of CTD and its dental manifestations.Conclusion. The incidence of CTD in males in the age group of 15–18 years is 43 %. The most informative prognostic factor was the relationship of tracheobronchial dyskinesia with prognathia, deep bite, narrowing of the jaws, generalized gingivitis. The interrelation of signs of СTD of the cardiovascular system and bone-joint changes with gum recession, chronic gingivitis, prognathia and deep bite was also revealed.

Diagnostic yield and novel candidate genes by next generation sequencing in 166 children with intrahepatic cholestasis.

Cholestatic liver disease is a leading referral to pediatric liver transplant centers. Inherited disorders are the second most frequent cause of cholestasis in the first month of life. We retrospectively characterized the genotype and phenotype of 166 participants with intrahepatic cholestasis, and re-analyzed phenotype and whole-exome sequencing (WES) data from patients with previously undetermined genetic etiology for newly published genes and novel candidates. Functional validations of selected variants were conducted in cultured cells. Overall, we identified disease-causing variants in 31% (52/166) of our study participants. Of the 52 individuals, 18 (35%) had metabolic liver diseases, 9 (17%) had syndromic cholestasis, 9 (17%) had progressive familial intrahepatic cholestasis, 3 (6%) had bile acid synthesis defects, 3(6%) had infantile liver failure and 10 (19%) had a phenocopy of intrahepatic cholestasis. By reverse phenotyping, we identified a de novo variant c.1883G > A in FAM111B of a case with high glutamyl transpeptidase (GGT) cholestasis. By re-analyzing WES data, two patients were newly solved, who had compound heterozygous variants in recently published genes KIF12 and USP53, respectively. Our additional search for novel candidates in unsolved WES families revealed four potential novel candidate genes (NCOA6, CCDC88B, USP24 and ATP11C), among which the patients with variants in NCOA6 and ATP11C recapitulate the cholestasis phenotype in mice models. In a single-center pediatric cohort, we identified monogenic variants in 22 known human intrahepatic cholestasis or phenocopy genes, explaining up to 31% of the intrahepatic cholestasis patients. Our findings suggest that re-evaluating existing WES data from well-phenotyped patients on a regular basis can increase the diagnostic yield for cholestatic liver disease in children.

Diagnosis of α-thalassaemia by colorimetric gap loop mediated isothermal amplification

α-Thalassaemia is an inherited haemoglobin disorder that results from the defective synthesis of α-globin protein. Couples whom both carry the α-thalassaemia 1 gene are at risk of having a foetus with the most severe thalassaemia, Hb Bart’s hydrops fetalis, with a risk of maternal mortality. However, haematological parameters alone cannot distinguish between a α-thalassaemia 1 carrier and a homozygous α-thalassaemia 2, in which one α-globin gene has been deleted on each chromosome. A rapid and accurate molecular detection assay is essential for prevention of the disease in populations where α-thalassaemia 1 is common. Multiplex Gap-PCR analysis is widely used for diagnosis of α-thalassaemia. However, the technique requires a thermocycler and post-amplification processing, which limits its application in primary care or in rural areas in developing countries. Loop mediated isothermal amplification (LAMP) amplifies target DNA at a constant temperature and does not require a thermocycler. This study developed a colorimetric Gap-LAMP using malachite green to allow naked eye visualization of two deletional α-thalassaemia 1 commonly found in Asian populations, the Southeast Asian type (--SEA) and the Thai type (--THAI) deletions. The Gap-LAMP was performed on DNA samples from 410 individuals carrying various α-thalassaemia gene defects with 100% concordance with conventional Gap-PCR analysis. This method eliminates post-amplification processing or the use of expensive sophisticated equipment and allows screening large populations for the prevention and control of α-thalassaemia.

Molecular diagnosis of hereditary hemolytic anemias: Recent updates

AbstractHereditary hemolytic anemia (HHA) is a heterogeneous group of disorders due to genetically caused defects in red blood cell membrane structure, enzymes, heme and globin synthesis, erythroid proliferation, and differentiation. Traditionally, the diagnostic process is complex and includes a plethora of tests from routine to highly specialized ones. The inclusion of molecular testing has significantly improved the diagnostic yield. The value of molecular testing is broader than just rendering the correct diagnosis, as it may also guide therapeutic decisions. As more molecular modalities become available for clinical use, it is imperative to understand their benefits and disadvantages pertaining to the HHA diagnostics. Re‐evaluation of the traditional diagnostic workflow may also bring forth additional benefits. This review focuses on the current state of molecular testing for HHA.

AMPK negatively regulates RANKL-induced osteoclast differentiation by controlling oxidative stress

AMP-activated protein kinase (AMPK) is a crucial energy sensor of cellular metabolism under various metabolic stresses, such as oxidative stress and inflammation. AMPK deficiency increases osteoclast numbers and reduces bone mass; however, the precise mechanisms remain unclear. This study aimed to clarify the mechanistic connection between AMPK and osteoclast differentiation, and the potential role of AMPK in the anti-resorptive effects of several phytochemicals. We found that receptor activator of nuclear factor-kappa B (NF-κB) ligand (RANKL)-induced osteoclast differentiation, osteoclastic gene expression, and activation of mitogen-activated protein kinase (MAPK) and NF-κB were promoted in cells transfected with AMPK siRNA. AMPK knockdown led to defective synthesis of heme oxygenase-1, an antioxidant enzyme, and the upstream mediator, nuclear factor erythroid-2-related factor 2. Furthermore, treatment with N-acetyl-l-cysteine, an antioxidant, abolished osteoclast differentiation and MAPK/NF-κB activation induced by AMPK knockdown. AMPK activators, hesperetin, gallic acid, resveratrol, and curcumin, suppressed osteoclast differentiation via the activation of AMPK. These results suggest that AMPK inhibits RANKL-induced osteoclast differentiation by enhancing antioxidant defense system and regulating oxidative stress. AMPK activation by dietary-derived phytochemicals may be effective for the treatment of bone diseases.

Postmortem Identification of Vascular Ehlers-Danlos Syndrome in a Lung Transplant Recipient.

Postmortem Identification of Vascular Ehlers-Danlos Syndrome in a Lung Transplant Recipient.

Designing a one-bit coplanar QCA ALU using a novel robust area-efficient three-input majority gate design

Quantum-dot cellular automata (QCA) which is a suitable alternative to conventional CMOS technology is susceptible to some defects in chemical synthesis and deposition phases of circuit fabrication. Besides, the majority gate is one of the most important primary gates for designing digital circuits in this emerging technology. Designing a fault-tolerant majority gate is one of the hot topics in QCA technology. Most previous works tried to improve the majority gate reliability by increasing the number of QCA cells which resulted in occupying more area. In this paper we propose a novel area-efficient three-input majority gate which can tolerate the single-cell omission and extra-cell deposition defects by 86% and 75%, respectively. The proposed majority gate consists of 11 simple QCA cells with $$0.006\,$$ µ $$\hbox {m}^{2}$$ and 1.62 e-002 MeV area and energy consumption, respectively. A complete fault tolerance analysis for our proposed majority gate against cell omission, extra-cell deposition, and cell displacement and misalignment defects is also provided. We design a fault-tolerant coplanar fulladder/fullsubtractor and a two-to-one multiplexer using the proposed majority gate and compare it with the same previous works. Simulation results from QCADesigner 2.0.3 and QCADesigner-E show that in all cases our proposed robust circuits can reduce the area consumption. Finally, we implement a fault-tolerant coplanar one-bit ALU using the proposed circuits that can perform four logical and mathematical operations.

Nucleolar protein treacle ribosome biogenesis factor 1 maintains gastric cancer cell proliferation by regulating R-loop associated DNA replication stress.

Gastric cancer (GC) is a common malignant neoplasm in the gastrointestinal tract, accounting for high mortality globally. Treacle ribosome biogenesis factor 1 (TCOF1) is a nucleolar protein, which has been reported to be implicated in the pathogenesis of Treacher Collins syndrome and the development of several types of human cancer. However, the role of TCOF1 in GC is not known. Immunohistochemistry was carried out to determine TCOF1 expression in GC tissues. Immunofluorescence, co-IP, and DNA fiber assays were conducted to investigate the function of TCOF1 in GC-derived BGC-823 and SGC-7901 cell lines. TCOF1 expression was aberrantly increased in GC tissues compared with adjacent normal tissues. In addition, we found that TCOF1 left the nucleolus and localized to R-loops (DNA/RNA hybrids) during S phase in GC cells. Furthermore, TCOF1 interacted with DDX5 and suppressed R-loop levels. Knockdown of TCOF1 led to increased nucleoplasmic R-loops specifically during S phase, which restrained DNA replication and cell proliferation. Overexpression of R-loop eraser RNaseH1 rescued the DNA synthesis defects and decreased DNA damage caused by TCOF1 depletion. These findings demonstrate a novel role of TCOF1 in maintaining GC cell proliferation by alleviating R-loop associated DNA replication stress.

Morphological and Ultrastructural Collagen Defects: Impact and Implications in Dentinogenesis Imperfecta.

Collagen is the building block for the extracellular matrix in bone, teeth and other fibrous tissues. Osteogenesis imperfecta (OI), or brittle bone disease, is a heritable disorder that results from defective collagen synthesis or metabolism, resulting in bone fragility. The dental manifestation of OI is dentinogenesis imperfecta (DI), a genetic disorder that affects dentin structure and clinical appearance, with a characteristic feature of greyish-brown discolouration. The aim of this study was to conduct a systematic review to identify and/or define any ultrastructural changes in dentinal collagen in DI. Established databases were searched: Cochrane Library, OVID Embase, OVID Medline and PubMed/Medline. Search strategies included: Collagen Ultrastructure, DI and OI. Inclusion criteria were studies written in English, published after 1990, that examined human dental collagen of teeth affected by DI. A Cochrane data extraction form was modified and used for data collection. The final dataset included seventeen studies published from 1993 to 2021. The most prevalent findings on collagen in DI teeth were increased coarse collagen fibres and decreased fibre quantity. Additional findings included changes to fibre orientation (i.e., random to parallel) and differences to the fibre organisation (i.e., regular to irregular). Ultrastructural defects and anomalies included uncoiled collagen fibres and increased D-banding periodicity. Studies in collagen structure in DI reported changes to the surface topography, quantity, organisation and orientation of the fibres. Moreover, ultrastructural defects such as the packing/coiling and D-banding of the fibrils, as well as differences in the presence of other collagens are also noted. Taken together, this study provides an understanding of the changes in collagen and its impact on clinical translation, paving the way for innovative treatments in dental treatment.

Examining the structural, magnetic and dielectric properties of exchange spring nanocomposite magnets comprising Ba0.5Sr0.5Fe12O19 and Zn0.5Co0.5Fe2O4

Exchange-coupled hard/soft ferrite nanoparticles are prospective to squeeze out a part of expensive magnets based on rare earth elements. However, the known exchange-coupled composite ferrite nanoparticles often suffer from the lack of a powerful hard core, high defective synthesis of magnetic phases and a poor interface between them. This work is featured by the use of highly coercive Ba0.5Sr0.5Fe12O19 magnets prepared by sol–gel combustion. Here in we demonstrate the synthesis of magnetic nanocomposites comprising Ba0.5Sr0.5Fe12O19 and Zn0.5Co0.5Fe2O4 hard/ soft ferrites by gradually increasing the share of spinel ferrites in the hard ferrites. Four samples of nanocomposites were prepared with the increasing order of hard ferrites using simple solgel auto-combustion method. Thermal breakdown examinations have been performed using TGA/DSC on the as-synthesised material from 0 °C to 1250 °C, and the temperature stability of the sample was detailed. The XRD analyses proved the presence of hexagonal and cubic crystal structure in each nanocomposite. Transmission Electron Microscopy was used to examine the morphology and topology of the nanocomposites. Hard and soft ferrites were detected in rod and non-spherical microstructures, correspondingly. The bending and the stretching vibrations in the sample was studied by using Fourier Transform Spectroscopy. The magnetic response of the synthesised samples was studied by using the Vibrating Sample Magnetometry. The prepared Nano powders displayed a highest coercivity Hc of 6307 Oe for pure hard ferrite while the pure spinel ferrite displayed a coercivity of 80 Oe. All the synthesized samples showed smooth M−H curves and single peak on dM/dH against H curves this indicates that complete exchange-coupled effects between the phases are achieved. The saturation magnetization increased with the increase in the content of spinel ferrite whereas the coercivity decreased with the increase in the spinel content.

Novel likely pathogenic variant in NR5A1 gene in a Tanzanian child with 46,XY differences of sex development, inherited from the mosaic father.

Pathogenic variants in the nuclear receptor subfamily 5 group A member 1 gene (NR5A1), which encodes steroidogenic factor 1 (SF1), result in 46,XY and 46,XX differences of sex development (DSD). In 46,XY individuals with a pathogenic variant in the NR5A1 gene a variable phenotype ranging from mild to severe is seen, including adrenal failure, testis dysgenesis, androgen synthesis defects, hypospadias and anorchia with microphallus and infertility. We report the clinical, endocrinological and genetic characteristics of a patient with 46,XY DSD with a novel likely pathogenic missense variant in the NR5A1 gene. A retrospective evaluation of the medical history, physical examination, limited endocrinological laboratory analysis and genetic analysis with DSD gene panel testing was performed. A 1.5-month-old individual was referred with ambiguous genitalia. The karyotype was 46,XY. The endocrinological analyses were within normal male reference including a normal response of cortisol within an adrenocorticotropic hormone test. A novel heterozygous missense variant c.206G>C p.(Arg69Pro) in the NR5A1 gene was detected. This variant was present in mosaic form (~20%) in his unaffected father. Because another missense variant at the same position and other missense variants involving the same highly conserved codon have been reported, we consider this NR5A1 variant in this 46,XY DSD patient as likely pathogenic in accordance with the ACMG/AMP 2015 guidelines causing ambiguous genitalia but no adrenal insufficiency. This variant was inherited from the apparently unaffected mosaic father, which might have implications for the recurrence risk in this family. The importance of performing trio (patient and parents) sequencing is crucial in pointing out the origin of inheritance. In a 46,XY differences of sex development patient, a normal adrenal function does not rule out an NR5A1 mutation. With the support of a dedicated overseas institute partnership, we could solve this complex clinical case by molecular diagnosis in a resource-limited setting.

Epilepsy Phenotypes of Vitamin B6-Dependent Diseases: An Updated Systematic Review

Vitamin B6-dependent epilepsies include treatable diseases responding to pyridoxine or pyridoxal-5Iphosphate (ALDH7A1 deficiency, PNPO deficiency, PLP binding protein deficiency, hyperprolinemia type II and hypophosphatasia and glycosylphosphatidylinositol anchor synthesis defects). We conducted a systematic review of published pediatric cases with a confirmed molecular genetic diagnosis of vitamin B6-dependent epilepsy according to PRISMA guidelines. Data on demographic features, seizure semiology, EEG patterns, neuroimaging, treatment, and developmental outcomes were collected. 497 published patients fulfilled the inclusion criteria. Seizure onset manifested at 59.8 ± 291.6 days (67.8% of cases in the first month of life). Clonic, tonic-clonic, and myoclonic seizures accounted for two-thirds of the cases, while epileptic spasms were observed in 7.6%. Burst-suppression/suppression-burst represented the most frequently reported specific EEG pattern (14.4%), mainly in PLPB, ALDH7A1, and PNPO deficiency. Pyridoxine was administered to 312 patients (18.5% intravenously, 76.9% orally, 4.6% not specified), and 180 also received antiseizure medications. Pyridoxine dosage ranged between 1 and 55 mg/kg/die. Complete seizure freedom was achieved in 160 patients, while a significant seizure reduction occurred in 38. PLP, lysine-restricted diet, and arginine supplementation were used in a small proportion of patients with variable efficacy. Global developmental delay was established in 30.5% of a few patients in whom neurocognitive tests were performed. Despite the wide variability, the most frequent hallmarks of the epilepsy phenotype in patients with vitamin B6-dependent seizures include generalized or focal motor seizure semiology and a burst suppression/suppression burst pattern in EEG.

MoMih1 is indispensable for asexual development, cell wall integrity, and pathogenicity of Magnaporthe oryzae.

Asexual spore serves as essential inoculum of rice blast during the disease cycle, and differentiation of young conidium from conidiophore is intimately regulated by cell cycle. Mih1 encodes a dual-specificity phosphatase that involved in the G2/M transition of the mitotic cell cycle by regulating the Cdk1 activity in eukaryotes. Till now, the roles of Mih1 homologue, however, remain unclear in Magnaporthe oryzae. We here functionally characterized the Mih1 homologue MoMih1 in M. oryzae. MoMih1 is localized to both the cytoplasm and nucleus and can physically interact with the CDK protein MoCdc28 in vivo. Loss of MoMih1 led to delayed nucleus division and a high level of Tyr15 phosphorylation of MoCdc28. The MoMih1 mutants showed retarded mycelial growth with a defective polar growth, less fungal biomass, and shorter distance between diaphragms, compared with the KU80. Asexual reproduction altered in MoMih1 mutants, with both abnormal conidial morphogenesis and decreased conidiation. The MoMih1 mutants severely attenuated the virulence to host plants due to the impaired ability of penetration and biotrophic growth. The incapability of scavenging of host-derived reactive oxygen species, which was possibly ascribed to the severely decreased extracellular enzymes activities, were partially associated with deficiency of pathogenicity. Besides, the MoMih1 mutants displayed also improper localization of retromer protein MoVps26 and polarisome component MoSpa2, and defects of cell wall integrity (CWI), melanin pigmentation, chitin synthesis, and hydrophobicity. In conclusion, our results demonstrate that MoMih1 plays pleiotropic roles during fungal development and plant infection of M. oryzae.

Brazilian registry of patients with porphyria: REBRAPPO study

BackgroundPorphyrias are a rare group of disease due to inherited defects of heme synthesis with important systemic manifestations and great burden of disease for patients and families due to the exceptional course of disease with disabling chronic symptoms interposed by life-threatening acute attacks. Unfortunately, the porphyrias are usually underrecognized reflecting a lack of medical and disease awareness as well as few studies about natural history in large cohorts of patients. The main aim of this article is present consistent data about natural history and burden of disease in a large Brazilian cohort.MethodsWe conducted a national cross-sectional registry with retrospective clinical data of Brazilian patients with porphyria collected with Brazilian patients Association with Porphyria in collaboration with a tertiary care center for rare diseases.ResultsA cohort of 172 patients was analyzed in which 148 (86%) patients had the diagnosis of acute hepatic porphyria [AHP] that needed a mean of 62.04 medical visits and 9.6 years to achieve a definitive diagnosis. About AHP cohort, the most common first clinical manifestation were abdominal pain in 77 (52%) patients and acute muscle weakness in 23 (15.5%) with 73 (49.3%) patients presenting only one attack during disease course and 37 (25%) exhibiting 4 or more attacks in the last year. Of note, 105 patients with AHP reported chronic manifestations and the scores for quality of life are lower when compared with general healthy population.ConclusionsBrazilian patients with AHP had a higher prevalence of chronic disabling manifestations and a poor quality of life like other cohorts and a higher proportion of patients with recurrent attacks than previously reported.

Influence of Eu3+ dopant on the third order nonlinear optical properties of PbO/PMMA nanocomposites

ABSTRACT PbO/PMMA, 3 and 6 mol% ion-doped PbO/PMMA nanocomposites were synthesised using an easy chemical precipitation method. For all of the nanocomposites, the XRD pattern confirms the orthorhombic structure of PbO. The morphology of PbO nanoparticles in PMMA is revealed by the SEM graph. The formation of nanocomposites containing Eu3+ doped PbO nanoparticles in PMMA is confirmed by FTIR. When Eu3+ doped PbO nanoparticles in PMMA are compared to bulk PbO, UV–Vis optical absorption findings demonstrate a blue shift on the absorption band. The optical band gap energy decreases with increasing Eu3+ dopant concentration and is related to red-shifted phenomena. The PL spectra reveal an emission peak associated with blue emission caused by a synthesis defect. For 6 mol% Eu3+ ion doped PbO/PMMA nanocomposites, third-order nonlinear optical parameters such as nonlinear optical susceptibility (χ(3)), nonlinear optical refractive index (n2), and nonlinear optical absorption coefficient (β) are determined by Z-scan technique, and the values are found to be 4.468 × 10−6 esu, 1.257 × 10−7cm2/W, and 9.837 × 10−3 cm/W, respectively. The strong nonlinearity in the current Eu3+ ion-doped PbO/PMMA nanocomposites empowers its promising applications in third-order nonlinear optical devices.

Synthesis and crystal and defect structures of polycrystalline Cu2SrSnS4 and Cu1.9SrSnS4 powders

The polycrystalline samples of Cu2 – δSrSnS4 with a trigonal structure were prepared by solid-phase ampoule synthesis with a long annealing time (1944 h), and their crystal lattice parameters were refined and Raman spectra were obtained. For the first time, the effect of defect structure on the lifetimes of photogenerated current carriers in the polycrystalline powders was examined by combining time-resolved microwave photoconductivity and cathodoluminescence methods. A significant increase in the lifetimes during the conversion of Cu2SrSnS4 into Cu1.9SrSnS4 was found, which was probably due to changes in the defect structure.