A distinct mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) phenotype associates with YARS2 mutations

Nuclear-encoded disorders of mitochondrial translation are clinically and genetically heterogeneous. Genetic causes include defects of mitochondrial aminoacyl-tRNA synthetases, and factors required for initiation, elongation and termination of protein synthesis as well as ribosome recycling. We report on a new case of myopathy, lactic acidosis and sideroblastic anemia (MLASA) syndrome caused by defective mitochondrial tyrosyl aminoacylation. The patient presented at 1 year with anemia initially attributed to iron deficiency. Bone marrow aspirate at 5 years revealed ringed sideroblasts but transfusion dependency did not occur until 11 years. Other clinical features included lactic acidosis, poor weight gain, hypertrophic cardiomyopathy and severe myopathy leading to respiratory failure necessitating ventilatory support. Long-range PCR excluded mitochondrial DNA rearrangements. Clinical diagnosis of MLASA prompted direct sequence analysis of the YARS2 gene encoding the mitochondrial tyrosyl-tRNA synthetase, which revealed homozygosity for a known pathogenic mutation, c.156C>G;p.F52L. Comparison with four previously reported cases demonstrated remarkable clinical homogeneity. First line investigation of MLASA should include direct sequence analysis of YARS2 and PUS1 (encoding a tRNA modification factor) rather than muscle biopsy. Early genetic diagnosis is essential for counseling and to facilitate appropriate supportive therapy. Reasons for segregation of specific clinical phenotypes with particular mitochondrial aminoacyl tRNA-synthetase defects remain unknown. © 2013 Wiley Periodicals, Inc

Signal transducer and activator of transcription 2 deficiency is a novel disorder of mitochondrial fission

Defects of mitochondrial dynamics are emerging causes of neurological disease. In two children presenting with severe neurological deterioration following viral infection we identified a novel homozygous STAT2 mutation, c.1836C4A (p.Cys612Ter), using whole exome sequencing. In muscle and fibroblasts from these patients, and a third unrelated STAT2-deficient patient, we observed extremely elongated mitochondria. Western blot analysis revealed absence of the STAT2 protein and that the mitochondrial fission protein DRP1 (encoded by DNM1L) is inactive, as shown by its phosphorylation state. All three patients harboured 15 decreased levels of DRP1 phosphorylated at serine residue 616 (P-DRP1S616), a post-translational modification known to activate DRP1, and increased levels of DRP1 phosphorylated at serine 637 (P-DRP1S637), associated with the inactive state of the DRP1 GTPase. Knockdown of STAT2 in SHSY5Y cells recapitulated the fission defect, with elongated mitochondria and decreased PDRP1 S616 levels. Furthermore the mitochondrial fission defect in patient fibroblasts was rescued following lentiviral transduction with wild-type STAT2 in all three patients, with normalization of mitochondrial length and increased P-DRP1S616 levels. Taken 20 together, these findings implicate STAT2 as a novel regulator of DRP1 phosphorylation at serine 616, and thus of mitochondrial fission, and suggest that there are interactions between immunity and mitochondria. This is the first study to link the innate immune system to mitochondrial dynamics and morphology. We hypothesize that variability in JAK-STAT signalling may contribute to the phenotypic heterogeneity of mitochondrial disease, and may explain why some patients with underlying mitochondrial disease decompensate after seemingly trivial viral infections. Modulating JAK-STAT activity may represent a novel 25 therapeutic avenue for mitochondrial diseases, which remain largely untreatable. This may also be relevant for more common neurodegenerative diseases, including Alzheimer’s, Huntington’s and Parkinson’s diseases, in which abnormalities of mitochondrial morphology have been implicated in disease pathogenesis

A review on conventional and modern breeding approaches for developing climate resilient crop varieties: NA

The escalating threat of climate change is a major challenge to global food security. One of the ways to mitigate its impact is by developing crops that can withstand environmental stresses such as drought, heat, and salinity. Plant breeders have been employing conventional and modern approaches to achieve climate-resilient crops. Climate-resilient crops refer to both crop and crop varieties that exhibit improved tolerance towards biotic and abiotic stresses. These crops possess the capacity to maintain or even increase their yields when exposed to various stress conditions, such as drought, flood, heat, chilling, freezing and salinity. Conventional breeding entails selecting and crossing plants with desirable traits, while modern breeding deploys molecular techniques to identify and transfer specific genes associated with stress tolerance. However, the effectiveness of both methods is contingent on the crop species and the targeted stress. Advancements in gene editing, such as CRISPER-cas9  and genomics-assisted breeding, offer new opportunities to hasten the development of climate-resilient crops. These new technologies include Marker Assisted Selection, Genome-Wide Association Studies, Mutation breeding, Transcriptomics, Genomics, and more. The review concludes that these cutting-edge techniques have the potential to enhance the speed and precision of developing crops that can endure the challenges posed by climate change

Experimental investigation of the advance velocity in the convergent rectangular surface jet stream with and without longitudinal slope

In this study, results of experiments about the trajectory and the advance of inclined and convergent rectangular surface jet into stagnant ambient have been presented. In order to discharge process simulation was used a flume with 3.2 m length, 0.6 m width, and 0.9 m height and a rectangular channel with 6 cm width. Discharge channel was designed in the four angle of convergence 12.5, 25, 45 and 90 degree. This channel injected the jet stream to form of tangent to the surface of ambient and in three different slopes 0, 4 and 8 percent. Receiving fluid had been prepared from urban water. As well as the jet fluid had been prepared from the salt liquidation in water and in three concentrations 5, 15 and 45 gr/l. After running the experiments and using of images routing process were analyzed the data. In this regard, hydraulic and geometric parameters on the trajectory and the advance velocity of jet were investigated. According to the results, increase the slope and decrease the angle of convergence causes increase in length of trajectory and decrease in the advance velocity of jet. Reduce the densimetric Froude number causes decrease in length of trajectory. Under the effect of buoyant force, by changing the slope from 0 to 8 percent and convergence angle from 90 to 12.5 degree, the ratio of advance velocity of jet stream to average velocity of that is reduced to 60 percent. Also, in order to investigate of influence of convergence on the movement path of flow, by comparison of trajectory in convergent channel and simple channel, more relative advance was seen in convergent channel

Profiling of Amatoxins and Phallotoxins in the Genus Lepiota by Liquid Chromatography Combined with UV Absorbance and Mass Spectrometry

Species in the mushroom genus Lepiota can cause fatal mushroom poisonings due to their content of amatoxins such as α-amanitin. Previous studies of the toxin composition of poisonous Lepiota species relied on analytical methods of low sensitivity or resolution. Using liquid chromatography coupled to UV absorbance and mass spectrometry, we analyzed the spectrum of peptide toxins present in six Italian species of Lepiota, including multiple samples of three of them collected in different locations. Field taxonomic identifications were confirmed by sequencing of the internal transcribed spacer (ITS) regions. For comparison, we also analyzed specimens of Amanita phalloides from Italy and California, a specimen of A. virosa from Italy, and a laboratory-grown sample of Galerina marginata. α-Amanitin, β-amanitin, amanin, and amaninamide were detected in all samples of L. brunneoincarnata, and α-amanitin and γ-amanitin were detected in all samples of L. josserandii. Phallotoxins were not detected in either species. No amatoxins or phallotoxins were detected in L. clypeolaria, L. cristata, L. echinacea, or L. magnispora. The Italian and California isolates of A. phalloides had similar profiles of amatoxins and phallotoxins, although the California isolate contained more β-amanitin relative to α-amanitin. Amaninamide was detected only in A. virosa

Comparison of Intra-articular Platelet Rich Plasma versus Corticosteroid Injections for the Treatment of Moderate Knee Osteoarthritis

Objective:  To compare the efficacy of intra-articular injections of prednisolone acetate and platelet rich plasma in cases of moderate knee osteoarthritis. Study design: Prospective comparative study. Place and Duration of study: Department of Orthopedic Surgery, Khairpur Medical College, Khairpur Mirs, from January 2021 till December 2021 Methodology: A total of 100 patients were selected for the study and were randomly divided into two equal groups. Group C patients received intra-articular corticosteroid injection along with local anesthetic (Prednisolone acetate 40 mg + 3 ml of 0.5% bupivacaine) under ultrasound guidance. Group P patients received 3 injections of PRP, each of 8 ml volume given at one week’s interval. Patients with signs of hemodynamic compromise, sepsis, past history of any intra-articular injection in the same joint were also excluded from the study. Follow up of patients was carried out at 1, 3 and 6 months. The Western Ontario and McMaster Universities Osteoarthritis (WOMAC) scale was used to assess the patients prior to injection and then at each follow up. WOMAC scale consists of three subsets i-e pain, stiffness and physical function. Results: Demographic data was comparable between both groups. Pre-injection WOMAC score in group C and P was 71.54±12.18 and 75.20±8.58 respectively (p-value=0.086); after one month of injections, it was 34.20±10.48 and 35.38±6.31 respectively (p-value=0.580). After 3 months of injection, it was 33.20±8.13 and 31.10±5.50 respectively (p-value=0.195). After 6 months of injection, it was 35.32±10.41 and 32.10±6.63 respectively (p-value=0.68). Conclusion: It is concluded in our study that intra-articular injections of prednisolone acetate and PRP are equally effective in patients of moderate knee osteoarthritis.

Altered Mitochondrial Function, Mitochondrial DNA and Reduced Metabolic Flexibility in Patients With Diabetic Nephropathy.

The purpose of this study was to determine if mitochondrial dysfunction plays a role in diabetic nephropathy (DN), a kidney disease which affects > 100 million people worldwide and is a leading cause of renal failure despite therapy. A cross-sectional study comparing DN with diabetes patients without kidney disease (DC) and healthy controls (HCs); and renal mesangial cells (HMCs) grown in normal and high glucose, was carried out. Patients with diabetes (DC) had increased circulating mitochondrial DNA (MtDNA), and HMCs increased their MtDNA within 24 h of hyperglycaemia. The increased MtDNA content in DCs and HMCs was not functional as transcription was unaltered/down-regulated, and MtDNA damage was present. MtDNA was increased in DC compared to HC, conversely, patients with DN had lower MtDNA than DC. Hyperglycaemic HMCs had fragmented mitochondria and TLR9 pathway activation, and in diabetic patients, mitophagy was reduced. Despite MtDNA content and integrity changing within 4 days, hyperglycaemic HMCs had a normal bio-energetic profile until 8 days, after which mitochondrial metabolism was progressively impaired. Peripheral blood mononuclear cells (PBMCs) from DN patients had reduced reserve capacity and maximal respiration, loss of metabolic flexibility and reduced Bioenergetic Health Index (BHI) compared to DC. Our data show that MtDNA changes precede bioenergetic dysfunction and that patients with DN have impaired mitochondrial metabolism compared to DC, leading us to propose that systemic mitochondrial dysfunction initiated by glucose induced MtDNA damage may be involved in the development of DN. Longitudinal studies are needed to define a potential cause-effect relationship between changes in MtDNA and bioenergetics in DN

Synthesis Of A Gemini Monomer And Cyclobutane-Containing Bifunctional Building Blocks For Novel Materials

Gemini monomer, a new monomeric class that consists of two monomeric units connected by a covalent linker, can offer a highly dense polymeric framework. Moreover, their ability to form twice the number of covalent bonds than the conventional monomer can afford polymers with high thermal and mechanical strength. The desired Gemini monomer, ethylene 1,2-bis (2,4-pentadienoate) (EBP), was synthesized in two steps. First, an acid precursor 2,4-pentadienoic acid was synthesized by the condensation of malonic acid and acrolein. Second, ethylene glycol was used to connect two 2,4-pentadienoic acid units to obtain the monomer. Later, EBP was polymerized in ambient and solvent-free conditions to yield poly[ethylene 1,2-bis(2,4-pentadienoate)] (PEBP). This polymer was found to be inert with most of the organic solvents (DMSO, DMF, etc.), and was thermally stable (T5% \u3e 300 °C) and displayed high Young’s modulus of up to 10.9 GPa with the mechanical strength of 159MPa. Semi-rigid, thermally stable, symmetrical aliphatic building blocks suitable for materials synthesis are uncommon. One such class of structures is cyclobutane-containing building blocks (CBs). They bridge the gap between their flexible aliphatic chain and rigid aromatic counterparts. The presence of one or more conformational strained four-membered aliphatic rings in CBs gives them a unique blend of rigidity and processability, making them viable in designing and synthesizing novel polymers, metal-organic material, etc. Herein, we report a novel strategy to synthesize a CB, trans-1,3-cyclobutane dimethanol (CBDO-1), a versatile building block that may also serve as a phenol-free BPA replacement. It was synthesized using a facile photoreaction and subsequent reduction. Specifically, an initial photodimerization of trans-cinnamic acid using 365 nm blacklight was carried out to form a trans-1,3-cyclobutane diacid, CBDA-1, which was then reduced with either NaBH4 in the presence of I2, or by catalytic hydrogenation using CuO-CrO3, to give the desired CBDO-1 in excellent yield. To highlight the potential application of this useful primary diol, CBDO-1 and various diacids were used to synthesize novel polyesters via conventional melt polymerization. The thermal properties of this new series of polyesters were studied, including the glass transition temperature, which ranged from 33 to 114 °C, and the decomposition temperature, which ranged from 381 to 424 °C. The ease of synthesis of this cyclobutane-containing CBDO-1 monomer, coupled with its desirable properties, will help develop alternatives for the widely used BPA, and lead to novel and useful materials that are not accessible employing thermal reactions alone. A diamine functionalized CB such as trans-1,3-cyclobutane diamine (CBAM-1) was obtained by the solid-state photodimerization trans-nitrostyrene in the slurry state using brine as a medium for forming a suspension. The characterization of CBAM-1 was done using NMR, FT-IR spectroscopy. For the first time, its structure was also determined by using SC-XRD. It was reckoned that semi-rigid CBAM-1 has the right balance of rigidity and flexibility, which can be translated into polyamides with increased processability and desired Tg suitable for various applications. Polyamides were synthesized using CBAM-1 and diacids such as succinic acid and terephthalic acid. Spectroscopic techniques were employed to characterize the polyamides, and their thermal properties were studied. A biomass-derived CB such as rctt-di-2-furanyl-1,2-cyclobutanedicarboxylic acid (CBDA-2) was used as a semi-rigid polytopic ligand to the synthesis of two different green metal-organic materials with Cu2+ and Co2+ as the metal centers via a solution method. Both the 2D coordination polymers have been characterized by X-ray crystal structure determination and FT-IR spectroscopy. Also, their thermal properties were studied by using TGA and DSC. During this thermal study, both materials showed visual thermochromic behavior

Ledarskap i klassrummet : En kvantitativ enkätstudie om kvinnliga och manliga lärares syn på ledarskap

Följande arbete baseras på en kvantitativ enkätstudie som syftade till att undersöka hurkvinnliga respektive manliga lärare ser på ledarskap i klassrummet, utifrån de aspekter avledarskapet lärarna ansåg vara särskilt viktiga respektive särskilt utmanande. Empirin samladesin med hjälp av en digital enkät som skickades ut till rektorer i tre kommuner, samt till trefacebookgrupper. Empirin analyserades sedan utifrån en bivariat analys för att kunna visa hurrespektive kön ser på ledarskap i klassrummet. Resultatet visade att de kvinnliga och manligarespondenterna generellt sett hade en liknande syn på viktiga respektive utmanade delar avledarskapet i klassrummet. Svaren kunde dock skilja sig åt gällande i vilken utsträckning de sågen aspekt som särskilt viktig respektive utmanande. Mot bakgrund av detta kunde vi draslutsatsen att de kvinnliga och manliga lärarna i vår studie, hade en syn på ledarskap som speglarbåde en uppgiftsorienterad och en socioemotionellt orienterad ledare.