69,356 research outputs found

    The physiology of lactic acid production by Lactobacillus delbreuckii in a cell recycle fermenter

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    The physiology of lactic acid production by Lactobacillus deZbreuckii NRRL B-445 in a continuous fermenter with partial cell recycle has been studied and compared with that observed in a conventional chemostat .Increased formation of ethanol and acetate occurred in the recycle fermenter although lactic acid remained the major product. The yield of lactic acid from biomass and the molar product ratio, lactate: ethanol + acetate, decreased with increasing recycle ratio. The volumetric productivity of lactic acid was enhanced in the recycle fermenter due to the complete utilization of glucose, the greatest productivity (12.1 Gl 1 h-1 at D=0.3 h-1) being achieved using the lowest recycle ratio (0.5). The change in product profile was phenotypic in nature and due to glucose limitation. The specific activity of lactate dehydrogenase and the specific rate of ATP formation were maintained during cell recycle fermentation. The cellular content of polysaccharide, protein, carbon and nitrogen also remained constant and culture viability was maintained. The biomass growth yield was reduced with increasing recycle ratio. A simple mathematical model was derived which described the biomass concentration produced in the recycle fermenter at steady state over a five-fold range of concentrating effect. The derived model included a constant specific rate of glucose consumption for non-anabolic (e. g. maintenance) functions. The results suggest that catabolism and anabolism were less closely coupled in the cell recycle fermenter than in the conventional chemostrat

    Epigenetics : a catalyst of plant immunity against pathogens

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    The plant immune system protects against pests and diseases. The recognition of stress-related molecular patterns triggers localised immune responses, which are often followed by longer-lasting systemic priming and/or up-regulation of defences. In some cases, this induced resistance (IR) can be transmitted to following generations. Such transgenerational IR is gradually reversed in the absence of stress at a rate that is proportional to the severity of disease experienced in previous generations. This review outlines the mechanisms by which epigenetic responses to pathogen infection shape the plant immune system across expanding time scales. We review the cis- and trans-acting mechanisms by which stress-inducible epigenetic changes at transposable elements (TEs) regulate genome-wide defence gene expression and draw particular attention to one regulatory model that is supported by recent evidence about the function of AGO1 and H2A.Z in transcriptional control of defence genes. Additionally, we explore how stress-induced mobilisation of epigenetically controlled TEs acts as a catalyst of Darwinian evolution by generating (epi)genetic diversity at environmentally responsive genes. This raises questions about the long-term evolutionary consequences of stress-induced diversification of the plant immune system in relation to the long-held dichotomy between Darwinian and Lamarckian evolution

    Mapping Super-Relaxed States of Myosin Heads in Sarcomeres using Oblique Angle Fluorescent Microscopy

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    We have utilised modern methods of super-resolution fluorescent microscopy to spatially map fluorescently labelled ATP molecules in relaxed rabbit psoas skeletal muscles. For our imaging process, we have labelled ATP molecules with Rhodamine and Z-lines with Alexa488. Data from imaging these fluorophores have been collected using oblique angle fluorescent microscopy and further analysed to map super relaxed states (SRX) of myosin heads on the thick filament. Our experiments have concluded that most SRX of myosin heads were found in the C-zone of the thick filament, while other zones of thick filament had smaller populations of SRX. Further introduction of mavacamten (MAVA) to our imaging system has revealed an increase in SRX in both D and P zones, while the C zone population of SRX had remained constant. Further experiments must be conducted to establish a clear pattern and further proof our findings

    What is the importance of sperm subpopulations?

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    .The study of sperm subpopulations spans three decades. The origin, meaning, and practical significance, however, are less clear. Current technology for assessing sperm morphology (CASA-Morph) and motility (CASA-Mot) has enabled the accurate evaluation of these features, and there are many options for data classification. Subpopulations could occur as a result of the stage of development of each spermatozoon in the subpopulation. Spermatogenesis might contribute to the production of these subpopulations. Insights from evolutionary biology and recent molecular research are indicative of the diversity among male gametes that could occur from unequal sharing of transcripts and other elements through cytoplasmic bridges between spermatids. Sperm cohorts exiting the gonads would contain different RNA and protein contents, affecting the spermatozoon physiology and associations with the surrounding environmental milieu. Subsequently, these differences could affect how spermatozoa interact with the environmental milieu (maturation, mixing with seminal plasma, and interacting with the environmental milieu, or female genital tract and female gamete). The emergence of sperm subpopulations as an outcome of evolution, related to the reproductive strategies of the species, genital tract structures, and copulatory and fertilization processes. This kind of approach in determining the importance of sperm subpopulations in fertilization capacity should have a practical impact for conducting reproductive technologies, inspiring and enabling new ways for the more efficient use of spermatozoa in the medical, animal breeding, and conservation fields. This manuscript is a contribution to the Special Issue in memory of Dr. Duane GarnerS

    Adenosine Associated Pre- and Postconditioning in Real Medical Practice

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    It has been established that adenosine is a universal trigger of the processes of preparation (conditioning) of the myocardium for ischemic injury, which is confirmed by randomized clinical trials AMISTAD II, TIMI-4, TIMI-9B. Adenosine is included in the guidelines of the ESC Task Force (European Society of Cardiology) as a means of basic therapy, as a representative of the class of potassium channel stimulants (2019) [1]. However, the use of adenosine as an injectable form for intracoronary or intravenous administration is associated with a number of side effects - rapid degradation of the drug in the bloodstream, the need for careful monitoring of systemic hemodynamics (hypotension, tachy- or bradyarrhythmia, ventricular tachycardia, atrioventricular block), frequent development of undesirable gastrointestinal manifestations. All this prompted the search for an alternative form of adenosine use, which would allow wider use of the potentially beneficial effect of adenosine on ischemic pre- and post-conditioning in real medical practice. More recently, on the pharmaceutical market of Ukraine for the first time appeared a pharmacological agent - Advocard, as a drug with the ability to start the processes of pre- and post-conditioning, with sublingual (oral) form of application. Advocard is an original combined polypill drug with three components: adenosine-5-triphosphate-gluconate-magnesium (II) trisodium salt (magladen) ‚Äď 18,6-29,25 mg, molsidomine ‚Äď 0,3 mg and folic acid - 0,45 mg. Recommendations for the use of the Advocard in medical practice are based on the results of clinical studies, which proved that the oral (sublingual) form of adenosine is not only effective and appropriate, but also safe with long-term use. The therapeutic efficacy of Advocard in chronic coronary syndromes [stable, vasospastic, microvascular angina (pain of small coronary vessels), painless myocardial ischemia] and acute coronary syndromes (STEMI / NSTEMI, instability to stenocardia) before or immediately after coronary stenting is in counteracting the mechanisms of reperfusion injury. Clinical practice has shown that Advocard is appropriate for the prevention of NO-REFLOW after opening the epicardial coronary artery, even with the result of TIMI-3. Thus, the Advocard opens the prospect of improving the effectiveness of coronary interventions and is an adjunct to complete myocardial revascularization

    Association of mitochondrial DNA haplogroups with endurance performance

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    Abstract Proper mitochondrial function is a key determinant of endurance performance. Mitochondria are cell organelles which are responsible for cellular energy production through oxidative phosphorylation (OXPHOS). The subunits of OXPHOS complexes are encoded in part by mitochondrial DNA (mtDNA). Previous research has indicated that variation in mtDNA affects endurance performance and a paucity of mtDNA haplogroup J and K has been detected among Finnish endurance athletes. Such a finding suggests that these mtDNA lineages are ‚Äúuncoupling genomes‚ÄĚ which favor heat generation instead of adenosine triphosphate (ATP). Here, the objective was to explore differences in mtDNA variants between elite endurance athletes, sprint athletes and controls. For this purpose, the rate of functional variants and the mutational load in mtDNA of Finnish athletes (n=141) and controls (n=77) was determined. The complete sequences enabled us to search for possible uncoupling variants within haplogroups J and K. Furthermore, the association of haplogroups J and K with physical performance was determined in a population-based cohort of 1,036 healthy Finnish men undergoing compulsory military service. Physical performance was evaluated by means of a 12-minute Cooper running test and muscle fitness index, both at the beginning and end of service. Additionally, the effects of long-term exercise intervention on branched-chain amino acid (BCAA) catabolism was evaluated. BCAAs are the major group of amino acids which are catabolized in skeletal muscle and their oxidation mainly takes place in mitochondria. Rare mtDNA variants were more common among endurance athletes than sprinters or controls (p=0.04), suggesting that rare variation may contribute to endurance performance. The fact that two of the sprinters harbored disease-causing mtDNA variants may indicate that sprinters have a better tolerance for deleterious mutations than endurance athletes. The association of mtDNA haploplogroups J and K with decreased endurance performance was present in the general population (p=0.041), although it was more apparent among the best-performing subjects that approach athletes with their endurance performance (p<0.001). Haplogroups J and K were not characterized by the presence of excessive rare variation. Instead, the functional effect of these lineages might be related to some of the common nonsynonymous variants that define these haplogroups. Variant m.14798T>C in MTCYB is present in both haplogroups and, based on molecular modelling, it may hamper the function of complex III and cause redox imbalance. We found that the elevation in BCAA concentration was larger in subjects harboring haplogroups J and K than in subjects with non-JK haplogroups (p=0.029). The results suggest that BCAA catabolism is a surrogate marker of lower respiratory chain activity attributed to these haplogroups.Tiivistelm√§ Mitokondriot ovat soluelimi√§, jotka tuottavat oksidatiivisessa fosforylaatiossa valtaosan elimist√∂n tarvitsemasta energiasta. T√§m√§n vuoksi mitokondrioiden toiminta vaikuttaa olennaisesti kest√§vyysurheilusuoritukseen. Mitokondrioilla on oma DNA (mtDNA) ja osa hengitysketjun alayksik√∂ist√§ rakennetaan siin√§ olevan ohjeen mukaisesti. Aiemmissa tutkimuksissa on havaittu, ett√§ mtDNA:n geneettinen muuntelu voi vaikuttaa energian tuotantoon ja mtDNA:n haploryhm√§t J ja K ovat harvinaisia suomalaisilla kest√§vyysurheilijoilla. On mahdollista, ett√§ n√§ihin haploryhmiin liittyy mitokondrion hengitysketjun toiminnan irtikytkeytyminen energian tuotannosta, jolloin muodostuu adenosiinitrifosfaatin (ATP) sijasta l√§mp√∂√§. T√§ss√§ tutkimuksessa m√§√§ritettiin mtDNA:n muuntelun suuruus suomalaisilla kest√§vyys- ja nopeusurheilijoilla (n=141) sek√§ terveill√§ kontrolleilla (n=77). Lis√§ksi tunnistettiin funktionaaliset variantit eli geenimuutokset, jotka voivat vaikuttaa syntyv√§n proteiinin toimintaan. Haploryhmien J ja K sekvensseist√§ tunnistettiin hengitysketjun irtikytkent√§√§n my√∂t√§vaikuttavat variantit. N√§iden haploryhmien vaikutusta fyysisen kunnon kehitykseen arvioitiin tutkimalla varusmiespalvelusta suorittavista nuorista miehist√§ koostuvaa v√§est√∂otosta (n=1,036). Varusmiesaineistoa k√§ytt√§m√§ll√§ tutkittiin my√∂s pitk√§kestoisen liikuntaharjoittelun vaikutusta haaraketjuisten aminohappojen (BCAA) aineenvaihduntaan. BCAA:t ovat aerobisessa liikuntasuorituksessa aminohapoista t√§rkeimpi√§ energianl√§hteit√§ ja niiden metabolia tapahtuu mitokondrioissa. Tutkimuksen perusteella harvinaiset funktionaaliset variantit olivat kest√§vyysurheilijoilla tavallisempia kuin nopeusurheilijoilla tai kontrolleilla (p=0.04). T√§m√§ voi viitata siihen, ett√§ mtDNA:n harvinainen variaatio parantaa hengitysketjun toimintaa ja edesauttaa kest√§vyysurheilusuoritusta. Kahdella tutkituista nopeusurheilijoista todettiin mitokondriotaudille altistava geenivirhe. On mahdollista, ett√§ nopeusurheilijat siet√§v√§t paremmin taudille altistavia mtDNA:n mutaatioita, koska urheilusuorituksen aikainen energian tuotanto perustuu heill√§ ensisijaisesti anaerobiseen glykolyysiin oksidatiivisen fosforylaation sijasta. Haploryhm√§t J ja K yhdistyiv√§t v√§est√∂otoksessa alentuneeseen kest√§vyyskunnon kehitykseen (p=0.041) ja haploryhmien vaikutus korostui tarkasteltaessa parhaimmassa kunnossa olevaa varusmiesten joukkoa (p<0.001). Haploryhmien J ja K sekvensseiss√§ ei havaittu runsaasti harvinaisia variantteja, kun taas yleiset nonsynonyymiset muutokset olivat niiss√§ tavallista yleisempi√§. N√§iden haploryhmien funktionaalinen vaikutus voikin selitty√§ haploryhmi√§ m√§√§ritt√§vill√§ yleisill√§ varianteilla. N√§ist√§ MTCYB-geenin variantti m.14798T>C on yhteinen molemmille haploryhmille ja se voi molekulaarisen mallintamisen perusteella haitata kompleksin III toimintaa ja aiheuttaa happoem√§stasapainon h√§iri√∂n. BCAA-seerumipitoisuuden todettiin harjoittelujakson aikana kasvavan voimakkaammin haploryhm√§√§n J tai K kuuluvilla varusmiehill√§ kuin ei-JK haploryhmiin kuuluvilla varusmiehill√§. Tulos voi olla seurausta hidastuneesta BCAA-kataboliasta ja viitata siihen, ett√§ BCAA:n metabolia on heikentyneen oksidatiivisen fosforylaation surrogaatti

    Medicina personalizada en lactantes con cáncer: Estudio farmacogenético de polimorfismos relacionados con toxicidad y respuesta a la quimioterapia

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    Introducci√≥n La farmacogen√©tica es una herramienta de la ‚ÄúMedicina personalizada‚ÄĚ que contribuye a optimizar los tratamientos antineopl√°sicos, adapt√°ndolos a las caracter√≠sticas gen√©ticas particulares de cada individuo, maximizando su eficacia y minimizando su toxicidad. El lactante con c√°ncer es un paciente de particular vulnerabilidad y sus comorbilidades tiene una especial repercusi√≥n vital. El estudio farmacogen√©tico en esta poblaci√≥n resulta pionero y novedoso en nuestro medio. La identificaci√≥n de marcadores predictivos espec√≠ficos permitir√° individualizar m√°s la terap√©utica en esta poblaci√≥n tan fr√°gil y mejorar en consecuencia su calidad de vida y su pron√≥stico vital. Material y m√©todos Estudio de cohortes ambispectivo de pacientes oncol√≥gicos entre 1 y 18 meses de edad, receptores de quimioterapia en el Hospital La Fe de Valencia, en el periodo comprendido entre enero 2007 y agosto 2019. La parte retrospectiva comprende hasta diciembre 2015, el estudio prospectivo desde enero 2016 hasta agosto 2019. En primer lugar, se realiza un an√°lisis descriptivo de variables epidemiol√≥gicas, cl√≠nico/biol√≥gicas, terap√©uticas y pron√≥sticas de 72 pacientes con dichas caracter√≠sticas. Se describe la toxicidad derivada de sus 578 ciclos de quimioterapia (37 variables cl√≠nicas), el tiempo de seguimiento y su supervivencia (meses). En segundo lugar, se realiza un estudio anal√≠tico cuyo objetivo es correlacionar los polimorfismos gen√©ticos relacionados con la quimioterapia de 64 de los pacientes, la toxicidad grave secundaria al tratamiento (‚Č• grado 3 seg√ļn CTAE 4.0) y su supervivencia. El genotipado se realiza en el Centro Nacional de Genotipado (CEGEN) mediante la tecnolog√≠a MassArray (AgenaBioscience), previa configuraci√≥n de un panel farmacogen√©tico pedi√°trico en base a las evidencias recogidas en la base de datos PharmGKB, fichas t√©cnicas de los medicamentos y consorcios internacionales expertos. El an√°lisis estad√≠stico descriptivo se realiza con los programas Excel 2016 y R: las variables cualitativas con el recuento num√©rico (porcentaje) y las variables cuantitativas como mediana +/- rango intercuart√≠lico ante ausencia de normalidad en la distribuci√≥n de los datos (p <0,05, prueba de Kolmogorov-Smirnov). En el an√°lisis de supervivencia se utiliza el estimador Kaplan-Meier. El an√°lisis estad√≠stico anal√≠tico de correlaci√≥n entre polimorfismos y toxicidad se realiza mediante regresi√≥n log√≠stica penalizada por Elastic Net empleando R. El an√°lisis estad√≠stico anal√≠tico de correlaci√≥n entre polimorfismos y reca√≠da/muerte se realiza mediante regresi√≥n de Cox penalizada por Elastic Net. Resultados Las variables epidemiol√≥gicas, cl√≠nico/biol√≥gicas y terap√©uticas de los pacientes de la muestra son consecuentes con las descritas en la literatura del lactante con c√°ncer. Las neoplasias con mayor impacto negativo en la supervivencia son la leucemia mielobl√°stica aguda y los tumores del sistema nervioso central. La toxicidad m√°s prevalente es hematol√≥gica, digestiva e infecciosa. Existe correlaci√≥n entre la toxicidad grave secundaria a los quimioter√°picos en forma de anemia, neutropenia y/o trombopenia y 46 polimorfismos gen√©ticos diferentes. As√≠ mismo se encuentra asociaci√≥n estad√≠sticamente significativa entre la supervivencia global y la supervivencia libre de enfermedad y ciertos polimorfismos gen√©ticos (26 y 13 respectivamente). Los polimorfismos obtenidos pertenecen a genes encargados del transporte (6 genes) y metabolismo (17 genes) de los f√°rmacos, de la reparaci√≥n del material gen√©tico y la supresi√≥n tumoral (5 genes) y de otras funciones biol√≥gicas (4 genes). Conclusi√≥n Los resultados del presente estudio muestran correlaci√≥n estad√≠stica entre 46 polimorfismos de genes implicados en la cin√©tica farmacol√≥gica y la reparaci√≥n del material gen√©tico y la variabilidad en la toxicidad quimioter√°pica y supervivencia de pacientes lactantes con c√°ncer. En definitiva, aportaciones de la farmacogen√©tica que pueden contribuir a la optimizaci√≥n del tratamiento antineopl√°sico en esta poblaci√≥n particular y a la predicci√≥n de sus riesgos, de especial impacto en los supervivientes del c√°ncer infantil
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