Rotation of DNA around intact strand in human topoisomerase I implies distinct mechanisms for positive and negative supercoil relaxation

Topoisomerases are enzymes of quintessence to the upkeep of superhelical DNA, and are vital for replication, transcription and recombination. An atomic-resolution model for human topoisomerase I in covalent complex with DNA is simulated using molecular dynamics with external potentials that mimic torque and bias the DNA duplex downstream of a single-strand cut to rotate around the intact strand, according to the prevailing enzymatic mechanism. The simulations reveal the first dynamical picture of how topoisomerase accommodates large-scale motion of DNA as it changes its supercoiling state, and indicate that relaxation of positive and negative supercoils are fundamentally different. To relax positive supercoils, two separate domains (the ‘lips’) of the protein open up by about 10–14 Å, whereas to relax negative supercoils, a continuous loop connecting the upper and lower parts (and which was a hinge for opening the lips) stretches about 12 Å while the lips remain unseparated. Normal mode analysis is additionally used to characterize the functional flexibility of the protein. Remarkably, the same combination of low-frequency eigenvectors exhibit the dominant contribution for both rotation mechanisms through a see-saw motion. The simulated mechanisms suggest mutations to control the relaxation of either type of supercoiling selectively and advance a hypothesis for the debated role of the N-terminal domain in supercoil relaxation

Urtikarija kao rijetka nuspojava polietilen glikola-3350 kod djeteta: prikaz slučaja

Polyethylene glycol electrolyte (PEG-3350) solution is usually used for bowel emptying before co-lonoscopy in adults. It has also been reported to be safe in children. It is thought that bowel irrigation with this solution can be a useful treatment alternative for poisoning with slow releasing drugs, swallowed packaged substances, enteric coated drugs, drugs not binding to charcoal, and heavy metals in children. Due to high molecular weight of PEG-3350, its absorption from the intestinal mucosa is very low (0.2%). Therefore, it is less likely to have side effects. A three-year-old girl bit and ate one-third of an alkali battery and was brought to our pediatric emergency unit. Vital signs and results of physical examination and laboratory investigations were normal. Irrigation of the bowels with PEG-3350 solution given orally at a rate of 20 mL/kg/h was initiated. Upon excretion of feces of normal appearance in the sixth hour, irrigation was continued. Since rashes and itching started throughout her body in the thirtieth hour after administration of 9 L PEG-3350, the irrigation was discontinued and the patient was administered antihistamines. Rashes and itching regressed within one hour of its discontinuation. This suggested that they were due to the irrigation solution. There are five adult cases of allergic reactions to PEG-3350 reported in the literature. The case presented is the first pediatric patient developing allergic reaction to PEG-3350.Otopina polietilen glikola (PEG-3350) najčešće se primjenjuje za pražnjenje crijeva prije kolonoskopije u odraslih osoba, a opisuje se kao sigurno sredstvo i u djece. Smatra se da ispiranje crijeva ovom otopinom može biti korisna alternativa za liječenje otrovanja lijekovima sa sporim otpuštanjem, progutanim pakovanjima nekih tvari, lijekovima sa zaštitnom ovojnicom za probavni sustav, lijekovima koji se ne vežu na ugljen te teškim metalima u djece. Zbog velike molekularne težine vrlo mali dio PEG-3350 (0,2%) se apsorbira iz crijevne sluznice pa su stoga nuspojave manje vjerojatne. Djevojčica u dobi od tri godine zagrizla je i progutala jednu trećinu alkalne baterije pa je dovedena u našu hitnu pedijatrijsku službu. Vitalni znaci kao i rezultati fizikalnog pregleda i laboratorijskih pretraga bili su normalni. Započeto je ispiranje crijeva otopinom PEG-3350 peroralno, 20 mL/kg/h. Nakon što je dijete imalo stolicu normalnog izgleda u šestom satu, ispiranje je nastavljeno. Međutim, nakon što je djevojčica primila 9 L PEG-3350, u tridesetom satu davanja otopine nastupio je osip i svrbež po čitavom tijelu pa je ispiranje crijeva prekinuto i djetetu su dani antihistaminici. Osip i svrbež su se povukli unutar jednog sata od prestanka ispiranja otopinom PEG-3350. U literaturi je opisano pet slučajeva alergijskih reakcija na PEG-3350 u odraslih osoba. Ovaj prikaz opisuje prvi slučaj alergijske reakcije na PEG-3350 u djeteta

FORWARD AND INVERSE MODELLING OF A GRAVITY FIELD RESULTING FROM A DENSITY INTERFACE USING PARK-OLDENBURG METHOD

Gravite anomalisine neden olan bozucu kütlenin bulunması için kullanılan ters çözüm algoritmasına ulaşabilmek için, iki boyutlu, gömülü ve engebeli topografya modelinin neden olduğu gravite anomalisinin hızlı hesabı için kullanılan formül yeniden düzenlenmiştir. Yöntem, bozucu topografyayı simgeleyen h(x) fonksiyonunun kuvvetlerinin Fourier dönüşümleri toplamını alarak gravite anomalisinin Fourier dönüşümünü hesaplar. Fourier dönüşümü hızlı hesaplanabildiği için bu yöntem, hesaplamada, gravitasyonel alanının her bir yapı için ayrı ayrı hesaplanıp toplanarak elde edilmesinden daha hızlıdır. Yöntemin hızı, pratik bir yöntem olarak sunulmasını sağlamaktadır. Ters çözümünün çoğulluğu bozucu kütle ile onu çevreleyen ortam arasındaki yoğunluk farkı Ï ve ters çözümün yapıldığı seviye zo olmak üzere iki bağımsız parametre ile tanımlanır. Bu iki parametreyi belirleyen ek bilgi olmaksızın, gravite yorumundaki belirsizlik azaltılamaz. Yineleme işleminin yakınsamasını artırmak için alçak geçişli süzgeç uygulanmaktadır. Ancak yoğunluğun çok küçük yada zo değerinin çok büyük olduğu durumlarda, ilksel gözlenen anomaliyi sağlayan topoğrafya ya ulaşılamadığı bulunmuştur. Ters çözüm algoritmasının çok fazla sayıdaki model noktasına, sayısal duyarlılıkta önemli bir azalma veya hesaplama süresinde önemli bir artış olmaksızın uygulanabiliyor olması, yöntemi oldukça etkin yapmaktadır. In order to reach the inverse solution for the perturbing body giving rise to the gravitational anomaly through the rearrangement of the formula used for the rapid calculation of such anomaly caused by a two dimensional uneven layer of material. The scheme calculates the Fourier transform of the gravitational anomaly as the sum of Fourier transforms of powers of the perturbing topography. This method is computationally much more efficient than calculating the gravitational field by breaking up the model into a set of prisms whose contributions are calculated separately and summed. Essentially this method comprises of computations involving Fourier transformations, which are relatively fast and straightforward with the FFT algorithm. Its speed makes the method to be presented as a practical one. The effects of the two parameters, the density contrast (Ï) and the level at which the inversion is made (zo) are observed, cause the nonuniqueness of the inversion. Without additional information constraining these parameters, the ambiguity in the gravity interpretation can not be reduced. Convergence of the inversion is ensured by a suitable low pass filter in frequency domain. However, if the assumed density was too small or reference level too large, no topography could be found which would give rise to an observed anomaly. The ability of this inversion scheme to handle large numbers of model points without greatly decreasing the numerical stability or greatly increasing the computation time makes it particularly attractive

The Importance of Bedside Ultrasonography in Confirming the Location of Endotracheal Tube

Objective. Endotracheal intubation may be associated with lethal complications when not applied in appropriate manner. In this study, we aimed to examine the efficiency of transcricoid and pulmonary ultrasonography in confirming the position of the tube in comparison with classical methods. Methods. This study was carried out between 2016 and 2017 in Turkey and was registered in Clinical Trials under number NCT03081221. The location of the tube was confirmed using methods such as monitoring the vocal cords during direct laryngoscopy, condensation on endotracheal tube during respiration, epigastric-pulmonary auscultation, radiography and capnometry. After that, the transcricoid and pulmonary ultrasonography were implemented by the blinded pediatric emergency care specialist. Results. 64 cases who needed advanced airway requirements were involved in this study. The double-line appearance could not be obtained from one patient only when using transcricoid ultrasonography, but the bilateral pleural shift movement was observed among all the cases by using pulmonary ultrasonography (sensitive: 98%-100%). Conclusion. The determination of endoesophageal, endotracheal and endobronchial intubations can be easily made by using transcricoid and pulmonary ultrasonography. The use of ultrasonography may significantly contribute to critical airway management as fast, accurate and on time

Source Data and Codes for xHAT

<p>Data and anlysis scripts for the study where we predict a specific hairpin trimer complex is the transition state of amyloid fibril formation in proteins.</p&gt

Source Data and Codes for xHAT

<p>Data and anlysis scripts for the study where we predict a specific hairpin trimer complex is the transition state of amyloid fibril formation in proteins.</p&gt

Rotation of DNA around intact strand in human topoisomerase I implies distinct mechanisms for positive and negative supercoil relaxation.

Topoisomerases are enzymes of quintessence to the upkeep of superhelical DNA, and are vital for replication, transcription and recombination. An atomic-resolution model for human topoisomerase I in covalent complex with DNA is simulated using molecular dynamics with external potentials that mimic torque and bias the DNA duplex downstream of a single-strand cut to rotate around the intact strand, according to the prevailing enzymatic mechanism. The simulations reveal the first dynamical picture of how topoisomerase accommodates large-scale motion of DNA as it changes its supercoiling state, and indicate that relaxation of positive and negative supercoils are fundamentally different. To relax positive supercoils, two separate domains (the 'lips') of the protein open up by about 10-14 A, whereas to relax negative supercoils, a continuous loop connecting the upper and lower parts (and which was a hinge for opening the lips) stretches about 12 A while the lips remain unseparated. Normal mode analysis is additionally used to characterize the functional flexibility of the protein. Remarkably, the same combination of low-frequency eigenvectors exhibit the dominant contribution for both rotation mechanisms through a see-saw motion. The simulated mechanisms suggest mutations to control the relaxation of either type of supercoiling selectively and advance a hypothesis for the debated role of the N-terminal domain in supercoil relaxation