Bayesian estimation of the self-similarity exponent of the Nile River fluctuation

The aim of this paper is to estimate the Hurst parameter of Fractional Gaussian Noise (FGN) using Bayesian inference. We propose an estimation technique that takes into account the full correlation structure of this process. Instead of using the integrated time series and then applying an estimator for its Hurst exponent, we propose to use the noise signal directly. As an application we analyze the time series of the Nile River, where we find a posterior distribution which is compatible with previous findings. In addition, our technique provides natural error bars for the Hurst exponent

Методика определения характеристик компонентов сеанса лучевой терапии для различных методов облучения онкологических пациентов с использованием медицинских линейных ускорителей и гамма-терапевтических аппаратов

One of the main factors affecting the effectiveness of radiation therapy is the constancy of the patient’s position on the treatment table created by immobilization devices of various designs and held throughout the entire irradiation procedure, which guarantees the accuracy of the delivery of the prescribed dose distribution. The purpose of the work was to establish the numerical values of the dominant components of a radiation therapy session for each of the irradiation techniques most commonly used in clinical practice of the radiation therapy.To determine the numerical values of the components of the radiation therapy session, the authors have measured each component for some clinical cases of patients’ irradiation placed. The patients had been diagnosed with the following malignant tumours: prostate cancer, breast cancer, lung cancer, head and neck tumours. More than 2000 individual measurements have been carried out with the help of such medical linear accelerators as "Clinac", "Unique", "Truebeam", and the gamma-therapeutic apparatus named "Theratron".The numerical values of the time spent on 3 groups of parameters of an irradiation session were established: the mechanical parameters of the radiation therapy equipment, the functional characteristics of the irradiation systems and the parameters that directly depend on the personnel involved in an irradiation procedure.According to the measurement results, the flow diagram for the procedures of verifying a patient’s position on the therapeutic table (2 different techniques), preceding their irradiation and the radiation therapy procedures themselves was proposed. It has been shown that a number of session components can run in parallel to each other thus optimizing the time spent by a patient in the treatment room.Using the obtained values of the time spent on the radiation session parameters it is possible to actualize the mathematical model that will allow the medical physicist to determine in advance the duration of the irradiation session at the stage of treatment planning and choose a radiation therapy technique taking into account the individual parameters of the irradiation session in each particular clinical case.Одним из основных факторов, влияющих на эффективность лучевой терапии является соблюдение постоянства положения пациента на лечебном столе с использованием фиксирующих приспособлений различных конструкций на протяжении всей процедуры их облучения, что гарантирует точность доставки предписанной дозы излучения. Цель работы – установление численных величин доминирующих компонентов сеанса лучевой терапии для каждой из методик облучения, наиболее применяемых в клинической практике лучевой терапии.Для установления численных величин компонентов сеанса лучевой терапии авторами проведены экспериментальные измерения каждого из них для некоторых клинических случаев облучения пациентов с локализациями злокачественных новообразований: рак предстательной железы, рак молочной железы, рак легкого, опухоли головы и шеи (более 2000 индивидуальных измерений), осуществляемых с использованием медицинских линейных ускорителей следующих моделей: «Clinac», «Unique», «Truebeam», а также гамма-терапевтического аппарата «Theratron».Установлены численные значения затрачиваемого времени для 3-х групп параметров сеанса облучения: механические параметры аппаратов лучевой терапии, функциональные характеристики систем реализации облучения и параметры, напрямую зависящие от персонала, участвующего в проведении процедуры облучения.Предложена блок-схема для процедур верификации положения пациента на терапевтическом столе (две различные методики), предшествующей облучению пациента и непосредственно процедурам лучевой терапии. Показано, что ряд компонентов сеанса может осуществляться параллельно друг другу, за счёт чего время, проводимое пациентом в процедурном помещении, может быть оптимизированно.С использованием полученных значений затрачиваемого времени для параметров сеанса облучения возможна реализация математической модели, которая позволит предварительно определить длительность сеанса облучения на этапе предлучевой подготовки и выбрать методику лучевой терапии с учетом индивидуальных параметров облучения в каждом конкретном клиническом случае

Molecular Structure of Amyloid Fibrils Controls the Relationship between Fibrillar Size and Toxicity

According to the prevailing view, soluble oligomers or small fibrillar fragments are considered to be the most toxic species in prion diseases. To test this hypothesis, two conformationally different amyloid states were produced from the same highly pure recombinant full-length prion protein (rPrP). The cytotoxic potential of intact fibrils and fibrillar fragments generated by sonication from these two states was tested using cultured cells.For one amyloid state, fibril fragmentation was found to enhance its cytotoxic potential, whereas for another amyloid state formed within the same amino acid sequence, the fragmented fibrils were found to be substantially less toxic than the intact fibrils. Consistent with the previous studies, the toxic effects were more pronounced for cell cultures expressing normal isoform of the prion protein (PrP(C)) at high levels confirming that cytotoxicity was in part PrP(C)-dependent. Silencing of PrP(C) expression by small hairpin RNAs designed to silence expression of human PrP(C) (shRNA-PrP(C)) diminished the deleterious effects of the two amyloid states to a different extent, suggesting that the role of PrP(C)-mediated and PrP(C)-independent mechanisms depends on the structure of the aggregates.This work provides a direct illustration that the relationship between an amyloid's physical dimension and its toxic potential is not unidirectional but is controlled by the molecular structure of prion protein (PrP) molecules within aggregated states. Depending on the structure, a decrease in size of amyloid fibrils can either enhance or abolish their cytotoxic effect. Regardless of the molecular structure or size of PrP aggregates, silencing of PrP(C) expression can be exploited to reduce their deleterious effects

Recombinant prion protein induces a new transmissible prion disease in wild-type animals

Prion disease is a neurodegenerative malady, which is believed to be transmitted via a prion protein in its abnormal conformation (PrPSc). Previous studies have failed to demonstrate that prion disease could be induced in wild-type animals using recombinant prion protein (rPrP) produced in Escherichia coli. Here, we report that prion infectivity was generated in Syrian hamsters after inoculating full-length rPrP that had been converted into the cross-β-sheet amyloid form and subjected to annealing. Serial transmission gave rise to a disease phenotype with highly unique clinical and neuropathological features. Among them were the deposition of large PrPSc plaques in subpial and subependymal areas in brain and spinal cord, very minor lesioning of the hippocampus and cerebellum, and a very slow progression of disease after onset of clinical signs despite the accumulation of large amounts of PrPSc in the brain. The length of the clinical duration is more typical of human and large animal prion diseases, than those of rodents. Our studies establish that transmissible prion disease can be induced in wild-type animals by inoculation of rPrP and introduce a valuable new model of prion diseases

Highly Efficient Protein Misfolding Cyclic Amplification

Protein misfolding cyclic amplification (PMCA) provides faithful replication of mammalian prions in vitro and has numerous applications in prion research. However, the low efficiency of conversion of PrPC into PrPSc in PMCA limits the applicability of PMCA for many uses including structural studies of infectious prions. It also implies that only a small sub-fraction of PrPC may be available for conversion. Here we show that the yield, rate, and robustness of prion conversion and the sensitivity of prion detection are significantly improved by a simple modification of the PMCA format. Conducting PMCA reactions in the presence of Teflon beads (PMCAb) increased the conversion of PrPC into PrPSc from ∼10% to up to 100%. In PMCAb, a single 24-hour round consistently amplified PrPSc by 600-700-fold. Furthermore, the sensitivity of prion detection in one round (24 hours) increased by 2-3 orders of magnitude. Using serial PMCAb, a 1012-fold dilution of scrapie brain material could be amplified to the level detectible by Western blotting in 3 rounds (72 hours). The improvements in amplification efficiency were observed for the commonly used hamster 263K strain and for the synthetic strain SSLOW that otherwise amplifies poorly in PMCA. The increase in the amplification efficiency did not come at the expense of prion replication specificity. The current study demonstrates that poor conversion efficiencies observed previously have not been due to the scarcity of a sub-fraction of PrPC susceptible to conversion nor due to limited concentrations of essential cellular cofactors required for conversion. The new PMCAb format offers immediate practical benefits and opens new avenues for developing fast ultrasensitive assays and for producing abundant quantities of PrPSc in vitro

PrP aggregation can be seeded by pre-formed recombinant PrP amyloid fibrils without the replication of infectious prions

Mammalian prions are unusual infectious agents, as they are thought to consist solely of aggregates of misfolded prion protein (PrP). Generation of synthetic prions, composed of recombinant PrP (recPrP) refolded into fibrils, has been utilised to address whether PrP aggregates are, indeed, infectious prions. In several reports, neurological disease similar to transmissible spongiform encephalopathy (TSE) has been described following inoculation and passage of various forms of fibrils in transgenic mice and hamsters. However, in studies described here, we show that inoculation of recPrP fibrils does not cause TSE disease, but, instead, seeds the formation of PrP amyloid plaques in PrP-P101L knock-in transgenic mice (101LL). Importantly, both WT-recPrP fibrils and 101L-recPrP fibrils can seed plaque formation, indicating that the fibrillar conformation, and not the primary sequence of PrP in the inoculum, is important in initiating seeding. No replication of infectious prions or TSE disease was observed following both primary inoculation and subsequent subpassage. These data, therefore, argue against recPrP fibrils being infectious prions and, instead, indicate that these pre-formed seeds are acting to accelerate the formation of PrP amyloid plaques in 101LL Tg mice. In addition, these data reproduce a phenotype which was previously observed in 101LL mice following inoculation with brain extract containing in vivo-generated PrP amyloid fibrils, which has not been shown for other synthetic prion models. These data are reminiscent of the “prion-like” spread of aggregated forms of the beta-amyloid peptide (Aβ), α-synuclein and tau observed following inoculation of transgenic mice with pre-formed seeds of each misfolded protein. Hence, even when the protein is PrP, misfolding and aggregation do not reproduce the full clinicopathological phenotype of disease. The initiation and spread of protein aggregation in transgenic mouse lines following inoculation with pre-formed fibrils may, therefore, more closely resemble a seeded proteinopathy than an infectious TSE disease

Synthetic prions with novel strain-specified properties

Prions are infectious proteins that possess multiple self-propagating structures. The information for strains and structural specific barriers appears to be contained exclusively in the folding of the pathological isoform, PrP(Sc). Many recent studies determined that de novo prion strains could be generated in vitro from the structural conversion of recombinant (rec) prion protein (PrP) into amyloidal structures. Our aim was to elucidate the conformational diversity of pathological recPrP amyloids and their biological activities, as well as to gain novel insights in characterizing molecular events involved in mammalian prion conversion and propagation. To this end we generated infectious materials that possess different conformational structures. Our methodology for the prion conversion of recPrP required only purified rec full-length mouse (Mo) PrP and common chemicals. Neither infected brain extracts nor amplified PrP(Sc) were used. Following two different in vitro protocols recMoPrP converted to amyloid fibrils without any seeding factor. Mouse hypothalamic GT1 and neuroblastoma N2a cell lines were infected with these amyloid preparations as fast screening methodology to characterize the infectious materials. Remarkably, a large number of amyloid preparations were able to induce the conformational change of endogenous PrPC to harbor several distinctive proteinase-resistant PrP forms. One such preparation was characterized in vivo habouring a synthetic prion with novel strain specified neuropathological and biochemical properties