Translational and Regulatory Challenges for Exon Skipping Therapies

Several translational challenges are currently impeding the therapeutic development of antisense-mediated exon skipping approaches for rare diseases. Some of these are inherent to developing therapies for rare diseases, such as small patient numbers and limited information on natural history and interpretation of appropriate clinical outcome measures. Others are inherent to the antisense oligonucleotide (AON)-mediated exon skipping approach, which employs small modified DNA or RNA molecules to manipulate the splicing process. This is a new approach and only limited information is available on long-term safety and toxicity for most AON chemistries. Furthermore, AONs often act in a mutation-specific manner, in which case multiple AONs have to be developed for a single disease. A workshop focusing on preclinical development, trial design, outcome measures, and different forms of marketing authorization was organized by the regulatory models and biochemical outcome measures working groups of Cooperation of Science and Technology Action: "Networking towards clinical application of antisense-mediated exon skipping for rare diseases." The workshop included participants from patient organizations, academia, and members of staff from the European Medicine Agency and Medicine Evaluation Board (the Netherlands). This statement article contains the key outcomes of this meeting.status: publishe

QRAT+: Generalizing QRAT by a More Powerful QBF Redundancy Property

The QRAT (quantified resolution asymmetric tautology) proof system simulates virtually all inference rules applied in state of the art quantified Boolean formula (QBF) reasoning tools. It consists of rules to rewrite a QBF by adding and deleting clauses and universal literals that have a certain redundancy property. To check for this redundancy property in QRAT, propositional unit propagation (UP) is applied to the quantifier free, i.e., propositional part of the QBF. We generalize the redundancy property in the QRAT system by QBF specific UP (QUP). QUP extends UP by the universal reduction operation to eliminate universal literals from clauses. We apply QUP to an abstraction of the QBF where certain universal quantifiers are converted into existential ones. This way, we obtain a generalization of QRAT we call QRAT+. The redundancy property in QRAT+ based on QUP is more powerful than the one in QRAT based on UP. We report on proof theoretical improvements and experimental results to illustrate the benefits of QRAT+ for QBF preprocessing.Comment: preprint of a paper to be published at IJCAR 2018, LNCS, Springer, including appendi

Monitoring of rolling bearing failures as result of acceleration

The article discusses modern methods of diagnosing and technical diagnostics of irrigation pumping units to ensure reliability during operation. Using new designs of pumping power equipment and developing new operating modes provide for improving the mode of pumps based on improved diagnostics, significantly saving operating costs. Together with this provides detection, control, and prediction of multi-stage failure of the rolling bearing by monitoring the vibration trends of the centrifugal pump unit during operation

Technological challenges of 1-dimensional magnetic photonic crystals

Visible-region magnetic photonic crystals (MPC) designed for higher-order bandgap operation have been proposed to overcome the technological restrictions originating from the strong thickness dependency of the individual magnetic layer properties observed in MPC structures

Entanglement Measures for Single- and Multi-Reference Correlation Effects

Electron correlation effects are essential for an accurate ab initio description of molecules. A quantitative a priori knowledge of the single- or multi-reference nature of electronic structures as well as of the dominant contributions to the correlation energy can facilitate the decision regarding the optimum quantum chemical method of choice. We propose concepts from quantum information theory as orbital entanglement measures that allow us to evaluate the single- and multi-reference character of any molecular structure in a given orbital basis set. By studying these measures we can detect possible artifacts of small active spaces.Comment: 14 pages, 4 figure

The cost effectiveness of immunoglobulin vs. hematopoietic stem cell transplantation for CIDP

Background: Intravenous immunoglobulin (IVIG) is effective as standard first line therapy for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), but some patients remain dependent on its long-term use. Recently, we have reported that autologous non-myeloablative hematopoietic stem cell transplantation (HSCT) is an effective second line therapy for CIDP. Objectives: To compare the cost of chronic IVIG vs. autologous HSCT (a one-time therapy), we collected data on patients with CIDP undergoing HSCT between 2017 and 2019. This was compared with published literature on the costs and efficacy defined by the Inflammatory Neuropathy Cause And Treatment (INCAT) disability score, Medical Research Council (MRC) sum score, hand grip strength, and SF-36 quality of life (QOL) for CIDP. Methods: Between 2017 and 2019, nineteen patients with chronic CIDP (mean disease treatment duration prior to HSCT of 6 years) underwent autologous HSCT with mean cost of $108,577 per patient (range$56,327–277,119, standard deviation $53,092). After HSCT, 80$136,000 per year. Despite remaining treatment free, HSCT demonstrated greater improvement in efficacy compared to immunoglobulins. Recommendations: Given the long-term treatment-free remission and better outcome measurements, autologous HSCT is more cost effective than long-term IVIG treatment in patients with chronic CIDP. However, costs will depend on patient selection, the HSCT regimen, and regional variations. Further analysis of the health economics, i.e., cost/outcome ratio, of HSCT as therapy for chronically IVIG dependent CIDP is warranted

Accurate ab initio spin densities

We present an approach for the calculation of spin density distributions for molecules that require very large active spaces for a qualitatively correct description of their electronic structure. Our approach is based on the density-matrix renormalization group (DMRG) algorithm to calculate the spin density matrix elements as basic quantity for the spatially resolved spin density distribution. The spin density matrix elements are directly determined from the second-quantized elementary operators optimized by the DMRG algorithm. As an analytic convergence criterion for the spin density distribution, we employ our recently developed sampling-reconstruction scheme [J. Chem. Phys. 2011, 134, 224101] to build an accurate complete-active-space configuration-interaction (CASCI) wave function from the optimized matrix product states. The spin density matrix elements can then also be determined as an expectation value employing the reconstructed wave function expansion. Furthermore, the explicit reconstruction of a CASCI-type wave function provides insights into chemically interesting features of the molecule under study such as the distribution of $\alpha$- and $\beta$-electrons in terms of Slater determinants, CI coefficients, and natural orbitals. The methodology is applied to an iron nitrosyl complex which we have identified as a challenging system for standard approaches [J. Chem. Theory Comput. 2011, 7, 2740].Comment: 37 pages, 13 figure

Population of isomers in decay of the giant dipole resonance

The value of an isomeric ratio (IR) in N=81 isotones ($^{137}$Ba, $^{139}$Ce, $^{141}$Nd and $^{143}$Sm) is studied by means of the ($\gamma, n)$ reaction. This quantity measures a probability to populate the isomeric state in respect to the ground state population. In ($\gamma, n)$ reactions, the giant dipole resonance (GDR) is excited and after its decay by a neutron emission, the nucleus has an excitation energy of a few MeV. The forthcoming $\gamma$ decay by direct or cascade transitions deexcites the nucleus into an isomeric or ground state. It has been observed experimentally that the IR for $^{137}$Ba and $^{139}$Ce equals about 0.13 while in two heavier isotones it is even less than half the size. To explain this effect, the structure of the excited states in the energy region up to 6.5 MeV has been calculated within the Quasiparticle Phonon Model. Many states are found connected to the ground and isomeric states by $E1$, $E2$ and $M1$ transitions. The single-particle component of the wave function is responsible for the large values of the transitions. The calculated value of the isomeric ratio is in very good agreement with the experimental data for all isotones. A slightly different value of maximum energy with which the nuclei rest after neutron decay of the GDR is responsible for the reported effect of the A-dependence of the IR.Comment: 16 pages, 4 Fig

Разработка сменного ковшового рабочего органа с дополнительным захватом для каналоочистителя ОКН-0,5

The paper substantiates the necessity of developing new replaceable working bodies for the OKN-0.5 reclamation canal cleaner. The study emphasizes the significance and application features of bucket working bodies, considering the prevalent conditions of reclamation drainage canals, which often contain sediment, silting, and various types of vegetation. (Research purpose) The research objective is to investigate the process of cleaning the channel bottom and slopes using the proposed replaceable bucket. (Materials and methods) The paper proposes an enhanced design of a replaceable bucket with an additional gripper. (Results and discussion) The paper outlines the calculations conducted to determine the appropriate bucket width, dimensions of the additional gripper, the forces involved in clearing sediments and silting, and the machine's working capacity. A comprehensive three-dimensional model of the proposed working body with the additional gripper was created using Inventor Pro graphics package. Additionally, the bucket's structural strength was evaluated through finite element method calculations.  The canal cleaner’s stability was assessed with the inclusion of a separate hydraulic drive for the additional gripper, utilizing a mini-program generated in the Mathcad system. (Conclusions) The conclusions drawn from the study recommend a bucket width of 2000 millimeters and the development of an additional gripper with a hydraulic drive. The proposed design proves essential for securing sediments, grassy, and shrubby vegetation in the bucket until they can be efficiently unloaded onto the berm. Based on technical and operational data, the canal cleaner belongs to machines of positional periodic action, with a working capacity of 180-330 meters per hour. The research also identifies criteria for achieving high-quality cleaning of reclamation drainage canals up to 2.5 meters deep.Обосновали необходимость создания новых сменных рабочих органов мелиоративного каналоочистителя ОКН-0,5. Отметили значение и особенности применения ковшовых рабочих органов с учетом того, что состояние каналов мелиоративных осушительных систем характеризуется наличием наносов, заилений, травянистой и кустарниковой растительности. (Цель исследования) Изучить процесс очистки дна и откосов каналов с помощью разработанного сменного ковша. (Материалы и методы) Предложили уширенную конструкцию сепарированного ковша с дополнительным захватом. (Результаты и обсуждение) На основе выполненных расчетов определили ширину ковша, размеры дополнительного захвата, усилия, прилагаемые к ковшу при разработке наносов и заилений, а также производительность машины. Сформировали объемную модель-сборку предлагаемого рабочего органа с дополнительным захватом в графическом пакете Inventor Pro. Провели прочностные расчеты методом конечных элементов нового ковшового устройства с дополнительным захватом, определили запас прочности конструкции. С учетом утяжеления ковша за счет дополнительного захвата с отдельным гидроприводом рассчитана устойчивость каналоочистителя с помощью мини-программы, сформированной в системе Mathcad. (Выводы) Обосновали ширину 2000 миллиметров ковша и необходимость разработки дополнительного захвата с гидравлическим приводом. Предлагаемая конструкция необходима для фиксации в ковше наносов, травянистой и кустарниковой растительности до момента их выгрузки на берму. По технико-эксплуатационным показателям каналоочиститель относится к машинам позиционного периодического действия. Эксплуатационная производительность каналоочистителя может достигать 180-330 метров в час. Выявили критерии для качественной очистки осушительных мелиоративных каналов глубиной до 2,5 метра