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Abstract Background Alzheimer’s disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder that mainly affects older adults. One of the pathological hallmarks of AD is abnormally aggregated Tau protein that forms fibrillar deposits in the brain. In AD, Tau pathology correlates strongly with clinical symptoms, cognitive dysfunction, and neuronal death. Methods We aimed to develop novel therapeutic D-amino acid peptides as Tau fibrillization inhibitors. It has been previously demonstrated that D-amino acid peptides are protease stable and less immunogenic than L-peptides, and these characteristics may render them suitable for in vivo applications. Using a phage display procedure against wild type full-length Tau (TauFL), we selected a novel Tau binding L-peptide and synthesized its D-amino acid version ISAD1 and its retro inversed form, ISAD1rev, respectively. Results While ISAD1rev inhibited Tau aggregation only moderately, ISAD1 bound to Tau in the aggregation-prone PHF6 region and inhibited fibrillization of TauFL, disease-associated mutant full-length Tau (TauFLΔK, TauFL-A152T, TauFL-P301L), and pro-aggregant repeat domain Tau mutant (TauRDΔK). ISAD1 and ISAD1rev induced the formation of large high molecular weight TauFL and TauRDΔK oligomers that lack proper Thioflavin-positive β-sheet conformation even at lower concentrations. In silico modeling of ISAD1 Tau interaction at the PHF6 site revealed a binding mode similar to those known for other PHF6 binding peptides. Cell culture experiments demonstrated that ISAD1 and its inverse form are taken up by N2a-TauRDΔK cells efficiently and prevent cytotoxicity of externally added Tau fibrils as well as of internally expressed TauRDΔK. Conclusions ISAD1 and related peptides may be suitable for therapy development of AD by promoting off-pathway assembly of Tau, thus preventing its toxicity.

Abstract Tau aggregation into amyloid fibers based on the cross-beta structure is a hallmark of several Tauopathies, including Alzheimer Disease (AD). Trans-cellular propagation of Tau with pathological conformation has been suggested as a key disease mechanism. This is thought to cause the spreading of Tau pathology in AD by templated conversion of naive Tau in recipient cells into a pathological state, followed by assembly of pathological Tau fibers, similar to the mechanism of nucleated polymerization proposed for prion pathogenesis. In cell cultures, the process is often monitored by a FRET assay where the recipient cell expresses the Tau repeat domain (TauRD) with a pro-aggregant mutation, fused to GFP-based FRET pairs. Since the size of the reporter GFP (barrel of ~ 3 nm × 4 nm) is ~ 7 times larger than the β-strand distance (0.47 nm), this points to a potential steric clash. Hence, we investigated the influence of the GFP tag on TauFL or TauRD aggregation. Using biophysical methods (light scattering, atomic force microscopy (AFM), and scanning-transmission electron microscopy (STEM)), we found that the assembly of TauRD-GFP was severely inhibited and incompatible with that of Alzheimer filaments. These observations argue against the hypothesis that the propagation of Tau pathology in AD is caused by the prion-like templated aggregation of Tau protein, transmitted via cell-to-cell spreading of Tau. Thus, even though the observed local increase of FRET in recipient cells may be a valid hallmark of a pathological reaction, our data argue that it is caused by a process distinct from assembly of TauRD filaments.

Objective: Our primary objective was to compare the efficacy of streptokinase (SK), tenecteplase, and reteplase by studying patients' electrocardiogram Electrocardiogram(ECG) pre and post thrombolysis. The secondary objectives were to assess chest pain relief using Numerical Pain Rating Scale score and also to compare the side effects (bleeding, hypotension, and anaphylaxis) of three drugs. Materials and Methods: This study is a multicentric, prospective, randomized, comparative study. This study was conducted on 150 patients of ST-elevation myocardial infarction admitted in the wards/ICCU- Intensive Coronary Care Unit, Department of Cardiology, Mahatma Gandhi Memorial Hospital and Rohini Superspeciality Hospital. They were selectively divided into three groups. Group A consisted of patients who received SK (50), Group B who received tenecteplase (50), and Group C who received reteplase (50). The study period was 6 months. The follow-up was done in all the patients during their inhospital stay. Results: Post thrombolysis, reteplase, tenecteplase, and SK led to mean ST-Segment reduction of 64.9 ± 19.77, 52.43 ± 34.57, and 46.97 ± 33.09, respectively. The comparison between the three drugs revealed a significant difference (P = 0.0103). Conclusion: This study concluded that reteplase is most efficacious in the resolution of ST-elevation and also safer than other thrombolytics used.

In many areas, such as speech processing, communication, and measurement systems, where the actual signal is not directly available, Wiener deconvolution is a widely used signal restoration technique. The accuracy of the estimated signal in Wiener deconvolution is determined by the unknown filter parameter. To compute this unknown parameter, complex and time-consuming numerical as well as iterative computation approaches were proposed in the literature, which also often compute an unoptimized unknown filter parameter. To address the computational problem and estimate a more accurate unknown filter parameter, the authors reported an analytical solution in a prior work for a given signal to noise ratio. However, it was revealed that the actual optimum parameter value also varies with noise also. In this paper, the authors propose a new analytical solution for optimum parameter estimation that includes noise as well. The authors compared the modified analytical solution to existing numerical computation methods for different values of Signal to Noise Ratio and demonstrated that the proposed methods’ optimum parameter estimation is always close to the actual optimum value, which resulted in more accurate signal deconvolution. Proposed mathematical solutions are also verified with experimental signals, acquired in a laboratory. [ABSTRACT FROM AUTHOR]

Abstract Introduction Tau, a natively unfolded soluble protein, forms abnormal oligomers and insoluble filaments in several neurodegenerative diseases, including Alzheimer disease (AD). Tau‐induced toxicity is mainly due to oligomers rather than monomers or fibrils. Methods We have developed monoclonal antibodies against purified low‐n tau oligomers of the tau repeat domain as a tool to neutralize tau aggregation and toxicity. In vitro aggregation inhibition was tested by thioflavin S, dynamic light scattering (DLS), and atomic force microscopy (AFM). Using a split‐luciferase complementation assay and fluorescence‐activated cell sorting (FACS), the inhibition of aggregation was analyzed in an N2a cell model of tauopathy. Results Antibodies inhibited tau aggregation in vitro up to ~90% by blocking tau at an oligomeric state. Some antibodies were able to block tau dimerization/oligomerization in cells, as measured by a split‐luciferase complementation assay. Antibodies applied extracellularly were internalized and led to sequestration of tau into lysosomes for degradation. Discussion Novel low‐n tau oligomer specific monoclonal antibody inhibits Tau oligomerization in cells and promotes toxic tau clearance.

In the case of an ac cable, power transmission is limited by the length of the cable due to the capacitive reactive current component. It is well known that high-voltage direct current (HVDC) cables do not have such limitations. However, insulation-related thermal problems pose a limitation on the power capability of HVDC cables. The author presents a viable theoretical development, a logical extension to Whitehead's theory on thermal limitations of the insulation. The computation of the maximum power-carrying capability of HVDC cables subject to limits on the maximum operable temperature of the insulation is presented. The limitation on the power-carrying capability is closely associated with the electrothermal insulation failure. The effect of environmental interaction by way of external thermal resistance, an important aspect, is also considered in the formulations. The Lagrange multiplier method has been used to handle the ensuing optimization problem. The theory is based on an accepted theory of thermal breakdown in insulation and is an important and a coherent extension of great significance. Index Terms--Cable insulation, high-voltage direct current (HVDC) transmission, power cable thermal factors, power cables.

The surface voltage of an insulator assumes importance for understanding tracking and flashover characteristics. Until now, determination of surface voltage of insulating surfaces is left to simulation software and such simulations are left unverified experimentally, leading to uncertainty of the results, which may sometimes be erratic with improper choice of boundary or initial conditions or inaccurate material properties, nonlinearities etc. The paper presents a novel method, using which the surface voltage of any insulating surface such as insulator strings or transformer bushings can be measured. Unlike a conducting surface, the measurement of insulating surface voltage using voltage dividers would be erratic as the measuring arrangement itself will vary the voltage division due to the local unknown impedance between the insulated surface and hv conductor. Recently a method for measurement of surface voltage of an insulated conductor using cylindrical strips was reported. In this paper, based on analytical derivations, a more generalized method of measurement, applicable to any point on an insulating surface of arbitrary geometry is proposed using circular-disc strips. The proposed experimental method is applied to insulator strings and transformer bushings and validated by simulation of the entire systems. The simulation and experimental results are in excellent agreement. [ABSTRACT FROM AUTHOR]

The converter transformers are reported to fail generally on the thyristor-valve side, where complex alternating voltage waveforms superimposed with dc voltages would occur. The effect of these waveforms on the failure and endurance of the valve side winding insulation of the transformers is not yet understood, which is investigated here. In this paper, the voltage waveforms occurring in a converter transformer are obtained through PSCAD/EMTDC for a typical double pole ±500 kV, 1000 MW DC-link HVDC transmission system based on the CIGRE benchmark system. The waveforms are then amplified using a High Voltage amplifier for experimental breakdown investigations. Stepped-stress damage equalization method has been used for obtaining the lifetime characteristics from failure data. A comparison with life curve under pure sinusoidal and actual alternating voltages with superimposed dc and harmonic voltage has been made to understand why the converter transformers generally failed on the valve side. The results first time give fundamental reasons for the possible failure of the converter transformers and put forth important design considerations. [ABSTRACT FROM AUTHOR]

All real-time signals observed from various measurement systems require signal-processing techniques like the deconvolution, to compensate for the effect of transfer function of the systems. Wiener deconvolution is a widely used signal-processing technique for signal restoration. Often, if the power spectral density of signal and noise is unknown, the accuracy of the restored signal depends on an unknown filter parameter. In the literature, time-consuming, iterative, computational methods were reported to estimate the parameter. However, many of these methods give a range of optimum values instead of an unique value and often lead to either over-smoothing or under-smoothing. In this paper, novel analytical expressions are presented through which the unknown parameter can be estimated explicitly. The analytical results of this study are compared with the numerical methods, and they are found to be accurate and robust against numerical evaluation. Further, the results are demonstrated for signals obtained experimentally from the pulsed electroacoustic system and a network, in authors’ laboratory. [ABSTRACT FROM PUBLISHER]