BACE1 inhibition using 2’-OMePS steric blocking antisense oligonucleotides

Amyloid beta-peptide is produced by the cleavage of amyloid precursor protein by two secretases, a β-secretase, beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and a γ-secretase. It has been hypothesised that partial inhibition of BACE1 in individuals with a high risk of developing Alzheimer’s disease may be beneficial in preventing cognitive decline. In this study, we report the development of a novel antisense oligonucleotide (AO) that could efficiently downregulate the BACE1 transcript and partially inhibit BACE1 protein. We designed and synthesised a range of 2’-OMethyl-modified antisense oligonucleotides with a phosphorothioate backbone across various exons of the BACE1 transcript, of which AO2, targeting exon 2, efficiently downregulated BACE1 RNA expression by 90%. The sequence of AO2 was later synthesised with a phosphorodiamidate morpholino chemistry, which was found to be not as efficient at downregulating BACE1 expression as the 2’-OMethyl antisense oligonucleotides with a phosphorothioate backbone variant. AO2 also reduced BACE1 protein levels by 45%. In line with our results, we firmly believe that AO2 could be used as a potential preventative therapeutic strategy for Alzheimer’s diseas

Effect of Large Versus Small Range of Motion in the Various Intensities of Eccentric Exercise-Induced Muscle Pain and Strength

International Journal of Exercise Science 14(7): 1-18, 2021. The purpose was to investigate eccentric (ECC) exercise with full range of motion (FROM) induce a greater magnitude of delayed onset muscle soreness (DOMS), pain, functional limitations compared to partial range of motion (PROM; outer 60° of ROM). Thirty-four participants (men and women) aged between 18 and 30 years performed ECC exercise protocol on elbow and knee muscles (5 × 10 repetitions each session) using their 15%/25%/35% of maximal voluntary isometric contraction (MVIC) with PROM (week 2-4) and FROM (week 6-8). Two days a week, ECC exercises and remaining days the subjective and objective assessments were carried out (activities of daily living (ADL), pain (visual analogue scale (VAS), pain pressure threshold (PPT)), and MVIC. The ECC exercise with FROM showed moderate pain (0-3.5) in ADL (pulling a heavy object and descending stairs), VAS, and PPT for elbow extensors and knee flexors and showed a statistically significant difference (p ≤ 0.05) compared to PROM ECC protocol. The muscle strength was increased in FROM ECC exercise than PROM ECC exercise and ranged between 23.16% and 28.22%. ECC exercise performed with FROM induced a higher degree of DOMS, pain, ADL limitations than PROM. The study outcomes can be used for beginner sedentary older adults as well as young athletes

Mamdani Fuzzy Expert System Based Directional Relaying Approach for Six-Phase Transmission Line

Traditional directional relaying methods for 6-phase transmission lines have complex effort, and so there is still a need for novel direction relaying estimation scheme. This study presents a Mamdani-fuzzy expert system (MFES) approach for discriminating faulty section/zone, classifying faults and locating faults in 6-phase transmission lines. The 6-phase fundamental component of currents, voltages and phase angles are captured at single bus and are used in the protection scheme. Simulation results substantiate that the protection scheme is very successful against many parameters such as different fault types, fault resistances, transmission line fault locations and inception angles. A large number of fault case studies have been carried out to evaluate reach setting and % error of proposed method. It provides primary protection to transmission line length and also offers backup protection for a reverse section of transmission line. The experimental results show that the scheme performs better than the other schemes

Analysis of Automotive Cyber-Attacks on Highways using Partial Differential Equation Models

This is the author accepted manuscript.This paper considers scenarios wherein a group of malicious vehicles on a highway perform a cooperative attack with the motive of creating undesirable wave effects among other vehicles on the highway. The two species of vehicles - malicious vehicles and normal vehicles, and their associated interaction effects, are modeled using Partial Differential Equations (PDEs). The malicious vehicles, which may be arbitrarily distributed on the highway, perform a sequence of velocity changes with the objective of making the density/velocity profile on the highway, track a reference profile. This reference profile (chosen by the malicious vehicles) has the property that once generated, it spontaneously evolves into a shock wave that propagates along the highway. Analytical expressions governing the velocity inputs of the malicious vehicles with which they can generate such waves are determined, for perfect as well as imperfect information scenarios. Simulation results are presented to validate the theoryThe first two authors would like to acknowledge support from the National Science Foundation. This material is based upon work supported by the National Science Foundation under Grant IIS-1351677

Indirect Laser Sintering of Corrugated Flow Field Plates for Direct Methanol Fuel Cell Applications

Direct methanol fuel cells (DMFC) hold distinct advantages over traditional hydrogen-based fuel cells. Their commercialization, however, has been bound by many factors – especially their suboptimal efficiency. This work aims at enhancing the performance of DMFC through the use of corrugated flow field plates. Our objectives are two-fold – one, to increase the power density of DMFC by corrugating flow field plates and two, to introduce Laser sintering (LS) as an efficient and robust method for the manufacture of such plates. Corrugated flow field plates with 10% more surface area as compared to a planar design were made by LS & tested in a DMFC environment. Our results show that the particle size of the material used – Graphite – has a significant effect upon the green strength of LS parts. We also report the performance of corrugated flow field plates with 10% higher surface area (as compared to planar plates), channel width and depth of 2mm and an electrode area of 5 cm2. This study is the first experimental approach to the use of indirect LS for making such fuel cell components.Mechanical Engineerin

Fractal Inspired Hybrid Microstrip Patch Antenna for Surveillance Drone Applications

          Drone based surveillance and communication systems are playing a vital role in modern days for both military and civilian applications. Antennas with low profile, smaller size, and light weight are essential for the realization of these systems. A novel fractal-inspired hybrid microstrip patch antenna realized with Sierpinski gasket fractal slots cut in the radiating patch along with corresponding ground structure simultaneously defected with Sierpinski carpet fractal slots is reported for the first time. The antenna resonates at 2.4 GHz with a measured return loss of 17 dB, gain of 7 dB and measured 3 dB beamwidth is of the order of 70 deg. The current approach leads to the size reduction of the antenna to the extent of 55% in comparison to standard radiating patch antenna resonating at the same frequency. The fractal-inspired hybrid microstrip patch antenna is a promising candidate for drone-based surveillance and communication applications owing to its miniaturization and good directional radiation properties

Preemptive Resume Priority Call Center Model with Two Classes of MAP Arrivals

Generally in call centers, voice calls (say Type 1 calls) are given higher priority over e-mails (say Type 2 calls). An arriving Type 1 call has a preemptive priority over a Type 2 call in service, if any, and the preempted Type 2 call enters into a retrial buffer (of finite capacity). Any arriving call not able to get into service immediately will enter into the pool of repeated calls provided the buffer is not full; otherwise, the call is considered lost. The calls in the retrial pool are treated alike (like Type 1) and compete for service after a random amount of time, and can preempt a Type 2 call in service. We assume that the two types of calls arrive according to a Markovian arrival process (MAP) and the services are offered with preemptive priority rule. Under the assumption that the service times are exponentially distributed with possibly different rates, we analyze the model using matrix-analytic methods. Illustrative numerical examples to bring out the qualitative aspects of the model under study are presented

Development of novel chemically-modified nucleic acid molecules for efficient inhibition of human MAPT gene expression

The hyperphosphorylation of the microtubule-associated protein tau (MAPT) has been implicated in various neurological diseases, including Alzheimer’s disease. It has been hypothesized that the reduction of MAPT would result in depolymerizing neurofibrillary tangles and could be a potential strategy for the treatment of Alzheimer’s disease and other tauopathies. In this study, we report the development of novel DNAzymes and splice-modulating antisense oligonucleotides (AOs) for the efficient inhibition of MAPT. We designed and synthesized a range of DNAzymes and 2ʹ-O-methyl (2’-OMe)-modified AOs on a phosphorothioate (PS) backbone targeting various exons across the MAPT gene transcript. Our results demonstrated that RNV563, an arm-loop-arm-type DNAzyme targeting exon 13, and an AO candidate AO4, targeting exon 4, efficiently downregulated MAPT RNA expression by 58% and 96%, respectively. In addition, AO4 also reduced the MAPT protein level by 74%. In line with our results, we believe that AO4 could be used as a potential therapeutic molecule for Alzheimer’s disease and other tauopathies

Aggregation of Key with Searchable Encryption for Group Data Sharing

Data sharing is an important functionality in cloud storage. In this article, we show how to securely, efficiently, and flexibly share data with others in cloud storage. We describe new public-key cryptosystems which produce constant-size ciphertexts such that efficient delegation of decryption rights for any set of ciphertexts are possible. The novelty is that one can aggregate any set of secret keys and make them as compact as a single key, but encompassing the power of all the keys being aggregated. In other words, the secret key holder can release a constant-size aggregate key for flexible choices of ciphertext set in cloud storage, but the other encrypted files outside the set remain confidential. This compact aggregate key can be conveniently sent to others or be stored in a smart card with very limited secure storage. We provide formal security analysis of our schemes in the standard model. We also describe other application of our schemes. In particular, our schemes give the first public-key patient-controlled encryption for flexible hierarchy, which was yet to be known

Management of Thrips, Scirtothrips dorsalis Hood, on Rose under Open-Field and Protected Conditions

Investigation on management of thrips, Scirtothrips dorsalis Hood on roses under open-field and protected conditions was conducted during 2008-10 at Bengaluru. Clothianidin 50 WDG 20g a.i./ha proved best in terms of efficacy and cost. Vertimac, spinosad and Garlic Barrier agriculture (GB Ag ) were comparable in efficacy. GB Ag was on par with clothianidin besides being eco-friendly. GB Ag was found effective as a new molecule. Neem seed kernel extract (NSKE) proved to be superior to neem oil, pongamia oil and the commercial neem product, Nimbecidine. NSKE was also found to reduce thrips density to the extent of 64% - 88%. In rose fields where pest suppression measures are hardly practised, farmers can apply NSKE, monocrotophos or imidacloprid. Based on the cost of vertimac and spinosad, these can be recommended where cost-effective, as in commercial polyhouses growing roses