Advances in Applying Computer-Aided Drug Design for Neurodegenerative Diseases

Neurodegenerative diseases (NDs) including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease are incurable and affect millions of people worldwide. The development of treatments for this unmet clinical need is a major global research challenge. Computer-aided drug design (CADD) methods minimize the huge number of ligands that could be screened in biological assays, reducing the cost, time, and effort required to develop new drugs. In this review, we provide an introduction to CADD and examine the progress in applying CADD and other molecular docking studies to NDs. We provide an updated overview of potential therapeutic targets for various NDs and discuss some of the advantages and disadvantages of these tools.     

Coupling granule properties and granulation rates in high-shear granulation

It is possible to link granulation rates to granule properties. The linkage is by multiple dimension population balance equations that, by means of simplifying assumptions, can be reduced to multiple one-dimensional (1-D) population balance equations (PBEs). Using simple physically based models, this paper demonstrates how multiple one-dimensional population balance equations can describe the results of high-shear granulation experiments of two different materials, calcium carbonate and lactose. Good agreement between experimental and simulated results was achieved enabling the granulation rates to be defined by two model parameters: the critical binder volume fraction and the aggregation rate constant. The modelling framework presented in this paper also provides a basis for the kinetic analysis of granulation experiments so that with further work, it is possible to determine the effect of process conditions and material properties on the model parameters.     

Non-uniformity of binder distribution in high-shear granulation

Further experimental investigation based on a microscopic, or single granule, scale has been conducted to investigate the uniformity of binder composition within a given size class for high shear melt granulation. This work assesses whether there is significant non-uniformity of binder composition within size classes to warrant considering this level of detail to improving population balance modelling of high shear granulation. It is concluded that at early times in a batch granulation process there is a broad variation in binder content between individual granules and that this variation persists in granules of small size.     

Purification, characterization, and high performance liquid chromatography assay of Salmonella glucose-1-phosphate cytidylyltransferase from the cloned rfbF gene

We report the purification and characterization of glucose-1-phosphate cytidylyltransferase, the first of five enzymes committed to biosynthesis of CDP-D-abequose from Salmonella enterica strain LT2. The purification was greatly facilitated by using a cloned rfbF gene encoding this enzyme. Pure enzyme was obtained by 64-fold enrichment in three chromatography steps. The NH2-terminal sequence of the purified enzyme was in agreement with the sequence predicted from the nucleotide sequence of the rfbF gene. The SDS-polyacrylamide gel electrophoresis estimated subunit M(r) of 31,000 agrees well with the M(r) of 29,035 calculated from the amino acid composition deduced from the nucleotide sequence of the rfbF gene. The glucose-1-phosphate cytidylyltransferase catalyzes a reversible bimolecular group transfer reaction and steady-state kinetic measurements, including product inhibition patterns, indicate that this reaction proceeds by a "ping-pong" type of mechanism. The Km values for CTP, alpha-D-glucose 1-phosphate, CDP-D-glucose, and pyrophosphate are 0.28, 0.64, 0.11, and 1.89 mM, respectively.     

A critique of the application of sensory integration therapy to children with learning disabilities

Sensory integration (SI) therapy is a controversial--though popular--treatment for the remediation of motor and academic problems. It has been applied primarily to children with learning disabilities, under the assumption that such children (or at least a subgroup of them) have problems in sensory integration to which some or all of their learning difficulties can be ascribed. The present article critically examines the related issues of whether children with learning disabilities differentially exhibit concomitant problems in sensory integration, and whether such children are helped in any way by means specific to SI therapy. An overview of theoretical contentions and empirical findings pertaining to the first issue is presented, followed by a detailed review of recent studies in the SI therapy research literature, in an effort to resolve the second issue. Results of this critique raise serious doubts as to the validity or utility of SI therapy as an appropriate, indicated treatment for the clinical population in question--and, by extension, for any other groups diagnosed as having "sensory integrative dysfunction." It is concluded that the current fund of research findings may well be sufficient to declare SI therapy not merely an unproven, but a demonstrably ineffective, primary or adjunctive remedial treatment for learning disabilities and other disorders.     

Prosthetic valve endocarditis: superiority of surgical valve replacement versus medical therapy only

The objective of our study was to assess the long-term outcome of patients with prosthetic valve endocarditis. We used a multicenter, prospective, observational study design. Six university teaching hospitals with high volume cardiothoracic surgery participated. Seventy-four patients with prosthetic valve endocarditis as defined by explicit, objective criteria were selected for participation. All patients were followed up prospectively for 1 year. Thirty-one percent and 69% had development of endocarditis within 60 days of valve insertion ("early") and after 60 days ("late"), respectively. The most common causes were Staphylococcus epidermidis (40%), Staphylococcus aureus (20%), streptococcal species (18%), and aerobic gram-negative bacilli (11%). Physical signs of endocarditis (new or changing murmur, stigmata, emboli) were seen in 58%. At 6 months and 12 months, mortality was 46% and 47%, respectively. Surgical replacement of the infected valve led to significantly lower mortality (23%) as compared with medical therapy alone (56%), as assessed by both univariate and multivariate analyses (p < 0.05). Improved outcome was seen for the surgical group even when controlling for severity of illness at time of diagnosis. From these findings we conclude that accurate assessment of outcome in prosthetic valve endocarditis requires long-term follow-up of at least 6 months following diagnosis. Surgical therapy warrants greater scrutiny; evaluation in controlled clinical trials is appropriate.     

Electromyographic and neuromuscular variables in post-polio subjects

OBJECTIVE: Post-polio subjects experience functional deterioration many years after developing acute poliomyelitis and have been shown previously to have a deficit in strength recovery after isometric activity. This study characterized the size and stability of the motor units in a group of post-polio subjects with macro and single fiber electromyography (EMG) and correlated these variables with isometric strength, endurance, "work capacity," and strength recovery after fatiguing isometric exercise. DESIGN: A cohort of 12 post-polio subjects was tested for neuromuscular function. Electromyographic variables were determined on a separate day. SETTING: Volunteers were recruited from the community and tested in our neuromuscular research laboratory. SUBJECTS: A volunteer sample was obtained from advertisements. All subjects acknowledged post-polio syndrome symptoms. MAIN OUTCOME MEASURES: Neuromuscular variables were isometric knee extension peak torque, endurance (time to exhaustion) at 40% of maximal torque, tension time index, and recovery of torque at 10 minutes. Electromyographic variables were macro EMG and single fiber EMG (percent blocking and jitter). RESULTS: Macro EMG amplitude was ninefold the control value, and both jitter and blocking were greatly increased in comparison to control values. Isometric strength significantly (p < .05) correlated negatively with macro EMG amplitude. CONCLUSIONS: The weakest subjects had the greatest number of muscle fibers within the motor unit (as measured by macro EMG amplitude). Jitter and blocking did not correlate with neuromuscular function.     

Quantum Inspired Broadband Photonic Absorber: Potential Application as Solar Sail along with Mobility Analysis

Electromagnetic wideband absorption is still perceived as a critical and formidable challenge to address with an unambiguous photonic absorber. Subwavelength metamaterial (MM) unit cells with unique and controlled features have recently gained considerable interest. However, meta-atoms, generated using a quantum-inspired pattern distribution, are underwhelming in existing literature to design photonic absorbers and their potential application to manufacture solar sails is still quite uncommon. In this article, to create a flexible, polarization-insensitive, ultrathin, and broadband MM absorber, quantum interference pattern-inspired design is utilized. Herein, a novel approach to fabricating solar sails for the space exploration incorporates the proposed broadband photonic absorber rather than conventional reflectors. The quantum-inspired meta-absorber (QIMA) exhibits an absorption of over 91% for the visible domain, i.e., 380–800 nm under a conventional plane-polarized source. It is shown in the study that broadband absorbers are almost equivalent to excellent reflectors to design the solar sails in terms of the time-averaged force calculated by utilizing the Maxwell stress tensor method. Thus, the QIMA has the potential to be a viable alternative to reflectors in the design of futuristic solar sails for space exploration. The interference theory model is also utilized to assure the dependability of calculated data, and additionally, the standard AM1.5 solar spectrum is utilized to demonstrate the QIMA's solar-harvesting potentiality.     

Efficient Body-Transfer Wheelchair for Assisting Functionally ImpairedPeople

Functionally impaired people always have difficulty accomplishing activities of daily living. In this regard, tasks including toileting and bathing have a higher prevalence rate of injuries and greater risk of falling. In this study, a body-transfer wheelchair was developed to assist people in transferring from bed to wheelchair for bathing, and toileting. The body-transfer wheelchair is a semi-automatic wheelchair that has features such as a controlled leg and backrest, linkage commode slot, and height adjustment. The wheelchair consists of a seat and a main frame that can be detached to enable bathtub transfer. This mechanism lets the user stay on the seat while being transferred into the bathtub without any risk of falling. A linkage mechanism was developed as a part of the seat for ease of toileting. Kinematic and force analysis was conducted to calculate the force required for each actuator. It has been proved by the experimental results that the wheelchair can securely and comfortably transfer a patient from the bed to the toilet or bathtub. A survey has been conducted to evaluate the wheelchair prototype design idea. Two focus groups were chosen: one comprised of functionally impaired people, and the other comprised of caregivers. The results of the survey show that 60% of both functionally impaired people and caregivers would like to use the body-transfer wheelchair for toileting and bathing purpose. Additionally, on average 65% of both focus groups find it convenient to operate the body-transfer wheelchair independently.