Role and application of CRISPR-Cas9 in the management of Alzheimer's disease.

Alzheimer's disease (AD) is a serious health issue that has a significant social and economic impact worldwide. One of the key aetiological signs of the disease is a gradual reduction in cognitive function and irreversible neuronal death. According to a 2019 global report, more than 5.8 million people in the United States (USA) alone have received an AD diagnosis, with 45% of those people falling into the 75-84 years age range. According to the predictions, there will be 15 million affected people in the USA by 2050 due to the disease's steadily rising patient population. Cognitive function and memory formation steadily decline as a result of an irreversible neuron loss in AD, a chronic neurodegenerative illness. Amyloid-beta and phosphorylated Tau are produced and accumulate in large amounts, and glial cells are overactive. Additionally, weakened neurotrophin signalling and decreased synapse function are crucial aspects of AD. Memory loss, apathy, depression, and irritability are among the primary symptoms. The aetiology, pathophysiology, and causes of both cognitive decline and synaptic dysfunction are poorly understood despite extensive investigation. CRISPR/Cas9 is a promising gene-editing technique since it can fix certain gene sequences and has a lot of potential for treating AD and other human disorders. Regardless of hereditary considerations, an altered Aß metabolism is frequently seen in familial and sporadic AD. Therefore, since mutations in the PSEN-1, PSEN-2 and APP genes are a contributing factor to familial AD, CRISPR/Cas9 technology could address excessive Aß production or mutations in these genes. Overall, the potential of CRISPR-Cas9 technology outweighs it as currently the greatest gene-editing tool available for researching neurodegenerative diseases like AD.

Weak electronic correlations observed in magnetic Weyl Semimetal Mn3Ge.

Using angle-resolved photoemission spectroscopy (ARPES) and density functional theory (DFT) calculations, we systematically studied the electronic band structure of Mn3Ge in the vicinity of the Fermi level. We observe several bands crossing the Fermi level, confirming the metallic nature of the studied system. We further observe several flat bands along various high symmetry directions, consistent with the DFT calculations. The calculated partial density of states suggests a dominant Mn 3dorbital contribution to the total valence band DOS. With the help of orbital-resolved band structure calculations, we qualitatively identify the orbital information of the experimentally obtained band dispersions. Out-of-plane electronic band dispersions are explored by measuring the ARPES data at various photon energies. Importantly, our study suggests relatively weaker electronic correlations in Mn3Ge compared to Mn3Sn.

Charting the Progress of Epilepsy Classification: Navigating a Shifting Landscape.

Epilepsy, a neurological disorder characterized by recurrent seizures, has witnessed a remarkable transformation in its classification paradigm, driven by advances in clinical understanding, neuroimaging, and molecular genetics. This narrative review navigates the dynamic landscape of epilepsy classification, offering insights into recent developments, challenges, and the promising horizon. Historically, epilepsy classification relied heavily on clinical observations, categorizing seizures based on their phenomenology and presumed etiology. However, the field has profoundly shifted from a symptom-based approach to a more refined, multidimensional system. One pivotal aspect of this evolution is the integration of neuroimaging techniques, particularly magnetic resonance imaging (MRI) and functional imaging modalities. These tools have unveiled the intricate neural networks implicated in epilepsy, facilitating the identification of distinct brain abnormalities and the categorization of epilepsy subtypes based on structural and functional findings. Furthermore, the role of genetics has become increasingly prominent in epilepsy classification. Genetic discoveries have not only unraveled the molecular underpinnings of various epileptic syndromes but have also provided valuable diagnostic and prognostic insights. This narrative review delves into the expanding realm of genetic testing and its impact on tailoring treatment strategies to individual patients. As the classification landscape evolves, there are accompanying challenges. The narrative review underscores the transformative potential of artificial intelligence and machine learning in epilepsy classification. These technologies hold promise in automating the analysis of complex neuroimaging and genetic data, offering enhanced accuracy and efficiency in epilepsy diagnosis and classification. In conclusion, navigating the shifting landscape of epilepsy classification is a journey marked by progress, complexity, and the prospect of improved patient care. We are charting a course toward more precise diagnoses and tailored treatments by embracing advanced neuroimaging, genetics, and innovative technologies. As the field continues to evolve, collaborative efforts and a holistic understanding of epilepsy's diverse manifestations will be instrumental in harnessing the full potential of this dynamic landscape.

Individualizing Medicinal Therapy Post Heart Stent Implantation: Tailoring for Patient Factors.

The field of cardiovascular medicine is undergoing a transformative shift towards personalized medicinal therapy, particularly in the context of post stent implantation. This narrative review explores the significance, challenges, and future directions of individualized treatment strategies for patients with coronary stents. The review highlights the pivotal role of personalized approaches in optimizing treatment efficacy and minimizing adverse events. Real-world clinical studies and trials underscore the importance of tailoring antiplatelet therapy based on platelet function testing, genetic testing, and risk scoring. These studies reveal that personalized medicinal treatment improves clinical outcomes by balancing preventing thrombotic events and mitigating bleeding risks. Challenges, including cost, test availability, patient adherence, and ethical considerations, are discussed in depth, shedding light on the complexities of implementing personalized approaches. Technological advancements, including omics data integration, artificial intelligence, and big data analytics, shape the future of personalized medicinal therapy. These tools enable precise pharmacogenomic selection of medications and the development of integrated risk-scoring systems. Patient engagement and education are also central, with empowered patients and remote monitoring contributing to collaborative decision-making. In conclusion, the narrative review underscores that personalized medicinal therapy post stent implantation holds immense promise for revolutionizing cardiovascular care. By embracing a comprehensive approach that considers genetics, clinical factors, and patient preferences, healthcare providers can optimize treatment outcomes and improve patient quality of life. The evolving landscape of personalized medicine offers a glimpse into a future where tailored treatment strategies become the cornerstone of precision cardiovascular care.

Biosimilar strategic implementation at a large health system.

PURPOSE: This article highlights one health system's response to the market influx of biosimilars with the establishment of a process for formulary review and selection of preferred agents and support for therapeutic interchanges. SUMMARY: Through assessment of available literature, insurance payor coverage, and manufacturer-anticipated approvals of biosimilars, a strategic stance was developed to guide biosimilar order preparation, review, adoption, and implementation. The electronic medical record (EMR) is prepared for biosimilar implementation at least 6 to 12 months ahead of anticipated formulary review. The review includes assessment of a class (reference product and available biosimilars) after at least 2 biosimilars become available. Key health-system departments and clinicians are enlisted to support review of clinical, safety, and economic implications. Implementation of a preferred product relies on standard education, formulary availability, and staff awareness to address any perceived patient safety concerns and gather provider support. The standard steps developed now apply to all future biosimilar reviews, adoption plans, and ongoing monitoring. Barriers evaluated include changes in payor coverage and challenges in preparation of the EMR for future biosimilars, meeting precertification team education needs, and providing operational support for pharmacy inventory. CONCLUSION: To date, use of 5 preferred biosimilar products has led to significant cost savings to the institution, and the process has been endorsed by providers. The institution's successes can be attributed to clear communication with stakeholders and the development of a deliberate process, led by a multidisciplinary leadership team, for managing formulary, safety, and operational barriers in a thoughtful and systematic manner.

Control of a quadrotor with network induced time delay.

A backstepping controller augmented with a state predictor is proposed to control a quadrotor over a network subjected to both state and input time delay. The state predictor predicts the future values of the states by taking the measured delayed states as input. A backstepping control law is further designed based on these predicted states. It is shown with the aid of the Lyapunov-Razumikhin theorem that the error dynamics of the predictor is asymptotically stable. The cascade of state predictor and backstepping controller makes the tracking error dynamics of the quadrotor asymptotically stable. Simulation results are presented to validate the proposed approach.

Multiple Sclerosis Disease-Modifying Therapy and the COVID-19 Pandemic: Implications on the Risk of Infection and Future Vaccination.

The coronavirus 2019 (COVID-19) pandemic is expected to linger. Decisions regarding initiation or continuation of disease-modifying therapy for multiple sclerosis have to consider the potential relevance to the pandemic. Understanding the mechanism of action and the possible idiosyncratic effects of each therapeutic agent on the immune system is imperative during this special time. The infectious side-effect profile as well as the route and frequency of administration of each therapeutic agent should be carefully considered when selecting a new treatment or deciding on risk mitigation strategies for existing therapy. More importantly, the impact of each agent on the future severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2) vaccine should be carefully considered in treatment decisions. Moreover, some multiple sclerosis therapies may have beneficial antiviral effects against SARS-CoV-2 while others may have beneficial immune-modulating effects against the cytokine storm and hyperinflammatory phase of the disease. Conventional injectables have a favorable immune profile without an increased exposure risk and therefore may be suitable for mild multiple sclerosis during the pandemic. However, moderate and highly active multiple sclerosis will continue to require treatment with oral or intravenous high-potency agents but a number of risk mitigation strategies may have to be implemented. Immune-modulating therapies such as the fumerates, sphinogosine-1P modulators, and natalizumab may be anecdotally preferred over cell-depleting immunosuppressants during the pandemic from the immune profile standpoint. Within the cell-depleting agents, selective (ocrelizumab) or preferential (cladribine) depletion of B cells may be relatively safer than non-selective depletion of lymphocytes and innate immune cells (alemtuzumab). Patients who develop severe iatrogenic or idiosyncratic lymphopenia should be advised to maintain social distancing even in areas where lockdown has been removed or ameliorated. Patients with iatrogenic hypogammaglobulinemia may require prophylactic intravenous immunoglobulin therapy in certain situations. When the future SARS-CoV-2 vaccine becomes available, patients with multiple sclerosis should be advised that certain therapies may interfere with mounting a protective immune response to the vaccine and that serological confirmation of a response may be required after vaccination. They should also be aware that most multiple sclerosis therapies are incompatible with live vaccines if a live SARS-CoV-2 vaccine is developed. In this article, we review and compare disease-modifying therapies in terms of their effect on the immune system, published infection rates, potential impact on SARS-CoV-2 susceptibility, and vaccine-related implications. We propose risk mitigation strategies and practical approaches to disease-modifying therapy during the COVID-19 pandemic.

Current and emerging therapeutics for neuromyelitis optica spectrum disorder: Relevance to the COVID-19 pandemic.

Neuromyelitis optica spectrum disorder (NMOSD) can lead to immobility and bulbar weakness. This, in addition to the older age of onset and the higher rate of hospitalization compared to multiple sclerosis, makes this patient group a potential target for complicated COVID-19 infection. Moreover, many of the commonly used preventive therapies for NMOSD are cell-depleting immunouppsressants with increased risk of viral and bacterial infections. The emergence of several new NMOSD therapeutics, including immune-modulating agents, concurrently with the worldwide spread of the COVID-19 global pandemic call for careful therapeutic planning and add to the complexity of NMOSD management. Altering the common therapeutic approach to NMOSD during the pandemic may be necessary to balance both efficacy and safety of treatment. Selection of preventive therapy should take in consideration the viral exposure risk related to the route and frequency of administration and, most importantly, the immunological properties of each therapeutic agent and its potential impact on the risk of SARS-CoV-2 susceptibility and severity of infection. The impact of the therapeutic agent on the immune response against the future SARS-CoV-2 vaccine should also be considered in the clinical decision-making. In this review, we will discuss the immune response against SARS-CoV-2 and evaluate the potential impact of the current and emerging NMOSD therapeutics on infection risk, infection severity, and future SARS-CoV-2 vaccination. We propose a therapeutic approach to NMOSD during the COVID-19 pandemic based on analysis of the mechanism of action, route of administration, and side effect profile of each therapeutic agent.

Controller design for a class of nonlinear MIMO coupled system using multiple models and second level adaptation.

In this paper, an adaptive control method using multiple models with second level adaptation is proposed for a class of nonlinear multi-input multi-output (MIMO) coupled systems. Multiple estimation models are used to tune the unknown parameters at the first level. The second level adaptation provides a single parameter vector for the controller. A feedback linearization technique is used to design a state feedback control. The efficacy of the designed controller is validated by conducting real time experiment on a laboratory setup of twin rotor MIMO system (TRMS). The TRMS setup is discussed in detail and the experiments were performed for regulation and tracking problem for pitch and yaw control using different reference signals. An Extended Kalman Filter (EKF) has been used to observe the unavailable states of the TRMS.

Effect of seven Indian plant extracts on Fenton reaction-mediated damage to DNA constituents.

The influences of substoichiometric amounts of seven plant extracts in the Fenton reaction-mediated damage to deoxynucleosides, deoxynucleoside monophosphates, deoxynucleoside triphosphates, and supercoiled plasmid DNA were studied to rationalize anticancer properties reported in some of these extracts. Extracts from Acacia catechu, Emblica officinalis, Spondias dulcis, Terminalia belerica, Terminalia chebula, as well as gallic acid, epicatechin, chebulagic acid and chebulinic acid enhance the extent of damage in Fenton reactions with all monomeric substrates but protect supercoiled plasmid DNA, compared to standard Fenton reactions. The damage to pyrimidine nucleosides/nucleotides is enhanced by these extracts and compounds to a greater extent than for purine ones in a concentration dependent manner. Dolichos biflorus and Hemidesmus indicus extracts generally do not show this enhancement for the monomeric substrates though they protect plasmid DNA. Compared to standard Fenton reactions for deoxynucleosides with ethanol, the presence of these five plant extracts render ethanol scavenging less effective as the radical is generated in the vicinity of the target. Since substoichiometric amounts of these extracts and the four compounds produce this effect, a catalytic mechanism involving the presence of a ternary complex of the nucleoside/nucleotide substrate, a plant compound and the hydroxyl radical is proposed. Such a mechanism cannot operate for plasmid DNA as the planar rings in the extract compounds cannot stack with the duplex DNA bases. These plant extracts, by enhancing Fenton reaction-mediated damage to deoxynucleoside triphosphates, slow down DNA replication in rapidly dividing cancer cells, thus contributing to their anticancer properties.

Deoxyadenosine family: improved synthesis, DNA damage and repair, analogs as drugs.

Improved synthesis of 2'-deoxyadenosine using Escherichia coli overexpressing some enzymes and gram-scale chemical synthesis of 2'-deoxynucleoside 5'-triphosphates reported recently are described in this review. Other topics include DNA damage induced by chromium(VI), Fenton chemistry, photoinduction with lumazine, or by ultrasound in neutral solution; 8,5'-cyclo-2'-deoxyadenosine isomers as potential biomarkers; and a recapitulation of purine 5',8-cyclonucleoside studies. The mutagenicities of some products generated by oxidizing 2'-deoxyadenosine 5'-triphosphate, nucleotide pool sanitization, and translesion synthesis are also reviewed. Characterizing cross-linking between nucleosides in opposite strands of DNA and endonuclease V-mediated deoxyinosine excision repair are discussed. The use of purine nucleoside analogs in the treatment of rarer chronic lymphoid leukemias is reviewed. Some analogs at the C8 position induced delayed polymerization arrest during HIV-1 reverse transcription. The susceptibility of clinically metronidazole-resistant Trichomonas vaginalis to two analogs, toyocamycin and 2-fluoro-2'-deoxyadenosine, were tested in vitro. GS-9148, a dAMP analog, was translocated to the priming site in a complex with reverse transcriptase and double-stranded DNA to gain insight into the mechanism of reverse transcriptase inhibition.

Variable-gain controllers for nonlinear systems using the T-S fuzzy model.

This correspondence proposes two novel control schemes with variable state-feedback gain to stabilize a Takagi-Sugeno (T-S) fuzzy system. The T-S fuzzy model is expressed as a linear plant with nonlinear disturbance terms in both schemes. In controller I, the T-S fuzzy model is expressed as a linear plant around a nominal plant arbitrarily selected from the set of linear subsystems that the T-S fuzzy model consists of. The variable gain then becomes a function of a gain parameter that is computed to neutralize the effect of disturbance term, which is, in essence, the deviation of the actual system dynamics from the nominal plant as the system traverses a specific trajectory. This controller is shown to stabilize the T-S fuzzy model. In controller II, individual linear subsystems are locally stabilized. Fuzzy blending of individual control actions is shown to make the T-S fuzzy system Lyapunov stable. Although applicability of both control schemes depends on the norm bound of unmatched state disturbance, this constraint is relaxed further in controller II. The efficacy of controllers I and II has been tested on two nonlinear systems.