Shorter and Improved Access to the Key Tetracyclic Core of Sarpagine-Macroline-Ajmaline Indole Alkaloids: the Total Synthesis of Alkaloids Macrocarpines A-g, Talcarpine, N(4)-methyl-n(4),21-secotalpinine, Deoxyperaksine, Dihydroperaksine, Talpinine, O-acetyltalpinine, and N(4)-methyltalpinine

Extension of the asymmetric Pictet-Spengler (P-S) reaction to bulkier Nb-alkylated tryptophan derivatives resulted in a shorter and improved stereospecific access to the key bicyclo[3.3.1]nonane framework of bioactive C-19 methyl substituted sarpagine/macro-line/ajmaline indole alkaloids with excellent diastereoselectivity via internal asymmetric induction. The asymmetric Pictet-Spengler/Dieckmann protocol with bulky Nb-alkyl substituted systems enabled a more direct and two-step shorter route to this key architecture. Complete stereocontrol of the C-19 methyl function in either the α- or β-configuration was achieved which would enable one to gain rapid access to the crucial intermediates for the total synthesis of any member of this group of seventy alkaloids. The asymmetric Pictet-Spengler (P-S) reaction of chiral Nb-ethynyl substituted tryptophan methyl ester derivatives (from both D- and L-tryptophan) with a simple aliphatic aldehyde, exhibited unprecedented stereoselectivity toward either of the diastereomeric products. A simple variation of conditions altered the outcome of the cyclization from either 100% trans-selective to 100% cis-selective originating entirely from internal asymmetric induction under mild conditions. This resulted in the highly efficient access to both 1,3-cis-(1,2,3-trisubstituted tetrahydro-β-carbolines, THβCs) and 1,3-trans-(1,2,3-trisubstituted THβCs). By exploiting this very useful ambidextrous-diastereoselectivity, one can set the crucial C-3 and C-5 stereocenters of the C-19 methyl substituted sarpagine-macroline-ajmaline alkaloids beginning either with the DNA-encoded and cheaper L-(-)-tryptophan, as well as optionally from commercially available D-(+)-tryptophan. The unnatural enantiomers of bioactive natural alkaloids are potential drug candidates. The unnatural enantiomer of alkaloids may have similar drug-like properties or even better than the natural counterpart depending on the rate of metabolism. The ambidextrous Pictet-Spengler reaction has enabled one to access the key intermediates with the bicyclo[3.3.1] framework starting from either the natural L-tryptophan or the commercially available D-tryptophan. Logically, the ambidextrous nature of this P-S process would allow one ready access to the unnatural enantiomers of the alkaloids from this subgroup. As the proof of concept, which is important to illustrate the full potential of the ambidextrous P-S reaction, both D-tryptophan and L-tryptophan were employed to synthesize the key intermediates toward the natural enantiomers of alkaloids. Now the enantiomeric series of the same key intermediates could also be synthesized from both D- and L-tryptophan in high yield and optical purity via this P-S/Dieckmann protocol. One can make either the natural or the unnatural alkaloids from either starting amino acid ester, stereo and enantiospecifically at will. After gaining access to the bicyclo[3.3.1] framework via the ambidextrous Pictet-Spengler reaction, the focus turned to the completion of the total synthesis of a number of C-19 methyl substituted sarpagine/macroline/ajmaline indole alkaloids. As a step towards that, alkaloids with Na-H, Nb-CH3 substitution patterns were both of interest via the same route. An enolate driven copper-mediated cross-coupling process enabled a cheaper and greener access to the key pentacyclic intermediates required for the enantiospecific total synthesis of a number of C-19 methyl substituted sarpagine/macroline indole alkaloids. Replacement of palladium (60-68% yields) with copper iodide (82-89% yields) resulted in a much cleaner process in high yield. The formation of an unusual seven-membered cross-coupling product was completely inhibited by using TEMPO as a radical scavenger. Further functionalization led to the first enantiospecific total synthesis of macrocarpines D and E. After the successful completion of the total synthesis of several C(19)-methyl Na-H, Nb-CH3 substituted alkaloids, focus turned toward the total synthesis of a number of alkaloids bearing the Na-CH3, Nb-CH3 substitution pattern. In addition, a pair of sarpagine alkaloids, termed dihydroperaksine and deoxyperaksine bore the C-19 (S)-methyl substitution; this was opposite to the chirality in many of the alkaloids of this group. Access to these alkaloids in high yields illustrated the versatility of the strategy developed here to access alkaloids with either C-19 (S)- or (R)-methyl substituents. This effort resulted in the successful total synthesis of several bioactive alkaloids, as well as correction of the literature values for macrocarpine A and N4-methyl-N4,21-secotalpinine. A late stage Nb-demethylation of macrocarpines A and C afforded the Nb-H bearing alkaloids macrocarpines F and G, respectively. A similar transformation enabled access to the bioactive alkaloid talpinine from both talcarpine and N4-methyl-N4,21-secotalpinine. The other bioactive alkaloid O-acetyltalpinine was also prepared from synthetic talpinine in high yield. Finally, the unusual quaternary Nb-nitrogen function containing alkaloid N4-methyltalpinine that exhibited potent NFκB inhibitory activity was completed via facile transformations in excellent yield

EMG Signal Classification for Neuromuscular Disorders with Attention-Enhanced CNN

Amyotrophic Lateral Sclerosis (ALS) and Myopathy present considerable challenges in the realm of neuromuscular disorder diagnostics. In this study, we employ advanced deep-learning techniques to address the detection of ALS and Myopathy, two debilitating conditions. Our methodology begins with the extraction of informative features from raw electromyography (EMG) signals, leveraging the Log-spectrum, and Delta Log spectrum, which capture the frequency contents, and spectral and temporal characteristics of the signals. Subsequently, we applied a deep-learning model, SpectroEMG-Net, combined with Convolutional Neural Networks (CNNs) and Attention for the classification of three classes. The robustness of our approach is rigorously evaluated, demonstrating its remarkable performance in distinguishing among the classes: Myopathy, Normal, and ALS, with an outstanding overall accuracy of 92\%. This study marks a contribution to addressing the diagnostic challenges posed by neuromuscular disorders through a data-driven, multi-class classification approach, providing valuable insights into the potential for early and accurate detection

ResEMGNet: A Lightweight Residual Deep Learning Architecture for Neuromuscular Disorder Detection from Raw EMG Signals

Amyotrophic Lateral Sclerosis (ALS) and Myopathy are debilitating neuromuscular disorders that demand accurate and efficient diagnostic approaches. In this study, we harness the power of deep learning techniques to detect ALS and Myopathy. Convolutional Neural Networks (CNNs) have emerged as powerful tools in this context. We present ResEMGNet, designed to identify ALS and Myopathy directly from raw electromyography (EMG) signals. Unlike traditional methods that require intricate handcrafted feature extraction, ResEMGNet takes raw EMG data as input, reducing computational complexity and enhancing practicality. Our approach was rigorously evaluated using various metrics in comparison to existing methods. ResEMGNet exhibited exceptional subject-independent performance, achieving an impressive overall three-class accuracy of 94.43\%

Simultaneous Detection and Estimation of Catechol, Hydroquinone, and Resorcinol in Binary and Ternary Mixtures Using Electrochemical Techniques

Cyclic voltammetry (CV) and differential pulse voltammetry (DPV) were performed with a glassy carbon electrode (GCE) modified with polyglutamic acid (PGA) on the three dihydroxybenzene isomers, catechol (CT), hydroquinone (HQ), and resorcinol (RS). At bare GCE, these isomers exhibited voltammograms with highly overlapped redox peaks that impeded their simultaneous detection in binary and ternary mixtures. On the contrary, at PGA modified GCE binary and ternary mixtures of the dihydroxybenzene isomers showed well-resolved redox peaks in both CV and DPV experiments. This resolving ability of PGA modified GCE proves its potential to be exploited as an electrochemical sensor for the simultaneous detection of these isomers

A CNN based Multifaceted Signal Processing Framework for Heart Rate Proctoring Using Millimeter Wave Radar Ballistocardiography

The recent pandemic has refocused the medical world's attention on the diagnostic techniques associated with cardiovascular disease. Heart rate provides a real-time snapshot of cardiovascular health. A more precise heart rate reading provides a better understanding of cardiac muscle activity. Although many existing diagnostic techniques are approaching the limits of perfection, there remains potential for further development. In this paper, we propose MIBINET, a convolutional neural network for real-time proctoring of heart rate via inter-beat-interval (IBI) from millimeter wave (mm-wave) radar ballistocardiography signals. This network can be used in hospitals, homes, and passenger vehicles due to its lightweight and contactless properties. It employs classical signal processing prior to fitting the data into the network. Although MIBINET is primarily designed to work on mm-wave signals, it is found equally effective on signals of various modalities such as PCG, ECG, and PPG. Extensive experimental results and a thorough comparison with the current state-of-the-art on mm-wave signals demonstrate the viability and versatility of the proposed methodology. Keywords: Cardiovascular disease, contactless measurement, heart rate, IBI, mm-wave radar, neural networkComment: 13 pages, 10 figures, Submitted to Elsevier's Array Journa

The influence of different ethnicity in Malaysia on parental preference towards behaviour management techniques in paediatric dentistry

Uncooperative or disruptive behaviour can interfere with quality of care, increase the length of treatment time and increase risk of injury to the child. The challenge of treating children who are unable or unwilling to cooperate has led to the development of a variety of behaviour management techniques. The aim of this study is to assess the parental acceptance of different behaviour management techniques (BMT) used during dental treatment of children in three major ethnic group (Malay, Indian and Chinese) of Malaysia. This was a cross-sectional comparative study involving convenient sampling method, using a sample of 72 parents attending Paediatric Dentistry Clinic, Hospital USM and Klinik Pergigian UKM, Universiti Kebangsaan Malaysia. A videotape presentation was produced to demonstrate ten of the AAPD approved BMTs to the selected parents in the following order: TSD, VC, Modelling, PR, Distraction, PP/A, HOM, NO, OS and GA. Statistical analyses was done for descriptive statistics such as mean values, standard deviations, standard errors and coefficients of variation were measured. Multiple comparisons were done by One Way Anova with Post-Hoc analysis and Fisher Extract test. Among 72 parents, 43 were males and 29 were female parents. With respect to ethnicity Malay (50%) were more when compared to Chinese (25%) and Indian (25%). However, parents with college degree (48.6%) was found to be more with income range 2001-5000 RM (55.6%).Further, a higher mean was reported in tell-show-do (93.47±14.26) method of behaviour management technique, followed by audio-visual (81.94±18.05), parental presence/absence (73.89±22.62). There was no statistically significant difference among all the independent ethnic groups with p-value > 0.05 except modelling technique which showed a significant difference with p-value 0.047. There was statistically significant difference between three groups when compared to modelling BMT. Post Hoc Analysis with multiple comparisons by Bonferroni, only comparison between Chinese and Indian shown statistically significant mean difference (p- Value=0.047). We conclude that tell-show-do, distraction, modelling, parental presence/ absence has been shown to produce similarly acceptable results amongst Malaysian parents with statistically insignificant differences in the amount of approval given for the techniques. Physical restraint, oral sedation and general anesthesia were the least approved in the current study

Completion of the Total Synthesis of Several Bioactive Sarpagine/Macroline Alkaloids including the Important NF-κB Inhibitor N4-Methyltalpinine

The unification of the general synthetic strategy regarding the important and emerging group of C-19 methyl-substituted sarpagine/macroline alkaloids has culminated in the completion of the total synthesis of several bioactive alkaloids. Key transformations include an ACE-Cl mediated late-stage N(4)-demethylation and an anhydrous acid-mediated intramolecular quaternary hemiaminal formation between a tertiary amine and an aldehyde function to allow efficient access to several biologically important alkaloids from this group. Herein, the enantiospecific total synthesis of the first known sarpagine/macroline alkaloid with NF-κB inhibitory activity, N(4)-methyltalpinine (as a chloride salt), as well as the anticancer alkaloids talpinine, O-acetyltalpinine, and macrocarpines F–G, are described