DETECTION OF ARTIAL FIBRILLATION DISORDER BY ECG USING DISCRETE WAVELET TRANSFORMS

Atrial fibrillation (A-fib) is the most common cardiac disorder. To efficiently treat or inhibit, an automatic detection based on electrocardiograph (ECG)monitoring is significantly required. ECG is a key function in the analysis of the heart functioning and diagnostic of diseases. Currently, a computer basedsystem is used to analyze the ECG signal. The main aim of this project is to analyze a heart malfunctions named as A-fib, using discrete wavelet transforms(DWT). The ECG signals were decomposed into time-frequency representations using DWT, and the statistical features were calculated to describe theirdistribution. The DWT detailed coefficients are used to obtain various parameters of the ECG signal such as the mean, variance, standard deviation, andentropy of the signal. An analysis had been made with these parameters of various patients with normal heart functioning and A-fib to identify the disorder.Keywords: Atrial fibrillation, Electrocardiogram, Discrete wavelet transforms

Clustering of Marine Oil-Spill Extent Using Sentinel-1 Dual Polarimetric Scattering Spectrum

Oil spills pose a significant threat to the maritime ecosystem. Identifying an oil spill is vital to assess its spread and drift to nearby coastal areas. Synthetic aperture radar (SAR) sensors are viable for mapping and monitoring marine oil spills. This study proposes a new technique that utilizes the dual-polarimetric Sentinel-1 SAR data. The method is based on projecting the 2 × 2 covariance matrix onto distinct random realizations of the normalized scattering configuration. We then obtain the dual-polarimetric spectrum of the scattering-type parameter, θDP. The θDP spectrum is then used in the unsupervised K-means clustering technique to segment oil spills from the rest. The cluster findings are then compared to the accuracies obtained using the standard scattering-type parameters from the eigen-decomposition approach (VV, VH) intensities and Otsu thresholding of [H + α + A] parameter. We demonstrate the proposed approach by clustering marine oil-spill extent over parts of India, Kuwait, the UAE, and the Mediterranean Sea obtained by Sentinel-1 SAR images. We observed that the clustering accuracy of the proposed technique outperforms the ones obtained from the channel (i.e., VV and VH) intensities, Otsu thresholding of [H + α + A] parameter, and the eigen-decomposition-based method. The proposed approach improves the overall accuracy by ≈8% and ≈20%, respectively, over different study areas

Chemical pulldown combined with mass spectrometry to identify the molecular targets of antimalarials in cell-free lysates

Here, we provide a protocol using chemical pulldown combined with mass spectrometry (LC-MS/MS) to identify drug targets in Plasmodium falciparum. This approach works upon the principle that a resin-bound inhibitor selectively binds its molecular target(s) in cell-free lysates. We describe the preparation of drug beads and P. falciparum lysate, followed by chemical pulldown, sample fractionation, and LC-MS/MS analysis. We then detail how to identify specifically bound proteins by comparing protein enrichment in DMSO-treated relative to drug-treated lysates via quantitative proteomics. For complete details on the use and execution of this protocol, please refer to Milne et al. (2022).(1

ResMAP – a saturation mutagenesis platform enabling parallel profiling of target-specific resistance conferring mutations in <i>Plasmodium</i>

New and improved drugs are required for the treatment and ultimate eradication of malaria. The efficacy of front-line therapies is now threatened by emerging drug resistance, thus new tools to support the development of drugs with a lower propensity for resistance are needed. Here, we describe the development of a resistance mapping and profiling (ResMAP) platform for the identification of resistance-conferring mutations in Plasmodium drug targets. Proof-of-concept studies focused on interrogating the antimalarial drug target, P. falciparum lysyl tRNA synthetase (PfKRS). Saturation mutagenesis was used to construct a plasmid library encoding all conceivable mutations within a 20 residue span at the base of the PfKRS ATP binding pocket. The superior transfection efficiency of P. knowlesi was exploited to generate a high coverage parasite library expressing PfKRS bearing all possible amino acid changes within this region of the enzyme. Selection of the library with PfKRS inhibitors, cladosporin and DDD01510706, successfully identified multiple resistance-conferring substitutions. Genetic validation of a subset of these mutations confirmed their direct role in resistance, with computational modelling used to dissect the structural basis of resistance. The application of ResMAP to inform the development of resistance-resilient antimalarials of the future is discussed

Sterol 14-alpha demethylase (CYP51) activity in Leishmania donovani is likely dependent upon cytochrome P450 reductase 1

Liposomal amphotericin B is an important frontline drug for the treatment of visceral leishmaniasis, a neglected disease of poverty. The mechanism of action of amphotericin B (AmB) is thought to involve interaction with ergosterol and other ergostane sterols, resulting in disruption of the integrity and key functions of the plasma membrane. Emergence of clinically refractory isolates of L. donovani and L. infantum is an ongoing issue and knowledge of potential resistance mechanisms can help to alleviate this problem. Here we report the characterisation of four independently selected L. donovani clones that are resistant to AmB. Whole genome sequencing revealed that in three of the moderately resistant clones, resistance was due solely to the deletion of a gene encoding C24-sterol methyltransferase (SMT1). The fourth, hyper-resistant resistant clone (&gt;60-fold) was found to have a 24 bp deletion in both alleles of a gene encoding a putative cytochrome P450 reductase (P450R1). Metabolic profiling indicated these parasites were virtually devoid of ergosterol (0.2% versus 18% of total sterols in wild-type) and had a marked accumulation of 14-methylfecosterol (75% versus 0.1% of total sterols in wild-type) and other 14-alpha methylcholestanes. These are substrates for sterol 14-alpha demethylase (CYP51) suggesting that this enzyme may be a bona fide P450R specifically involved in electron transfer from NADPH to CYP51 during catalysis. Deletion of P450R1 in wild-type cells phenocopied the metabolic changes observed in our AmB hyper-resistant clone as well as in CYP51 nulls. Likewise, addition of a wild type P450R1 gene restored sterol profiles to wild type. Our studies indicate that P450R1 is essential for L. donovani amastigote viability, thus loss of this gene is unlikely to be a driver of clinical resistance. Nevertheless, investigating the mechanisms underpinning AmB resistance in these cells provided insights that refine our understanding of the L. donovani sterol biosynthetic pathway

Sterol 14-alpha demethylase (CYP51) activity in Leishmania donovani is likely dependent upon cytochrome P450 reductase 1

Funding: This work was supported by the following Wellcome Trust (https://wellcome.org/) grants: 203134/Z/16/Z (SW and AHF) and 218448/Z/19/Z (SW). LBT, MT, VCL, GD and RW were supported through the grants awarded to SW. MPB was funded by an MRC (https://www.ukri.org/councils/ mrc/) Newton grant: MR/S0196501. SKW is part of the Glasgow University CMVLS research facility.Liposomal amphotericin B is an important frontline drug for the treatment of visceral leishmaniasis, a neglected disease of poverty. The mechanism of action of amphotericin B (AmB) is thought to involve interaction with ergosterol and other ergostane sterols, resulting in disruption of the integrity and key functions of the plasma membrane. Emergence of clinically refractory isolates of Leishmania donovani and L. infantum is an ongoing issue and knowledge of potential resistance mechanisms can help to alleviate this problem. Here we report the characterisation of four independently selected L. donovani clones that are resistant to AmB. Whole genome sequencing revealed that in three of the moderately resistant clones, resistance was due solely to the deletion of a gene encoding C24-sterol methyltransferase (SMT1). The fourth, hyper-resistant resistant clone (>60-fold) was found to have a 24 bp deletion in both alleles of a gene encoding a putative cytochrome P450 reductase (P450R1). Metabolic profiling indicated these parasites were virtually devoid of ergosterol (0.2% versus 18% of total sterols in wild-type) and had a marked accumulation of 14-methylfecosterol (75% versus 0.1% of total sterols in wild-type) and other 14-alpha methylcholestanes. These are substrates for sterol 14-alpha demethylase (CYP51) suggesting that this enzyme may be a bona fide P450R specifically involved in electron transfer from NADPH to CYP51 during catalysis. Deletion of P450R1 in wild-type cells phenocopied the metabolic changes observed in our AmB hyper-resistant clone as well as in CYP51 nulls. Likewise, addition of a wild type P450R1 gene restored sterol profiles to wild type. Our studies indicate that P450R1 is essential for L. donovani amastigote viability, thus loss of this gene is unlikely to be a driver of clinical resistance. Nevertheless, investigating the mechanisms underpinning AmB resistance in these cells provided insights that refine our understanding of the L. donovani sterol biosynthetic pathway. Peer reviewe

Characterizing the normal proteome of human ciliary body

BACKGROUND: The ciliary body is the circumferential muscular tissue located just behind the iris in the anterior chamber of the eye. It plays a pivotal role in the production of aqueous humor, maintenance of the lens zonules and accommodation by changing the shape of the crystalline lens. The ciliary body is the major target of drugs against glaucoma as its inhibition leads to a drop in intraocular pressure. A molecular study of the ciliary body could provide a better understanding about the pathophysiological processes that occur in glaucoma. Thus far, no large-scale proteomic investigation has been reported for the human ciliary body. RESULTS: In this study, we have carried out an in-depth LC-MS/MS-based proteomic analysis of normal human ciliary body and have identified 2,815 proteins. We identified a number of proteins that were previously not described in the ciliary body including importin 5 (IPO5), atlastin-2 (ATL2), B-cell receptor associated protein 29 (BCAP29), basigin (BSG), calpain-1 (CAPN1), copine 6 (CPNE6), fibulin 1 (FBLN1) and galectin 1 (LGALS1). We compared the plasma proteome with the ciliary body proteome and found that the large majority of proteins in the ciliary body were also detectable in the plasma while 896 proteins were unique to the ciliary body. We also classified proteins using pathway enrichment analysis and found most of proteins associated with ubiquitin pathway, EIF2 signaling, glycolysis and gluconeogenesis. CONCLUSIONS: More than 95% of the identified proteins have not been previously described in the ciliary body proteome. This is the largest catalogue of proteins reported thus far in the ciliary body that should provide new insights into our understanding of the factors involved in maintaining the secretion of aqueous humor. The identification of these proteins will aid in understanding various eye diseases of the anterior segment such as glaucoma and presbyopia

DESI Survey Validation Spectra Reveal an Increasing Fraction of Recently Quenched Galaxies at z∼1z\sim1

We utilize $\sim17000$ bright Luminous Red Galaxies (LRGs) from the novel Dark Energy Spectroscopic Instrument Survey Validation spectroscopic sample, leveraging its deep ($\sim2.5$ hour/galaxy exposure time) spectra to characterize the contribution of recently quenched galaxies to the massive galaxy population at $0.4<z<1.3$. We use Prospector to infer non-parametric star formation histories and identify a significant population of post-starburst galaxies that have joined the quiescent population within the past $\sim1$ Gyr. The highest redshift subset (277 at $z>1$) of our sample of recently quenched galaxies represents the largest spectroscopic sample of post-starburst galaxies at that epoch. At $0.4<z<0.8$, we measure the number density of quiescent LRGs, finding that recently quenched galaxies constitute a growing fraction of the massive galaxy population with increasing lookback time. Finally, we quantify the importance of this population amongst massive ($\mathrm{log}(M_\star/M_\odot)>11.2$) LRGs by measuring the fraction of stellar mass each galaxy formed in the Gyr before observation, $f_{\mathrm{1 Gyr}}$. Although galaxies with $f_{\mathrm{1 Gyr}}>0.1$ are rare at $z\sim0.4$ ($\lesssim 0.5\%$ of the population), by $z\sim0.8$ they constitute $\sim3\%$ of massive galaxies. Relaxing this threshold, we find that galaxies with $f_\mathrm{1 Gyr}>5\%$ constitute $\sim10\%$ of the massive galaxy population at $z\sim0.8$. We also identify a small but significant sample of galaxies at $z=1.1-1.3$ that formed with $f_{\mathrm{1 Gyr}}>50\%$, implying that they may be analogues to high-redshift quiescent galaxies that formed on similar timescales. Future analysis of this unprecedented sample promises to illuminate the physical mechanisms that drive the quenching of massive galaxies after cosmic noon.Comment: Submitted to ApJ Letters after DESI Collaboration Review. 14 pages, 5 figures, comments welcome

A compendium of molecules involved in vector-pathogen interactions pertaining to malaria

Malaria is a vector-borne disease causing extensive morbidity, debility and mortality. Development of resistance to drugs among parasites and to conventional insecticides among vector-mosquitoes necessitates innovative measures to combat this disease. Identification of molecules involved in the maintenance of complex developmental cycles of the parasites within the vector and the host can provide attractive targets to intervene in the disease transmission. In the last decade, several efforts have been made in identifying such molecules involved in mosquito-parasite interactions and, subsequently, validating their role in the development of parasites within the vector. In this study, a list of mosquito proteins, which facilitate or inhibit the development of malaria parasites in the midgut, haemolymph and salivary glands of mosquitoes, is compiled. A total of 94 molecules have been reported and validated for their role in the development of malaria parasites inside the vector. This compendium of molecules will serve as a centralized resource to biomedical researchers investigating vector-pathogen interactions and malaria transmission. © 2013 Sreenivasamurthy et al.; licensee BioMed Central Ltd

Development of a 2,4-diaminothiazole series for the treatment of human African trypanosomiasis highlights the importance of static-cidal screening of analogues

While treatment options for human African trypanosomiasis (HAT) have improved significantly, there is still a need for new drugs with eradication now a realistic possibility. Here, we report the development of 2,4-diaminothiazoles that demonstrate significant potency against Trypanosoma brucei, the causative agent of HAT. Using phenotypic screening to guide structure-activity relationships, potent drug-like inhibitors were developed. Proof of concept was established in an animal model of the hemolymphatic stage of HAT. To treat the meningoencephalitic stage of infection, compounds were optimized for pharmacokinetic properties, including blood-brain barrier penetration. However, in vivo efficacy was not achieved, in part due to compounds evolving from a cytocidal to a cytostatic mechanism of action. Subsequent studies identified a nonessential kinase involved in the inositol biosynthesis pathway as the molecular target of these cytostatic compounds. These studies highlight the need for cytocidal drugs for the treatment of HAT and the importance of static-cidal screening of analogues