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Abstract This article introduces a novel FIR filter using a Radix-2r multiplier combined with 4:2 and 3:2 compressors for denoising Electrooculography (EOG) signals. This approach replaces traditional ripple-carry adders with compressors to add the partial products generated by the Radix-2r multiplier, resulting in reduced delay and energy consumption. The FIR filter is implemented in gate-level Verilog HDL, verified using ModelSim and Altera DSP Builder, and synthesized with the Cadence RTL compiler. Compared to conventional designs, the proposed filter achieves a 71.48% reduction in area, 73.28% reduction in power, 51.84% reduction in delay, 86.22% reduction in the area-delay product (ADP), and 92.38% reduction in energy-per-operation (EPS), significantly outperforming the SOPOT filter.

Non-invasive strategies that can identify oral malignant and dysplastic oral potentially-malignant lesions (OPML) are necessary in cancer screening and long-term surveillance. Optical coherence tomography (OCT) can be a rapid, real time and non-invasive imaging method for frequent patient surveillance. Here, we report the validation of a portable, robust OCT device in 232 patients (lesions: 347) in different clinical settings. The device deployed with algorithm-based automated diagnosis, showed efficacy in delineation of oral benign and normal (n = 151), OPML (n = 121), and malignant lesions (n = 75) in community and tertiary care settings. This study showed that OCT images analyzed by automated image processing algorithm could distinguish the dysplastic-OPML and malignant lesions with a sensitivity of 95% and 93%, respectively. Furthermore, we explored the ability of multiple (n = 14) artificial neural network (ANN) based feature extraction techniques for delineation high grade-OPML (moderate/severe dysplasia). The support vector machine (SVM) model built over ANN, delineated high-grade dysplasia with sensitivity of 83%, which in turn, can be employed to triage patients for tertiary care. The study provides evidence towards the utility of the robust and low-cost OCT instrument as a point-of-care device in resource-constrained settings and the potential clinical application of device in screening and surveillance of oral cancer.

In the recent times, non-orthogonal multiple access (NOMA) can be seen as a paradigm shift for next generations of communication networks such as the fifth generation (5G) and beyond 5G networks. Owing to its remarkable benefits, even NOMA has been employed for the sixth generation (6G) systems as well. NOMA, in spite of bestowing with an enhancement in spectral efficiency (SE) by enabling the users to exploit the same orthogonal resource blocks with the aid of power domain multiplexing, is not devoid of its drawbacks. A slight variation of the channel conditions corresponding to NOMA users and the rapid increase in the number of users results in significant degradation in the performance of NOMA system. Therefore, to circumvent such drawbacks, it is vital to employ hybrid multiple access (HMA) strategies such as the combination of both orthogonal multiple access (OMA) and NOMA. In this context, this paper proposes novel user pairing (UP) strategy for downlink power domain (PD) NOMA system over Rayleigh fading channel with perfect and imperfect successive interference cancellation (pSIC/ipSIC) comprising of even number of NOMA users. It is to be noted that these NOMA users which are served by the base station (BS) can be paired according to their channel conditions with improved sum rates (SR). If an odd number of NOMA users are in one group and one group has more users than the others, one user may be left unpaired, making pairing difficult. Considering this, we present an efficient UP method that pairs unpaired users with one of the existing pairings instead of utilizing OMA benefit. Finding an ideal (best) pair to serve the unpaired user is the major aim of our proposed method. Furthermore, we worked towards enhancing the total SR which is also known as pair sum rate (PSR) and we even provided power allocation (PA) optimization process for each pair in order to maximize the SR/PSR of our proposed UP NOMA system. In addition, we derive various key metrics such as the upper and lower bounds of PA coefficients, imperfect SIC parameter, and channel gain difference parameter for NOMA paired users. Further, we provide an elaborate analytical framework for various performance metrics such as the PSR, ergodic pair sum rate (EPSR), and outage probability (OP) expressions for the proposed downlink PD-NOMA system over Rayleigh fading channels.

Abstract Malaria epidemics can be triggered by fluctuations in temperature and precipitation that influence vector mosquitoes and the malaria parasite. Identifying and monitoring environmental risk factors can thus provide early warning of future outbreaks. Satellite Earth observations provide relevant measurements, but obtaining these data requires substantial expertise, computational resources, and internet bandwidth. To support malaria forecasting in Ethiopia, we developed software for Retrieving Environmental Analytics for Climate and Health (REACH). REACH is a cloud-based application for accessing data on land surface temperature, spectral indices, and precipitation using the Google Earth Engine (GEE) platform. REACH can be implemented using the GEE code editor and JavaScript API, as a standalone web app, or as package with the Python API. Users provide a date range and data for 852 districts in Ethiopia are automatically summarized and downloaded as tables. REACH was successfully used in Ethiopia to support a pilot malaria early warning project in the Amhara region. The software can be extended to new locations and modified to access other environmental datasets through GEE.

Current drugs for treating human cytomegalovirus (HCMV) infections are limited by resistance and treatment-associated toxicities. In developing mechanistically novel HCMV antivirals, we discovered an N-benzyl hydroxypyridone carboxamide antiviral hit (8a) inhibiting HCMV in submicromolar range. We describe herein the structure–activity relationship (SAR) for 8a, and the characterization of potent analogs for cytotoxicity/cytostatic property, the preliminary mechanism of action, and the absorption, distribution, metabolism and excretion (ADME) properties. The SAR revealed a few pharmacophore features conferring optimal antiviral profile, including the 5-OH, the N-1 benzyl, at least one –CH2− in the linker, and a di-halogen substituted phenyl ring in the amide moiety. In the end, we identified numerous analogs with sub-micromolar antiviral potency and good selectivity index. The preliminary mechanism of action characterization used a pUL89-C biochemical endonuclease assay, a virus entry assay, a time-of-addition assay, and a compound withdrawal assay. ADME profiling measuring aqueous solubility, plasma and liver microsomal stability, and parallel artificial membrane permeability assay (PAMPA) permeability demonstrated largely favorable drug-like properties. Together, these studies validate the N-benzyl hydroxypyridone carboxamide as a viable chemotype for potent and mechanistically distinct antivirals against HCMV.

Wheat blast is a serious disease caused by the fungus Magnaporthe oryzae (Triticum pathotype) (MoT). The objective of this study was to determine the effect of the 2NS translocation from Aegilops ventricosa (Zhuk.) Chennav on wheat head and leaf blast resistance. Disease phenotyping experiments were conducted in growth chamber, greenhouse, and field environments. Among 418 cultivars of wheat (Triticum aestivum L.), those with 2NS had 50.4 to 72.3% less head blast than those without 2NS when inoculated with an older MoT isolate under growth chamber conditions. When inoculated with recently collected isolates, cultivars with 2NS had 64.0 to 80.5% less head blast. Under greenhouse conditions when lines were inoculated with an older MoT isolate, those with 2NS had a significant head blast reduction. With newer isolates, not all lines with 2NS showed a significant reduction in head blast, suggesting that the genetic background and/or environment may influence the expression of any resistance conferred by 2NS. However, when near-isogenic lines (NILs) with and without 2NS were planted in the field, there was strong evidence that 2NS conferred resistance to head blast. Results from foliar inoculations suggest that the resistance to head infection that is imparted by the 2NS translocation does not confer resistance to foliar disease. In conclusion, the 2NS translocation was associated with significant reductions in head blast in both spring and winter wheat.

Since the 1960s, a single class of agent has been licensed targeting virus-encoded ion channels, or ‘viroporins’, contrasting the success of channel blocking drugs in other areas of medicine. Although resistance arose to these prototypic adamantane inhibitors of the influenza A virus (IAV) M2 proton channel, a growing number of clinically and economically important viruses are now recognised to encode essential viroporins providing potential targets for modern drug discovery. We describe the first rationally designed viroporin inhibitor with a comprehensive structure-activity relationship (SAR). This step-change in understanding not only revealed a second biological function for the p7 viroporin from hepatitis C virus (HCV) during virus entry, but also enabled the synthesis of a labelled tool compound that retained biological activity. Hence, p7 inhibitors (p7i) represent a unique class of HCV antiviral targeting both the spread and establishment of infection, as well as a precedent for future viroporin-targeted drug discovery.

Pandemic influenza A virus (IAV) remains a significant threat to global health. Preparedness relies primarily upon a single class of neuraminidase (NA) targeted antivirals, against which resistance is steadily growing. The M2 proton channel is an alternative clinically proven antiviral target, yet a near-ubiquitous S31N polymorphism in M2 evokes resistance to licensed adamantane drugs. Hence, inhibitors capable of targeting N31 containing M2 (M2-N31) are highly desirable. Rational in silico design and in vitro screens delineated compounds favouring either lumenal or peripheral M2 binding, yielding effective M2-N31 inhibitors in both cases. Hits included adamantanes as well as novel compounds, with some showing low micromolar potency versus pandemic "swine" H1N1 influenza (Eng195) in culture. Interestingly, a published adamantane-based M2-N31 inhibitor rapidly selected a resistant V27A polymorphism (M2-A27/N31), whereas this was not the case for non-adamantane compounds. Nevertheless, combinations of adamantanes and novel compounds achieved synergistic antiviral effects, and the latter synergised with the neuraminidase inhibitor (NAi), Zanamivir. Thus, site-directed drug combinations show potential to rejuvenate M2 as an antiviral target whilst reducing the risk of drug resistance.

Outages in an overhead power distribution system are caused by multiple environmental factors, such as weather, trees, and animal activity. Since they form a major portion of the outages, the ability to accurately estimate these outages is a significant step towards enhancing the reliability of power distribution systems. Earlier research with statistical models, neural networks, and committee machines to estimate weather-related and animal-related outages has reported some success. In this paper, a deep neural network ensemble model for outage estimation is proposed. The entire input space is partitioned with a distinct neural network in the ensemble performing outage estimate in each partition. A novel algorithm is proposed to train the neural networks in the ensemble, while simultaneously partitioning the input space in a suitable manner. The proposed approach has been compared with the earlier approaches for outage estimation for four U.S. cities. The results suggest that the proposed method significantly improves the estimates of outages caused by wind and lightning in power distribution systems. A comparative analysis with a previously published model for animal-related outages further establishes the overall effectiveness of the deep neural network ensemble.

The constant interactions between plants and pathogens in the environment and the resulting outcomes are of significant importance for agriculture and agricultural scientists. Disease resistance genes in plant cultivars can break down in the field due to the evolution of pathogens under high selection pressure. Thus, the protection of crop plants against pathogens is a continuous arms race. Like any other type of crop plant, legumes are susceptible to many pathogens. The dawn of the genomic era, in which high-throughput and cost-effective genomic tools have become available, has revolutionized our understanding of the complex interactions between legumes and pathogens. Genomic tools have enabled a global view of transcriptome changes during these interactions, from which several key players in both the resistant and susceptible interactions have been identified. This review summarizes some of the large-scale genomic studies that have clarified the host transcriptional changes during interactions between legumes and their plant pathogens while highlighting some of the molecular breeding tools that are available to introgress the traits into breeding programs. These studies provide valuable insights into the molecular basis of different levels of host defenses in resistant and susceptible interactions.

HIV-1 capsid protein (CA) plays an important role in many steps of viral replication and represents an appealing antiviral target. Several CA-targeting small molecules of various chemotypes have been studied, but the peptidomimetic PF74 has drawn particular interest due to its potent antiviral activity, well-characterized binding mode, and unique mechanism of action. Importantly, PF74 competes against important host factors for binding, conferring highly desirable antiviral phenotypes. However, further development of PF74 is hindered by its prohibitively poor metabolic stability, which necessitates the search for structurally novel and metabolically stable chemotypes. We have conducted a pharmacophore-based shape similarity search for compounds mimicking PF74. We report herein the analog synthesis and structure-activity relationship (SAR) of two hits from the search, and a third hit designed via molecular hybridization. All analogs were characterized for their effect on CA hexamer stability, antiviral activity, and cytotoxicity. These assays identified three active compounds that moderately stabilize CA hexamer and inhibit HIV-1. The most potent analog (10) inhibited HIV-1 comparably to PF74 but demonstrated drastically improved metabolic stability in liver microsomes (31 min vs. 0.7 min t1/2). Collectively, the current studies identified a structurally novel and metabolically stable PF74-like chemotype for targeting HIV-1 CA.

Receptor tyrosine kinases (RTKs) are membrane proteins that control the flow of information through signal transduction pathways, impacting on different aspects of cell function. RTKs are characterized by a ligand-binding ectodomain, a single transmembrane α-helix, a cytosolic region comprising juxtamembrane and kinase domains followed by a flexible C-terminal tail. Somatic and germline RTK mutations can induce aberrant signal transduction to give rise to cardiovascular, developmental and oncogenic abnormalities. RTK overexpression occurs in certain cancers, correlating signal strength and disease incidence. Diverse RTK activation and signal transduction mechanisms are employed by cells during commitment to health or disease. Small molecule inhibitors are one means to target RTK function in disease initiation and progression. This review considers RTK structure, activation, and signal transduction and evaluates biological relevance to therapeutics and clinical outcomes.

BACKGROUND/AIMS:Low-volume polyethylene glycol (PEG) bowel preparations are better tolerated by patients than high-volume preparations and may achieve similar preparation quality. However, there is little data comparing their effects on a recommendation for an early repeat colonoscopy (because of a suboptimal preparation), procedure times, adenoma detection rate (ADR), and advanced adenoma detection rate (AADR). METHODS:This is a retrospective cohort study of outpatient colonoscopies performed during a one-year period at a single academic medical center in which low-volume MoviPrep® (n = 1841) or high-volume Colyte® (n = 1337) was used. All preparations were split-dosed. Appropriate covariates were included in regression models assessing suboptimal preparation quality (fair, poor, or inadequate), procedure times, recommendation for an early repeat colonoscopy, ADR, and AADR. RESULTS:MoviPrep® was associated with an increase in having a suboptimal bowel preparation (OR 1.36; 95% CI: 1.06-1.76), but it was not associated with differences in insertion (p = 0.43), withdrawal (p = 0.22), or total procedure times (p = 0.10). The adjusted percentage with a suboptimal preparation was 11.7% for patients using MoviPrep® and 8.8% for patients using Colyte®. MoviPrep® was not associated with a significant difference in overall ADR (OR 0.93; 95% CI: 0.78-1.11), AADR (OR 1.18; 95% CI: 0.87-1.62), or recommendation for early repeat colonoscopy (OR 1.16; 95% CI: 0.72-1.88). CONCLUSIONS:MoviPrep® was associated with a small absolute increase in having a suboptimal preparation, but did not affect recommendations for an early repeat colonoscopy, procedure times, or adenoma detection rates. Mechanisms to reduce financial barriers limiting low-volume preparations should be considered because of their favorable tolerability profile.

BACKGROUND/AIMS:Colonoscopy is performed on patients across a broad spectrum of demographic characteristics. These characteristics may aggregate by patient insurance provider and influence bowel preparation quality and the prevalence of adenomas. The purpose of this study was to evaluate the association of insurance status and suboptimal bowel preparation, recommendation for an early repeat colonoscopy due to suboptimal bowel preparation, adenoma detection rate (ADR), and advanced ADR (AADR). METHODS:This is a cohort study of outpatient colonoscopies (n = 3113) at a single academic medical center. Patient insurance status was categorized into five groups: 1) Medicare < 65y; 2) Medicare ≥ 65y; 3) Tricare/VA; 4) Medicaid/Colorado Indigent Care Program (CICP); and 5) commercial insurance. We used multivariable logistic or linear regression modeling to estimate the risks for the association between patient insurance and suboptimal bowel preparation, recommendation for an early repeat colonoscopy due to suboptimal bowel preparation, ADR, and AADR. Models were adjusted for appropriate covariates. RESULTS:Medicare patients < 65y (OR 4.91; 95% CI: 3.25-7.43) and Medicaid/CICP patients (OR 4.23; 95% CI: 2.65-7.65) were more likely to have a suboptimal preparation compared to commercial insurance patients. Medicare patients < 65y (OR 5.58; 95% CI: 2.85-10.92) and Medicaid/CICP patients (OR 3.64; CI: 1.60-8.28) were more likely to receive a recommendation for an early repeat colonoscopy compared to commercial insurance patients. Medicare patients < 65y had a significantly higher adjusted ADR (OR 1.50; 95% CI: 1.03-2.18) and adjusted AADR (OR 1.99; 95% CI: 1.15-3.44) compared to commercial insurance patients. CONCLUSIONS:Understanding the reasons for the higher rate of a suboptimal bowel preparation in Medicare < 65y and Medicaid/CICP patients and reducing this rate is critical to improving colonoscopy outcomes and reducing healthcare costs in these populations.

Background: Thompson hip hemiarthroplasty is a well-established procedure for the treatment of displaced intracapsular fracture neck of femur in the elderly. However, considerable debate exists regarding the use of cemented prosthesis in this elderly group of patients. The main purpose of our study was to analyse the outcomes following cemented and uncemented Thompson hemiarthroplasty of the hip with particular reference to cement-related morbidity and 30-day mortality. Methods: Of the 110 patients who underwent Thompson hemiarthroplasty for intracapsular hip fracture, 30 (27.3%) had cemented and 80 (72.7%) had uncemented prosthesis. The mean age was 83.2 years with 87 female patients. The thigh pain and mobility at discharge, the inpatient complications and the 30-day mortality rates were compared between the cemented and uncemented groups. Results: The study revealed no statistically significant differences in any of the postoperative outcome measures between the two groups. Conclusion: Cemented and uncemented Thompson hip hemiarthroplasty have similar outcomes at discharge. Patients who underwent cementation without pressurisation did not show any higher incidence of bone cement implantation syndrome compared to their uncemented counterparts. Uncemented Thompson hemiarthroplasty can be an option in patients with very poor cardiopulmonary reserve without any significant complications in the short term.

Protein kinases play a central role in tumor progression, regulating fundamental processes such as angiogenesis, proliferation and metastasis. Such enzymes are an increasingly important class of drug target with small molecule kinase inhibitors being a major focus in drug development. However, balancing drug specificity and efficacy is problematic with off-target effects and toxicity issues.We have utilized a rational in silico-based approach to demonstrate the design and study of a novel compound that acts as a dual inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2) and cyclin-dependent kinase 1 (CDK1). This compound acts by simultaneously inhibiting pro-angiogenic signal transduction and cell cycle progression in primary endothelial cells. JK-31 displays potent in vitro activity against recombinant VEGFR2 and CDK1/cyclin B proteins comparable to previously characterized inhibitors. Dual inhibition of the vascular endothelial growth factor A (VEGF-A)-mediated signaling response and CDK1-mediated mitotic entry elicits anti-angiogenic activity both in an endothelial-fibroblast co-culture model and a murine ex vivo model of angiogenesis.We deduce that JK-31 reduces the growth of both human endothelial cells and human breast cancer cells in vitro. This novel synthetic molecule has broad implications for development of similar multi-kinase inhibitors with anti-angiogenic and anti-cancer properties. In silico design is an attractive and innovative method to aid such drug discovery.

The nimesulide based novel glycolamide esters were designed and synthesized for the first time via a three-step method starting from nimesulide. Structures of the synthesized compounds were confirmed by spectroscopic analysis. All the synthesized compounds were examined for their cytotoxic effects in vitro, some of which showed significant cytotoxic activities against HCT-15 human colon cancer cell line.

The title compound, N-(4-methylsulfonamido-3-phenoxyphenyl)-9,10-dihydro-9,10-ethanoanthracene-11,12-dicarboximide was synthesized in high yield by reaction of N-(4-amino-2-phenoxyphenyl)methanesulfonamide and 9,10-dihydroanthracene-9,10-endo-α,β-succinic anhydride in glacial acetic acid. The structure of the compound was fully characterized by IR, 1H and 13C NMR, mass spectral analysis and elemental analysis.

Current drugs for treating human cytomegalovirus (HCMV) infections are limited by resistance and treatment-associated toxicities. In developing mechanistically novel HCMV antivirals, we discovered an N -benzyl hydroxypyridone carboxamide antiviral hit (8a) inhibiting HCMV in submicromolar range. We describe herein the structure–activity relationship (SAR) for 8a , and the characterization of potent analogs for cytotoxicity/cytostatic property, the preliminary mechanism of action, and the absorption, distribution, metabolism and excretion (ADME) properties. The SAR revealed a few pharmacophore features conferring optimal antiviral profile, including the 5-OH, the N-1 benzyl, at least one –CH 2 − in the linker, and a di-halogen substituted phenyl ring in the amide moiety. In the end, we identified numerous analogs with sub-micromolar antiviral potency and good selectivity index. The preliminary mechanism of action characterization used a pUL89-C biochemical endonuclease assay, a virus entry assay, a time-of-addition assay, and a compound withdrawal assay. ADME profiling measuring aqueous solubility, plasma and liver microsomal stability, and parallel artificial membrane permeability assay (PAMPA) permeability demonstrated largely favorable drug-like properties. Together, these studies validate the N -benzyl hydroxypyridone carboxamide as a viable chemotype for potent and mechanistically distinct antivirals against HCMV. Amidation of a previous HCMV pUL89-C inhibitor (5) produced a mechanistically distinct new lead (8a). Comprehensive SAR of 8a , and the characterization of an improved analog (12) are reported. [Display omitted] [ABSTRACT FROM AUTHOR]