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Combining Compressed Sensing and Neural Architecture Search for Sensor-Near Vibration Diagnostics

Combining Compressed Sensing and Neural Architecture Search for Sensor-Near Vibration Diagnostics

Glycan Complexity and Heterogeneity of Glycoproteins in Somatic Extracts and Secretome of the Infective Stage of the Helminth Fasciola hepatica

Fasciola hepatica is a global helminth parasite of humans and their livestock. The invasive stage of the parasite, the newly excysted juvenile (NEJs), relies on glycosylated excreted-secreted (ES) products and surface/somatic molecules to interact with host cells and tissues and to evade the host's immune responses, such as disarming complement and shedding bound antibody. While -omics technologies have generated extensive databases of NEJs’ proteins and their expression, detailed knowledge of the glycosylation of proteins is still lacking. Here, we employed glycan, glycopeptide, and proteomic analyses to determine the glycan profile of proteins within the NEJs’ somatic (Som) and ES extracts. These analyses characterized 123 NEJ glycoproteins, 71 of which are secreted proteins, and allowed us to map 356 glycopeptides and their associated 1690 N-glycan and 37 O-glycan forms to their respective proteins. We discovered abundant micro-heterogeneity in the glycosylation of individual glycosites and between different sites of multi-glycosylated proteins. The global heterogeneity across NEJs’ glycoproteome was refined to 53 N-glycan and 16 O-glycan structures, ranging from highly truncated paucimannosidic structures to complex glycans carrying multiple phosphorylcholine (PC) residues, and included various unassigned structures due to unique linkages, particularly in pentosylated O-glycans. Such exclusive glycans decorate some well-known secreted molecules involved in host invasion, including cathepsin B and L peptidases, and a variety of membrane-bound glycoproteins, suggesting that they participate in host interactions. Our findings show that F. hepatica NEJs generate exceptional protein variability via glycosylation, suggesting that their molecular portfolio that communicates with the host is far more complex than previously anticipated by transcriptomic and proteomic analyses. This study opens many avenues to understand the glycan biology of F. hepatica throughout its life-stages, as well as other helminth parasites, and allows us to probe the glycosylation of individual NEJs proteins in the search for innovative diagnostics and vaccines against fascioliasis.

The Tapeworm Hymenolepis diminuta as an Important Model Organism in the Experimental Parasitology of the 21st Century.

The tapeworm Hymenolepis diminuta is a common parasite of the small intestine in rodents but it can also infect humans. Due to its characteristics and ease of maintenance in the laboratory, H. diminuta is also an important model species in studies of cestodiasis, including the search for new drugs, treatments, diagnostics and biochemical processes, as well as its host-parasite interrelationships. A great deal of attention has been devoted to the immune response caused by H. diminuta in the host, and several studies indicate that infection with H. diminuta can reduce the severity of concomitant disease. Here, we present a critical review of the experimental research conducted with the use of H. diminuta as a model organism for over more than two decades (in the 21st century). The present review evaluates the tapeworm H. diminuta as a model organism for studying the molecular biology, biochemistry and immunology aspects of parasitology, as well as certain clinical applications. It also systematizes the latest research on this species. Its findings may contribute to a better understanding of the biology of tapeworms and their adaptation to parasitism, including complex correlations between H. diminuta and invertebrate and vertebrate hosts. It places particular emphasis on its value for the further development of modern experimental parasitology.

A Chaotic Oppositional Whale Optimisation Algorithm with Firefly Search for Medical Diagnostics

There is a growing interest in the study development of artificial intelligence and machine learning, especially regarding the support vector machine pattern classification method. This study proposes an enhanced implementation of the well-known whale optimisation algorithm, which combines chaotic and opposition-based learning strategies, which is adopted for hyper-parameter optimisation and feature selection machine learning challenges. The whale optimisation algorithm is a relatively recent addition to the group of swarm intelligence algorithms commonly used for optimisation. The Proposed improved whale optimisation algorithm was first tested for standard unconstrained CEC2017 benchmark suite and it was later adapted for simultaneous feature selection and support vector machine hyper-parameter tuning and validated for medical diagnostics by using breast cancer, diabetes, and erythemato-squamous dataset. The performance of the proposed model is compared with multiple competitive support vector machine models boosted with other metaheuristics, including another improved whale optimisation approach, particle swarm optimisation algorithm, bacterial foraging optimisation algorithms, and genetic algorithms. Results of the simulation show that the proposed model outperforms other competitors concerning the performance of classification and the selected subset feature size.

The landscape of antibody binding in SARS-CoV-2 infection.

The search for potential antibody-based diagnostics, vaccines, and therapeutics for pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has focused almost exclusively on the spike (S) and nucleocapsid (N) proteins. Coronavirus membrane (M), ORF3a, and ORF8 proteins are humoral immunogens in other coronaviruses (CoVs) but remain largely uninvestigated for SARS-CoV-2. Here, we use ultradense peptide microarray mapping to show that SARS-CoV-2 infection induces robust antibody responses to epitopes throughout the SARS-CoV-2 proteome, particularly in M, in which 1 epitope achieved excellent diagnostic accuracy. We map 79 B cell epitopes throughout the SARS-CoV-2 proteome and demonstrate that antibodies that develop in response to SARS-CoV-2 infection bind homologous peptide sequences in the 6 other known human CoVs. We also confirm reactivity against 4 of our top-ranking epitopes by enzyme-linked immunosorbent assay (ELISA). Illness severity correlated with increased reactivity to 9 SARS-CoV-2 epitopes in S, M, N, and ORF3a in our population. Our results demonstrate previously unknown, highly reactive B cell epitopes throughout the full proteome of SARS-CoV-2 and other CoV proteins.

Editorial: Coronavirus disease 2019 (COVID-19) - advances in epidemiology, diagnostics, treatments, host-directed therapies, pathogenesis, vaccines, and ongoing challenges.

Editorial: Coronavirus disease 2019 (COVID-19) - advances in epidemiology, diagnostics, treatments, host-directed therapies, pathogenesis, vaccines, and ongoing challenges.

Pathological Roles of Mitochondrial Oxidative Stress and Mitochondrial Dynamics in Cardiac Microvascular Ischemia/Reperfusion Injury.

Mitochondria are key regulators of cell fate through controlling ATP generation and releasing pro-apoptotic factors. Cardiac ischemia/reperfusion (I/R) injury to the coronary microcirculation has manifestations ranging in severity from reversible edema to interstitial hemorrhage. A number of mechanisms have been proposed to explain the cardiac microvascular I/R injury including edema, impaired vasomotion, coronary microembolization, and capillary destruction. In contrast to their role in cell types with higher energy demands, mitochondria in endothelial cells primarily function in signaling cellular responses to environmental cues. It is clear that abnormal mitochondrial signatures, including mitochondrial oxidative stress, mitochondrial fission, mitochondrial fusion, and mitophagy, play a substantial role in endothelial cell function. While the pathogenic role of each of these mitochondrial alterations in the endothelial cells I/R injury remains complex, profiling of mitochondrial oxidative stress and mitochondrial dynamics in endothelial cell dysfunction may offer promising potential targets in the search for novel diagnostics and therapeutics in cardiac microvascular I/R injury. The objective of this review is to discuss the role of mitochondrial oxidative stress on cardiac microvascular endothelial cells dysfunction. Mitochondrial dynamics, including mitochondrial fission and fusion, are critically discussed to understand their roles in endothelial cell survival. Finally, mitophagy, as a degradative mechanism for damaged mitochondria, is summarized to figure out its contribution to the progression of microvascular I/R injury.

Spatiotemporal Multi-Omics Mapping Generates a Molecular Atlas of the Aortic Valve and Reveals Networks Driving Disease.

No pharmacological therapy exists for calcific aortic valve disease (CAVD), which confers a dismal prognosis without invasive valve replacement. The search for therapeutics and early diagnostics is challenging because CAVD presents in multiple pathological stages. Moreover, it occurs in the context of a complex, multi-layered tissue architecture; a rich and abundant extracellular matrix phenotype; and a unique, highly plastic, and multipotent resident cell population. A total of 25 human stenotic aortic valves obtained from valve replacement surgeries were analyzed by multiple modalities, including transcriptomics and global unlabeled and label-based tandem-mass-tagged proteomics. Segmentation of valves into disease stage-specific samples was guided by near-infrared molecular imaging, and anatomic layer-specificity was facilitated by laser capture microdissection. Side-specific cell cultures were subjected to multiple calcifying stimuli, and their calcification potential and basal/stimulated proteomes were evaluated. Molecular (protein-protein) interaction networks were built, and their central proteins and disease associations were identified. Global transcriptional and protein expression signatures differed between the nondiseased, fibrotic, and calcific stages of CAVD. Anatomic aortic valve microlayers exhibited unique proteome profiles that were maintained throughout disease progression and identified glial fibrillary acidic protein as a specific marker of valvular interstitial cells from the spongiosa layer. CAVD disease progression was marked by an emergence of smooth muscle cell activation, inflammation, and calcification-related pathways. Proteins overrepresented in the disease-prone fibrosa are functionally annotated to fibrosis and calcification pathways, and we found that in vitro, fibrosa-derived valvular interstitial cells demonstrated greater calcification potential than those from the ventricularis. These studies confirmed that the microlayer-specific proteome was preserved in cultured valvular interstitial cells, and that valvular interstitial cells exposed to alkaline phosphatase-dependent and alkaline phosphatase-independent calcifying stimuli had distinct proteome profiles, both of which overlapped with that of the whole tissue. Analysis of protein-protein interaction networks found a significant closeness to multiple inflammatory and fibrotic diseases. A spatially and temporally resolved multi-omics, and network and systems biology strategy identifies the first molecular regulatory networks in CAVD, a cardiac condition without a pharmacological cure, and describes a novel means of systematic disease ontology that is broadly applicable to comprehensive omics studies of cardiovascular diseases.

Abstract 228: Multi-omics Mapping Generates a Molecular Atlas of the Aortic Valve and Reveals Networks Driving Disease

Background: No pharmacological therapy exists for calcific aortic valve disease (CAVD), which confers a dismal prognosis without valve replacement. The search for therapeutics and early diagnostics is challenging since CAVD presents in multiple pathological stages. Methods: A total of 25 human stenotic aortic valves obtained from valve replacement surgery were analyzed by multiple modalities, including transcriptomics and global unlabeled and tandem-mass-tagged proteomics by liquid chromatography-mass spectrometry. Results: Global transcriptional and protein expression signatures differed between the non-diseased, fibrotic, and calcific stages of CAVD, with consistent trends in gene and protein expression across disease stages. Anatomical aortic valve microlayers exhibited unique proteome profiles that were maintained throughout disease progression, and revealed GFAP as a specific marker of valvular interstitial cells (VICs) from the spongiosa layer. CAVD disease progression was marked by an emergence of smooth muscle cell activation, inflammation, and calcification-related pathways. Proteins overrepresented in the disease-prone fibrosa are functionally annotated to fibrosis and calcification pathways, and we found that, in vitro , fibrosa-derived VICs demonstrated greater calcification potential than those from the ventricularis. These studies confirmed that the microlayer-specific proteome was preserved in cultured VICs, and that VICs exposed to TNAP-dependent and TNAP-independent calcifying stimuli had distinct proteome profiles, both of which overlapped with that of the whole tissue. Network analysis of protein-protein interaction networks found a significant closeness to multiple inflammatory and fibrotic diseases. Conclusions: A spatially- and temporally-resolved multi-omics and systems biology strategy identifies the first molecular regulatory networks in CAVD, a cardiac condition without a pharmacological cure, and describes a strategy for endophenotype characterization that is broadly applicable to comprehensive omics studies of cardiovascular diseases.

Recent Advances in the Diagnosis and Detection of Opisthorchis viverrini Sensu Lato in Human and Intermediate Hosts for Use in Control and Elimination Programs.

Opisthorchiasis is a neglected tropical disease, caused by infection with the fish-borne trematode Opisthorchis viverrini sensu lato that afflicts more than 10million people in Southeast Asia, including Thailand, Lao PDR, Vietnam and Cambodia. The disease is characterized by a chronic infection that induces hepatobiliary inflammation, especially periductal fibrosis, which can be detected by ultrasonography. This chronic inflammation eventually leads to cholangiocarcinoma (CCA), a usually fatal bile duct cancer that develops in approximately 1% of O. viverrini-infected individuals. In Thailand alone, CCA kills up to 20,000 people every year and is therefore of substantial public health importance. Its socioeconomic impacts on impoverished families and communities are considerable. To reduce O. viverrini-associated morbidity and CCA, the primary intervention measures focus on opisthorchiasis control and elimination. Accurate diagnoses of O. viverrini infection, in both mammalian, snail and fish intermediate hosts, are important for achieving these goals. Despite extensive efforts over several decades to find sensitive and specific diagnostics for opisthorchiasis, a simple and robust diagnostic method is still required. Here we review earlier and current developments in the search for new diagnostics for opisthorchiasis, with practical applications in the research laboratory, the clinic and the field. Of the methods currently available, the urine antigen assay shows considerable potential for the diagnosis and screening of opisthorchiasis. Nevertheless, these new assays require validation, determination of their cost-effectiveness when applied for mass screening in an endemic setting in support of policy decisions for national public health programs aimed at the control and elimination of opisthorchiasis.

Advances in the Diagnosis of Human Schistosomiasis.

Schistosomiasis is a major neglected tropical disease that afflicts more than 240 million people, including many children and young adults, in the tropics and subtropics. The disease is characterized by chronic infections with significant residual morbidity and is of considerable public health importance, with substantial socioeconomic impacts on impoverished communities. Morbidity reduction and eventual elimination through integrated intervention measures are the focuses of current schistosomiasis control programs. Precise diagnosis of schistosome infections, in both mammalian and snail intermediate hosts, will play a pivotal role in achieving these goals. Nevertheless, despite extensive efforts over several decades, the search for sensitive and specific diagnostics for schistosomiasis is ongoing. Here we review the area, paying attention to earlier approaches but emphasizing recent developments in the search for new diagnostics for schistosomiasis with practical applications in the research laboratory, the clinic, and the field. Careful and rigorous validation of these assays and their cost-effectiveness will be needed, however, prior to their adoption in support of policy decisions for national public health programs aimed at the control and elimination of schistosomiasis.

Statistical diagnostics to identify galactic foregrounds in B-mode maps.

Recent developments in the search for inflationary gravitational waves in the cosmic microwave background polarization motivate the search for new diagnostics to distinguish the Galactic foreground contribution to B modes from the cosmic signal. We show that B modes from these foregrounds should exhibit a local hexadecapolar departure in power from statistical isotropy (SI). We present a simple algorithm to search for a uniform SI violation of this sort, as may arise in a sufficiently small patch of sky. We then show how to search for these effects if the orientation of the SI violation varies across the survey region, as is more likely to occur in surveys with more sky coverage. If detected, these departures from Gaussianity would indicate some level of Galactic foreground contamination in the B-mode maps. Given uncertainties about foreground properties, though, caution should be exercised in attributing a null detection to an absence of foregrounds.

Application of loop-mediated isothermal amplification assay for the sensitive and rapid diagnosis of visceral leishmaniasis and post-kala-azar dermal leishmaniasis

Loop-mediated isothermal amplification (LAMP) is at the forefront in the search for innovative diagnostics for rapid and specific amplification of target DNA under isothermal conditions. We have applied LAMP assay using SYBR Green for clear-cut naked eye detection of Leishmania (Leishmania) donovani in 200 clinical samples of visceral leishmaniasis (VL) and post-kala-azar dermal leishmaniasis (PKDL). The assay was positive in 53/55 VL blood samples (sensitivity, 96.4%; 95% confidence interval [CI], 87.7–99%), 15/15 VL bone marrow aspirate samples (sensitivity, 100%; 95% CI, 79.6–100%), 60/62 PKDL tissue biopsy samples (sensitivity, 96.8%; 95% CI, 88.9–99.1%), and 1/68 control samples (specificity, 98.5%; 95% CI, 92.1–99.7%). The assay was specific for L. (L.) donovani, the causative species for VL and negative for L. (L.) infantum, L. (L.) tropica, and L. (L.) major. This is the first comprehensive clinical study demonstrating the applicability of the LAMP assay for a rapid and reliable molecular diagnosis of VL and PKDL.

9IN - The Molecular Heterogeneity of Breast Tumors

ABSTRACT Breast Cancer (BC) is a complex disease caused by accumulation of genetic alterations leading to a disturbed balance between proliferation and apoptosis, genetic instability and acquisition of an invasive and resistant phenotype. The inherent heterogeneity, including the microenvironment, contributes to each tumors phenotype and dictate tumors molecular portraits. We have generated high-throughput data of tumors from mRNA and miRNA expression, SNP-CGH and DNA-methylation, paired-end sequencing, protein expression by RPPA, and metabolic profiles from HR-MAS MR analyses. We have explored to which extent combining the various profiles derived from each level, can further subdivide the initially discovered expression subclasses and improve prognostic potential. Patterns of genomic aberrations that underlie specific expression subgroups may infer paths of tumor progression and shed light on mechanisms involved. We recently developed two platform-independent algorithms to explore genomic architectural distortion using aCGH data to measure whole-arm gains and losses (WAAI) and complex rearrangements (CAAI), and were able to separate the cases into eight subgroups. Within each subgroup data from expression analyses, sequencing and ploidy indicated that progression occurs along separate paths into more complex genotypes. The results emphasized the relation among structural genomic alterations, molecular subtype, and clinical behavior and showed that objective score of genomic complexity (CAAI) is an independent prognostic marker. By integrating data from the patient's own genotype with multiple layers of data derived from the primary tumor, the different subclones within the tumor, as well as the metastases, we seek to reach a more fundamental understanding of the biological dynamics of breast cancer. This will facilitate identification of risk factors, search for novel cancer diagnostics, prediction of therapeutic effects and prognosis and identification of new targets for therapy, that may lead to a more personalized treatment of BC. Ref: Stephens P et al. Nature. 2009, Russnes HG et al. STM, 2010, Van LP et al. PNAS 2010, Kristensen VN et al, PNAS 2011, Russnes et al JCI, 2011, Curtis et al, Nature, 2012 Disclosure The author has declared no conflicts of interest.

Autoreactive antibodies raised by self derived de novo peptides can identify unrelated antigens on protein microarrays. Are autoantibodies really autoantibodies?

The development of arrays of human proteins has been a huge boon to the search for autoantibody diagnostics. Typically, slides with thousands of recombinant human proteins arrayed in an addressable fashion are incubated with sera from diseased or normal people. If an antibody binds a protein more in the diseased than in the normal cohort it is considered an autoantibody response. It is usually presumed that the autoantibody was elicited by the protein bound on the array. However, our studies using human protein and random peptide arrays indicate that antibody specificity may not be as high as commonly thought. Therefore we have tested the assumption of the source of autoantibodies. One test was to generate antibodies to two totally random peptides and bind these antibodies to a human protein array. One of the antibodies generated bound two human proteins. A second test was to generate an antibody to a frameshift peptide occurring in cancers. This antibody also bound several proteins on the array. We conclude that one should be cautious about assuming a particular autoantibody target on an array which elicited the original immune response.

LAMP for Human African Trypanosomiasis: A Comparative Study of Detection Formats

Loop-mediated isothermal amplification (LAMP) is at the forefront of the search for innovative diagnostics for human African trypanosomiasis (HAT). Several simple endpoint detection methods have been developed for LAMP and here we compare four of these: (i) visualization of turbidity; (ii) addition of hydroxynaphthol blue before incubation; (iii) addition of calcein with MnCl2 before incubation and (iv) addition of Quant-iT PicoGreen after incubation. These four methods were applied to four LAMP assays for the detection of human African trypanosomiasis, including two Trypanozoon specific and two Trypanosoma brucei rhodesiense specific reactions using DNA extracted from cryo-preserved procyclic form T. b. rhodesiense. A multi-observer study was performed to assess inter-observer reliability of two of these methods: hydroxynapthol blue and calcein with MnCl2, using DNA prepared from blood samples stored on Whatman FTA cards. Results showed that hydroxynaphthol blue was the best of the compared methods for easy, inexpensive, accurate and reliable interpretation of LAMP assays for HAT. Hydroxynapthol blue generates a violet to sky blue colour change that was easy to see and was consistently interpreted by independent observers. Visible turbidity detection is not possible for all currently available HAT LAMP reactions; Quant-iT PicoGreen is expensive and addition of calcein with MnCl2 adversely affects reaction sensitivity and was unpopular with several observers.

Selective Release of MicroRNA Species from Normal and Malignant Mammary Epithelial Cells

MicroRNAs (miRNAs) in body fluids are candidate diagnostics for a variety of conditions and diseases, including breast cancer. One premise for using extracellular miRNAs to diagnose disease is the notion that the abundance of the miRNAs in body fluids reflects their abundance in the abnormal cells causing the disease. As a result, the search for such diagnostics in body fluids has focused on miRNAs that are abundant in the cells of origin. Here we report that released miRNAs do not necessarily reflect the abundance of miRNA in the cell of origin. We find that release of miRNAs from cells into blood, milk and ductal fluids is selective and that the selection of released miRNAs may correlate with malignancy. In particular, the bulk of miR-451 and miR-1246 produced by malignant mammary epithelial cells was released, but the majority of these miRNAs produced by non-malignant mammary epithelial cells was retained. Our findings suggest the existence of a cellular selection mechanism for miRNA release and indicate that the extracellular and cellular miRNA profiles differ. This selective release of miRNAs is an important consideration for the identification of circulating miRNAs as biomarkers of disease.

Reflux and Respiration: The Search for Better Diagnostics

Pediatric Asthma, Allergy & ImmunologyVol. 16, No. 1 Letter to the EditorReflux and Respiration: The Search for Better DiagnosticsSulaiman Bharwani and John J. HerbstSulaiman BharwaniSearch for more papers by this author and John J. HerbstSearch for more papers by this authorPublished Online:8 Jul 2004https://doi.org/10.1089/088318703320910124AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail FiguresReferencesRelatedDetailsCited byLiteratureWatch8 July 2004 | Pediatric Asthma, Allergy & Immunology, Vol. 16, No. 2 Volume 16Issue 1Mar 2003 To cite this article:Sulaiman Bharwani and John J. Herbst.Reflux and Respiration: The Search for Better Diagnostics.Pediatric Asthma, Allergy & Immunology.Mar 2003.59-61.http://doi.org/10.1089/088318703320910124Published in Volume: 16 Issue 1: July 8, 2004PDF download

Recent developments in human African trypanosomiasis.

Sleeping sickness has re-emerged as a serious problem in sub-Saharan Africa, with an estimated 100000 deaths each year. South Sudan, the Democratic Republic of Congo and Angola have experienced serious epidemics of the Gambian form of the disease. The control of Gambian sleeping sickness, which relies primarily on active case finding followed by chemotherapy, is being threatened by problems of drug resistance. Recently, Rhodesian sleeping sickness has also posed a health risk to travellers visiting game parks in East Africa. Because of war-related constraints, which have prevented case detection, the prevalence of Gambian sleeping sickness commonly exceeds 5% and reached 29% in one focus in south Sudan. The incidence of Gambian infections refractory to melarsoprol treatment has also risen sharply in northern Uganda, northern Angola and southern Sudan, with failure rates as high as 26.9%. Molecular techniques based on the gene for human serum resistance (SRA) have enabled the identification of human infective parasites in the domestic animal reservoir. This molecular tool has shown that the Rhodesian form of the disease is being carried in cattle northwards in Uganda towards areas endemic for the Gambian form. The coalescence of distributions of the chronic and acute forms of the disease will present problems for both control and treatment. This review surveys the molecular tools that are improving our understanding of the epidemiology of sleeping sickness, and highlights the search for new diagnostics and drugs to deal with the disease.

Presence of mouse mammary tumor virus specifically alters the body odor of mice.

It has long been recognized that various genetic and metabolic human disorders alter body odor, which is not surprising because they may alter body chemistry. Thus, it has been suggested that some human diseases may be diagnosed by odor alone. In that regard, the mouse mammary tumor virus (MMTV) and its tumors of mice, which may have human counterparts, are of special interest because of the need for basic research possible only in inbred and genetically defined animals. Accordingly, we now show that the mouse MMTV, whether obtained environmentally or genetically transmitted, alters the body odor of mice in both males and females, and regardless of the presence or absence of tumors. These observations, together with the prospect of artificial human odor discrimination, may aid in the search for early human diagnostics.