Lipoarabinomannan modification as a source of phenotypic heterogeneity in host-adapted Mycobacterium abscessus isolates.

Mycobacterium abscessus is increasingly recognized as the causative agent of chronic pulmonary infections in humans. One of the genes found to be under strong evolutionary pressure during adaptation of M. abscessus to the human lung is embC which encodes an arabinosyltransferase required for the biosynthesis of the cell envelope lipoglycan, lipoarabinomannan (LAM). To assess the impact of patient-derived embC mutations on the physiology and virulence of M. abscessus, mutations were introduced in the isogenic background of M. abscessus ATCC 19977 and the resulting strains probed for phenotypic changes in a variety of in vitro and host cell-based assays relevant to infection. We show that patient-derived mutational variations in EmbC result in an unexpectedly large number of changes in the physiology of M. abscessus, and its interactions with innate immune cells. Not only did the mutants produce previously unknown forms of LAM with a truncated arabinan domain and 3-linked oligomannoside chains, they also displayed significantly altered cording, sliding motility, and biofilm-forming capacities. The mutants further differed from wild-type M. abscessus in their ability to replicate and induce inflammatory responses in human monocyte-derived macrophages and epithelial cells. The fact that different embC mutations were associated with distinct physiologic and pathogenic outcomes indicates that structural alterations in LAM caused by nonsynonymous nucleotide polymorphisms in embC may be a rapid, one-step, way for M. abscessus to generate broad-spectrum diversity beneficial to survival within the heterogeneous and constantly evolving environment of the infected human airway.

Role of succinyl substituents in the mannose-capping of lipoarabinomannan and control of inflammation in Mycobacterium tuberculosis infection.

The covalent modification of bacterial (lipo)polysaccharides with discrete substituents may impact their biosynthesis, export and/or biological activity. Whether mycobacteria use a similar strategy to control the biogenesis of its cell envelope polysaccharides and modulate their interaction with the host during infection is unknown despite the report of a number of tailoring substituents modifying the structure of these glycans. Here, we show that discrete succinyl substituents strategically positioned on Mycobacterium tuberculosis (Mtb) lipoarabinomannan govern the mannose-capping of this lipoglycan and, thus, much of the biological activity of the entire molecule. We further show that the absence of succinyl substituents on the two main cell envelope glycans of Mtb, arabinogalactan and lipoarabinomannan, leads to a significant increase of pro-inflammatory cytokines and chemokines in infected murine and human macrophages. Collectively, our results validate polysaccharide succinylation as a critical mechanism by which Mtb controls inflammation.

Alzheimer's polygenic risk scores are associated with cognitive phenotypes in Down syndrome.

INTRODUCTION: This study aimed to investigate the influence of the overall Alzheimer's disease (AD) genetic architecture on Down syndrome (DS) status, cognitive measures, and cerebrospinal fluid (CSF) biomarkers. METHODS: AD polygenic risk scores (PRS) were tested for association with DS-related traits. RESULTS: The AD risk PRS was associated with disease status in several cohorts of sporadic late- and early-onset and familial late-onset AD, but not in familial early-onset AD or DS. On the other hand, lower DS Mental Status Examination memory scores were associated with higher PRS, independent of intellectual disability and APOE (PRS including APOE, PRSAPOE , p = 2.84 × 10-4 ; PRS excluding APOE, PRSnonAPOE , p = 1.60 × 10-2 ). PRSAPOE exhibited significant associations with Aß42, tTau, pTau, and Aß42/40 ratio in DS. DISCUSSION: These data indicate that the AD genetic architecture influences cognitive and CSF phenotypes in DS adults, supporting common pathways that influence memory decline in both traits. HIGHLIGHTS: Examination of the polygenic risk of AD in DS presented here is the first of its kind. AD PRS influences memory aspects in DS individuals, independently of APOE genotype. These results point to an overlap between the genes and pathways that leads to AD and those that influence dementia and memory decline in the DS population. APOE ε4 is linked to DS cognitive decline, expanding cognitive insights in adults.

Molecular Gatekeeper Discovery: Workflow for Linking Multiple Exposure Biomarkers to Metabolomics.

The exposome reflects multiple exposures across the life-course that can affect health. Metabolomics can reveal the underlying molecular basis linking exposures to health conditions. Here, we explore the concept and general data analysis framework of "molecular gatekeepers"─key metabolites that link single or multiple exposure biomarkers with correlated clusters of endogenous metabolites─to inform health-relevant biological targets. We performed untargeted metabolomics on plasma from 152 adolescent girls participating in the Growing Up Healthy Study in New York City. We then performed network analysis to link metabolites to exposure biomarkers including five trace elements (Cd, Mn, Pb, Se, and Hg) and five perfluorinated chemicals (PFCs; n-PFOS, Sm-PFOS, n-PFOA, PFHxS, and PFNA). We found 144 molecular gatekeepers and annotated 22 of them. Lysophosphatidylcholine (16:0) and taurodeoxycholate were correlated with both n-PFOA and n-PFOS, suggesting a shared dysregulation from multiple xenobiotic exposures. Sphingomyelin (d18:2/14:0) was significantly associated with age at menarche; yet, no direct association was detected between any exposure biomarkers and age at menarche. Thus, molecular gatekeepers can also discover molecular linkages between exposure biomarkers and health outcomes that may otherwise be obscured by complex interactions in direct measurements.

Power analysis of single-cell RNA-sequencing experiments.

Single-cell RNA sequencing (scRNA-seq) has become an established and powerful method to investigate transcriptomic cell-to-cell variation, thereby revealing new cell types and providing insights into developmental processes and transcriptional stochasticity. A key question is how the variety of available protocols compare in terms of their ability to detect and accurately quantify gene expression. Here, we assessed the protocol sensitivity and accuracy of many published data sets, on the basis of spike-in standards and uniform data processing. For our workflow, we developed a flexible tool for counting the number of unique molecular identifiers (https://github.com/vals/umis/). We compared 15 protocols computationally and 4 protocols experimentally for batch-matched cell populations, in addition to investigating the effects of spike-in molecular degradation. Our analysis provides an integrated framework for comparing scRNA-seq protocols.

Improved Algorithmic Complexity for the 3SEQ Recombination Detection Algorithm.

Identifying recombinant sequences in an era of large genomic databases is challenging as it requires an efficient algorithm to identify candidate recombinants and parents, as well as appropriate statistical methods to correct for the large number of comparisons performed. In 2007, a computation was introduced for an exact nonparametric mosaicism statistic that gave high-precision P values for putative recombinants. This exact computation meant that multiple-comparisons corrected P values also had high precision, which is crucial when performing millions or billions of tests in large databases. Here, we introduce an improvement to the algorithmic complexity of this computation from O(mn3) to O(mn2), where m and n are the numbers of recombination-informative sites in the candidate recombinant. This new computation allows for recombination analysis to be performed in alignments with thousands of polymorphic sites. Benchmark runs are presented on viral genome sequence alignments, new features are introduced, and applications outside recombination analysis are discussed.

Poultry population dynamics and mortality risks in smallholder farms of the Mekong river delta region.

BACKGROUND: Poultry farming is widely practiced by rural households in Vietnam and the vast majority of domestic birds are kept on small household farms. However, smallholder poultry production is constrained by several issues such as infectious diseases, including avian influenza viruses whose circulation remains a threat to public health. This observational study describes the demographic structure and dynamics of small-scale poultry farms of the Mekong river delta region. METHOD: Fifty three farms were monitored over a 20-month period, with farm sizes, species, age, arrival/departure of poultry, and farm management practices recorded monthly. RESULTS: Median flock population sizes were 16 for chickens (IQR: 10-40), 32 for ducks (IQR: 18-101) and 11 for Muscovy ducks (IQR: 7-18); farm size distributions for the three species were heavily right-skewed. Muscovy ducks were kept for long periods and outdoors, while chickens and ducks were farmed indoors or in pens. Ducks had a markedly higher removal rate (broilers: 0.14/week; layer/breeders: 0.05/week) than chickens and Muscovy ducks (broilers: 0.07/week; layer/breeders: 0.01-0.02/week) and a higher degree of specialization resulting in a substantially shorter life span. The rate of mortality due to disease did not differ much among species, with birds being less likely to die from disease at older ages, but frequency of disease symptoms differed by species. Time series of disease-associated mortality were correlated with population size for Muscovy ducks (Kendall's coefficient τ = 0.49, p-value < 0.01) and with frequency of outdoor grazing for ducks (τ = 0.33, p-value = 0.05). CONCLUSION: The study highlights some challenges to disease control in small-scale multispecies poultry farms. The rate of interspecific contact and overlap between flocks of different ages is high, making small-scale farms a suitable environment for pathogens circulation. Muscovy ducks are farmed outdoors with little investment in biosecurity and few inter-farm movements. Ducks and chickens are more at-risk of introduction of pathogens through movements of birds from one farm to another. Ducks are farmed in large flocks with high turnover and, as a result, are more vulnerable to disease spread and require a higher vaccination coverage to maintain herd immunity.

Direct whole-genome deep-sequencing of human respiratory syncytial virus A and B from Vietnamese children identifies distinct patterns of inter- and intra-host evolution.

Human respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections in children ,2 years of age. Little is known about RSV intra-host genetic diversity over the course of infection or about the immune pressures that drive RSV molecular evolution. We performed whole-genome deep-sequencing on 53 RSV-positive samples (37 RSV subgroup A and 16 RSV subgroup B) collected from the upper airways of hospitalized children in southern Vietnam over two consecutive seasons. RSV A NA1 and RSV B BA9 were the predominant genotypes found in our samples, consistent with other reports on global RSV circulation during the same period. For both RSV A and B, the M gene was the most conserved, confirming its potential as a target for novel therapeutics. The G gene was the most variable and was the only gene under detectable positive selection. Further, positively selected sites inG were found in close proximity to and in some cases overlapped with predicted glycosylation motifs, suggesting that selection on amino acid glycosylation may drive viral genetic diversity. We further identified hotspots and coldspots of intra-host genetic diversity in the RSV genome, some of which may highlight previously unknown regions of functional importance.

A Neuropathology Case Report of a Woman with Down Syndrome who Remained Cognitively Stable.

In this neuropathology case report, we present findings from an individual with Down syndrome (DS) who remained cognitively stable despite Alzheimer's disease (AD) neuropathology. Clinical assessments, fluid biomarkers, neuroimaging, and neuropathological examinations were conducted to characterize her condition. Notably, her ApoE genotype was E2/3, which is associated with a decreased risk of dementia. Neuroimaging revealed stable yet elevated amyloid profiles and moderately elevated tau levels, while neuropathology indicated intermediate AD neuropathologic change with Lewy body pathology and cerebrovascular pathology. Despite the presence of AD pathology, the participant demonstrated intact cognitive functioning, potentially attributed to factors such as genetic variations, cognitive resilience, and environmental enrichment. The findings suggest a dissociation between clinical symptoms and neuropathological changes, emphasizing the complexity of AD progression in DS. Further investigation into factors influencing cognitive resilience in individuals with DS, including comorbidities and social functioning, is warranted. Understanding the mechanisms underlying cognitive stability in DS could offer insights into resilience to AD neuropathology in people with DS and in the general population and inform future interventions.

Migration and persistence of human influenza A viruses, Vietnam, 2001-2008.

Understanding global influenza migration and persistence is crucial for vaccine strain selection. Using 240 new human influenza A virus whole genomes collected in Vietnam during 2001-2008, we looked for persistence patterns and migratory connections between Vietnam and other countries. We found that viruses in Vietnam migrate to and from China, Hong Kong, Taiwan, Cambodia, Japan, South Korea, and the United States. We attempted to reduce geographic bias by generating phylogenies subsampled at the year and country levels. However, migration events in these phylogenies were still driven by the presence or absence of sequence data, indicating that an epidemiologic study design that controls for prevalence is required for robust migration analysis. With whole-genome data, most migration events are not detectable from the phylogeny of the hemagglutinin segment alone, although general migratory relationships between Vietnam and other countries are visible in the hemagglutinin phylogeny. It is possible that virus lineages in Vietnam persisted for >1 year.

A Modified BPaL Regimen for Tuberculosis Treatment replaces Linezolid with Inhaled Spectinamides.

The Nix-TB clinical trial evaluated a new 6-month regimen containing three-oral-drugs; bedaquiline (B), pretomanid (Pa) and linezolid (L) (BPaL regimen) for treatment of tuberculosis (TB). This regimen achieved remarkable results as almost 90% of the multidrug resistant (MDR) or extensively drug resistant (XDR) TB participants were cured but many patients also developed severe adverse effects (AEs). The AEs were associated with the long-term administration of the protein synthesis inhibitor linezolid. Spectinamide 1599 (S) is also a protein synthesis inhibitor of Mycobacterium tuberculosis with an excellent safety profile but which lacks oral bioavailability. Here we hypothesize that inhaled spectinamide 1599, combined with BPa --BPaS regimen--has similar efficacy to that of BPaL regimen while simultaneously avoiding the L-associated AEs. The BPaL and BPaS regimens were compared in the Balb/c and C3HeB/FeJ murine chronic TB efficacy models. After 4-weeks of treatment, both regimens promoted equivalent bactericidal effect in both TB murine models. However, treatment with BPaL resulted in significant weight loss and the complete blood count suggested development of anemia. These effects were not similarly observed in mice treated with BPaS. BPaL treatment also decreased myeloid to erythroid ratio and increased concentration of proinflammatory cytokines in bone marrow compared to mice receiving BPaS regimen. During therapy both regimens improved the lung lesion burden, reduced neutrophil and cytotoxic T cells counts while increased the number of B and helper and regulatory T cells. These combined data suggest that inhaled spectinamide 1599 combined with BPa is an effective TB regimen that avoids L-associated AEs. IMPORTANCE: Tuberculosis (TB) is an airborne infectious disease that spreads via aerosols containing Mycobacterium tuberculosis (Mtb), the causative agent of TB. TB can be cured by administration of 3-4 drugs for 6-9 months but there are limited treatment options for patients infected with multidrug (MDR) and extensively resistant (XDR) strains of Mtb. BPaL is a new all-oral combination of drugs consisting of Bedaquiline (B), Pretomanid (Pa) and Linezolid (L). This regimen was able to cure ∼90% of MDR and XDR TB patients in clinical trials but many patients developed severe adverse effects (AEs) associated to the long-term administration of linezolid. We evaluated a new regimen in which Linezolid in the BPaL regimen was replaced with inhaled spectinamide 1599. In the current study, we demonstrate that 4-weeks of treatment with inhaled spectinamide 1599 in combination with Bedaquiline and Pretomanid has equivalent efficacy to the BPaL drug combination and avoids the L-associated-AEs.

A combination of annual and nonannual forces drive respiratory disease in the tropics.

Background: It is well known that influenza and other respiratory viruses are wintertime-seasonal in temperate regions. However, respiratory disease seasonality in the tropics remains elusive. In this study, we aimed to characterize the seasonality of influenza-like illness (ILI) and influenza virus in Ho Chi Minh City (HCMC), Vietnam. Methods: We monitored the daily number of ILI patients in 89 outpatient clinics from January 2010 to December 2019. We collected nasal swabs and tested for influenza from a subset of clinics from May 2012 to December 2019. We used spectral analysis to describe the periodicities in the system. We evaluated the contribution of these periodicities to predicting ILI and influenza patterns through lognormal and gamma hurdle models. Findings: During ten years of community surveillance, 66,799 ILI reports were collected covering 2.9 million patient visits; 2604 nasal swabs were collected 559 of which were PCR-positive for influenza virus. Both annual and nonannual cycles were detected in the ILI time series, with the annual cycle showing 8.9% lower ILI activity (95% CI: 8.8%-9.0%) from February 24 to May 15. Nonannual cycles had substantial explanatory power for ILI trends (ΔAIC = 183) compared to all annual covariates (ΔAIC = 263). Near-annual signals were observed for PCR-confirmed influenza but were not consistent along in time or across influenza (sub)types. Interpretation: Our study reveals a unique pattern of respiratory disease dynamics in a tropical setting influenced by both annual and nonannual drivers. Timing of vaccination campaigns and hospital capacity planning may require a complex forecasting approach.

A combination of annual and nonannual forces drive respiratory disease in the tropics.

INTRODUCTION: It is well known that influenza and other respiratory viruses are wintertime-seasonal in temperate regions. However, respiratory disease seasonality in the tropics is less well understood. In this study, we aimed to characterise the seasonality of influenza-like illness (ILI) and influenza virus in Ho Chi Minh City, Vietnam. METHODS: We monitored the daily number of ILI patients in 89 outpatient clinics from January 2010 to December 2019. We collected nasal swabs and tested for influenza from a subset of clinics from May 2012 to December 2019. We used spectral analysis to describe the periodic signals in the system. We evaluated the contribution of these periodic signals to predicting ILI and influenza patterns through lognormal and gamma hurdle models. RESULTS: During 10 years of community surveillance, 66 799 ILI reports were collected covering 2.9 million patient visits; 2604 nasal swabs were collected, 559 of which were PCR-positive for influenza virus. Both annual and nonannual cycles were detected in the ILI time series, with the annual cycle showing 8.9% lower ILI activity (95% CI 8.8% to 9.0%) from February 24 to May 15. Nonannual cycles had substantial explanatory power for ILI trends (ΔAIC=183) compared with all annual covariates (ΔAIC=263) in lognormal regression. Near-annual signals were observed for PCR-confirmed influenza but were not consistent over time or across influenza (sub)types. The explanatory power of climate factors for ILI and influenza virus trends was weak. CONCLUSION: Our study reveals a unique pattern of respiratory disease dynamics in a tropical setting influenced by both annual and nonannual drivers, with influenza dynamics showing near-annual periodicities. Timing of vaccination campaigns and hospital capacity planning may require a complex forecasting approach.

Effect of imputation on gene network reconstruction from single-cell RNA-seq data.

Despite the advances in single-cell transcriptomics, the reconstruction of gene regulatory networks remains challenging. Both the large amount of zero counts in experimental data and the lack of a consensus preprocessing pipeline for single-cell RNA sequencing (scRNA-seq) data make it hard to infer networks. Imputation can be applied in order to enhance gene-gene correlations and facilitate downstream analysis. However, it is unclear what consequences imputation methods have on the reconstruction of gene regulatory networks. To study this, we evaluate the differences on the performance and structure of reconstructed networks before and after imputation in single-cell data. We observe an inflation of gene-gene correlations that affects the predicted network structures and may decrease the performance of network reconstruction in general. However, within the modest limits of achievable results, we also make a recommendation as to an advisable combination of algorithms while warning against the indiscriminate use of imputation before network reconstruction in general.

Triplication of Synaptojanin 1 in Alzheimer's Disease Pathology in Down Syndrome.

Down Syndrome (DS), caused by triplication of human chromosome 21 (Hsa21) is the most common form of intellectual disability worldwide. Recent progress in healthcare has resulted in a dramatic increase in the lifespan of individuals with DS. Unfortunately, most will develop Alzheimer's disease like dementia (DS-AD) as they age. Understanding similarities and differences between DS-AD and the other forms of the disease - i.e., late-onset AD (LOAD) and autosomal dominant AD (ADAD) - will provide important clues for the treatment of DS-AD. In addition to the APP gene that codes the precursor of the main component of amyloid plaques found in the brain of AD patients, other genes on Hsa21 are likely to contribute to disease initiation and progression. This review focuses on SYNJ1, coding the phosphoinositide phosphatase synaptojanin 1 (SYNJ1). First, we highlight the function of SYNJ1 in the brain. We then summarize the involvement of SYNJ1 in the different forms of AD at the genetic, transcriptomic, proteomic and neuropathology levels in humans. We further examine whether results in humans correlate with what has been described in murine and cellular models of the disease and report possible mechanistic links between SYNJ1 and the progression of the disease. Finally, we propose a set of questions that would further strengthen and clarify the role of SYNJ1 in the different forms of AD.

Poultry farmer response to disease outbreaks in smallholder farming systems in southern Vietnam.

Avian influenza outbreaks have been occurring on smallholder poultry farms in Asia for two decades. Farmer responses to these outbreaks can slow down or accelerate virus transmission. We used a longitudinal survey of 53 small-scale chicken farms in southern Vietnam to investigate the impact of outbreaks with disease-induced mortality on harvest rate, vaccination, and disinfection behaviors. We found that in small broiler flocks (≤16 birds/flock) the estimated probability of harvest was 56% higher when an outbreak occurred, and 214% higher if an outbreak with sudden deaths occurred in the same month. Vaccination and disinfection were strongly and positively correlated with the number of birds. Small-scale farmers - the overwhelming majority of poultry producers in low-income countries - tend to rely on rapid sale of birds to mitigate losses from diseases. As depopulated birds are sent to markets or trading networks, this reactive behavior has the potential to enhance onward transmission.

The past few decades have seen the circulation of avian influenza viruses increase in domesticated poultry, regularly creating outbreaks associated with heavy economic loss. In addition, these viruses can sometimes 'jump' into humans, potentially allowing new diseases ­ including pandemics ­ to emerge. The Mekong river delta, in southern Vietnam, is one of the regions with the highest circulation of avian influenza. There, a large number of farmers practice poultry farming on a small scale, with limited investments in disease prevention such as vaccination or disinfection. Yet, it was unclear how the emergence of an outbreak could change the behavior of farmers. To learn more, Delabouglise et al. monitored 53 poultry farms, with fewer than 1000 chickens per farm, monthly for over a year and a half. In particular, they tracked when outbreaks occurred on each farm, and how farmers reacted. Overall, poultry farms with more than 17 chickens were more likely to vaccinate their animals and use disinfection practices than smaller farms. However, disease outbreaks did not affect vaccination or disinfection practices. When an outbreak occurred, farmers with fewer than 17 chickens tended to sell their animals earlier. For instance, they were 214% more likely to send their animals to market if an outbreak with sudden deaths occurred that month. Even if they do not make as much money selling immature individuals, this strategy may allow them to mitigate economical loss: they can sell animals that may die soon, saving on feeding costs and potentially avoiding further contamination. However, as animals were often sold alive in markets or to itinerant sellers, this practice increases the risk of spreading diseases further along the trade circuits. These data could be most useful to regional animal health authorities, which have detailed knowledge of local farming systems and personal connections in the communities where they work. This can allow them to effect change. They could work with small poultry farmers to encourage them to adopt efficient disease management strategies. Ultimately, this could help control the spread of avian influenza viruses, and potentially help to avoid future pandemics.

Single-Cell Analysis Uncovers a Vast Diversity in Intracellular Viral Defective Interfering RNA Content Affecting the Large Cell-to-Cell Heterogeneity in Influenza A Virus Replication.

Virus replication displays a large cell-to-cell heterogeneity; yet, not all sources of this variability are known. Here, we study the effect of defective interfering (DI) particle (DIP) co-infection on cell-to-cell variability in influenza A virus (IAV) replication. DIPs contain a large internal deletion in one of their eight viral RNAs (vRNA) and are, thus, defective in virus replication. Moreover, they interfere with virus replication. Using single-cell isolation and reverse transcription polymerase chain reaction, we uncovered a large between-cell heterogeneity in the DI vRNA content of infected cells, which was confirmed for DI mRNAs by single-cell RNA sequencing. A high load of intracellular DI vRNAs and DI mRNAs was found in low-productive cells, indicating their contribution to the large cell-to-cell variability in virus release. Furthermore, we show that the magnitude of host cell mRNA expression (some factors may inhibit virus replication), but not the ribosome content, may further affect the strength of single-cell virus replication. Finally, we show that the load of viral mRNAs (facilitating viral protein production) and the DI mRNA content are, independently from one another, connected with single-cell virus production. Together, these insights advance single-cell virology research toward the elucidation of the complex multi-parametric origin of the large cell-to-cell heterogeneity in virus infections.

Serological inference of past primary and secondary dengue infection: implications for vaccination.

Owing to the finding that Dengvaxia® (the only licensed dengue vaccine to date) increases the risk of severe illness among seronegative recipients, the World Health Organization has recommended screening individuals for their serostatus prior to vaccination. To decide whether and how to carry out screening, it is necessary to estimate the transmission intensity of dengue and to understand the performance of the screening method. In this study, we inferred the annual force of infection (FOI; a measurement of transmission intensity) of dengue virus in three locations in Vietnam: An Giang (FOI = 0.04 for the below 10 years age group and FOI = 0.20 for the above 10 years age group), Ho Chi Minh City (FOI = 0.12) and Quang Ngai (FOI = 0.05). In addition, we show that using a quantitative approach to immunoglobulin G (IgG) levels (measured by indirect enzyme-linked immunosorbent assays) can help to distinguish individuals with primary exposures (primary seropositive) from those with secondary exposures (secondary seropositive). We found that primary-seropositive individuals-the main targets of the vaccine-tend to have a lower IgG level, and, thus, they have a higher chance of being misclassified as seronegative than secondary-seropositive cases. However, screening performance can be improved by incorporating patient age and transmission intensity into the interpretation of IgG levels.

The structure model of a cubic aperiodic phase ('quasicrystal without forbidden symmetry axes').

A model structure of the aperiodic cubic phase (a cubic quasicrystal) has been constructed as a periodical packing of hierarchical octahedral clusters which were composed of truncated tetrahedra (Friauf-Laves polyhedra) and chains of Frank-Kasper polyhedra with 14 vertices. The construction of the hierarchical model for the cubic aperiodic phase became possible due to the discovery of a new space subdivision with equal edges and with vertices belonging to two orbits of the space group Fm3m. The subdivision is characterized by unique values and unique relations between the coordinates of the starting points of two orbits. Calculated x-ray diffraction patterns for the proposed hierarchical model are in qualitative agreement with published experimental x-ray patterns for aperiodical phases observed in melt-quenched Mg-Al and Fe-Nb-B-Si alloys.

Model for the transformation of an icosahedral phase into a B2 crystalline phase.

A model for the transformation of an Al-Cu-Fe icosahedral quasicrystal into a crystal with a B2-type phase is proposed. The model is based on two assumptions: (1) the main building block for the quasicrystal structure is a hierarchical dodecahedron composed of two icosahedral clusters, coinciding with two different sections of the {3, 3, 5} polytope; (2) the transformation of the quasicrystal into a B2-type crystal phase can be described as the transition between 3D sections of two polytopes, namely {3, 3, 5} and {3, 4, 3}. In the framework of the proposed model, two experimental facts gain plausible explanations: the transformation of the Al-Cu-Fe quasicrystal into the BCC phase specifically and the orientational relationships observed between this BCC phase and the initial icosahedral quasicrystal.