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Abstract Biomarkers for Alzheimer's disease (AD) diagnosis do not always correlate reliably with cognitive symptoms, making clinical diagnosis inconsistent. In this study, the performance of a graphical neural network (GNN) classifier based on data‐driven diagnostic classes from unsupervised clustering on heterogeneous data is compared to the performance of a classifier using clinician diagnosis as an outcome. Unsupervised clustering on tau‐positron emission tomography (PET) and cognitive and functional assessment data was performed. Five clusters embedded in a non‐linear uniform manifold approximation and project (UMAP) space were identified. The individual clusters revealed specific feature characteristics with respect to clinical diagnosis of AD, gender, family history, age, and underlying neurological risk factors (NRFs). In particular, one cluster comprised mainly diagnosed AD cases. All cases within this cluster were re‐labelled AD cases. The re‐labelled cases are characterized by high cerebrospinal fluid amyloid beta (CSF Aβ) levels at a younger age, even though Aβ data was not used for clustering. A GNN model was trained using the re‐labelled data with a multiclass area‐under‐the‐curve (AUC) of 95.2%, higher than the AUC of a GNN trained on clinician diagnosis (91.7%; p = 0.02). Overall, our work suggests that more objective cluster‐based diagnostic labels combined with GNN classification may have value in clinical risk stratification and diagnosis of AD.

Abstract Universal stress proteins (USPs) are ubiquitously expressed in bacteria, archaea, and eukaryotes and play a lead role in adaptation to environmental conditions. They enable adaptation of bacterial pathogens to the conditions encountered in the human niche, including hypoxia, oxidative stress, osmotic stress, nutrient deficiency, or acid stress, thereby facilitating colonization. We previously reported that all six USP proteins encoded within a low‐oxygen activated (lxa) locus in Burkholderia cenocepacia showed increased abundance during chronic colonization of the cystic fibrosis (CF) lung. However, the role of USPs in chronic cystic fibrosis infection is not well understood. Structural modeling identified surface arginines on one lxa‐encoded USP, USP76, which suggested it mediated interactions with heparan sulfate. Using mutants derived from the B. cenocepacia strain, K56‐2, we show that USP76 is involved in host cell attachment. Pretreatment of lung epithelial cells with heparanase reduced the binding of the wild‐type and complement strains but not the Δusp76 mutant strain, indicating that USP76 is directly or indirectly involved in receptor recognition on the surface of epithelial cells. We also show that USP76 is required for growth and survival in many conditions associated with the CF lung, including acidic conditions and oxidative stress. Moreover, USP76 also has a role in survival in macrophages isolated from people with CF. Overall, while further elucidation of the exact mechanism(s) is required, we can conclude that USP76, which is upregulated during chronic infection, is involved in bacterial survival within CF macrophages, a hallmark of Burkholderia infection.

Abstract Common bean (Phaseolus vulgaris L.) is the main source of protein, fiber, and iron for Guatemala's poorest households. Bean rust (caused by Uromyces appendiculatus (Pers) Unger) can reduce seed yield up to 100%. There is limited information about U. appendiculatus virulence diversity in Guatemala, especially in the mid‐altitude highlands. To address this limitation, in 2015, 23 U. appendiculatus samples were collected in the Western Guatemalan Highlands and characterized as races 63‐1 and 31‐1 using the rust differential set. These two races, along with the newer race 20‐3 found in North Dakota, were used to evaluate the reaction in 372 climbing bean accessions from Guatemala. Most of the accessions were resistant: 82% to race 63‐1, 86% to race 31‐1, and 90% to race 20‐3. Based on a genome‐wide association study (GWAS) using 78,754 single nucleotide polymorphisms (SNPs), regions on Pv02 (38.13–38.22 Mb) and Pv04 (379 kb) were associated with resistance to race 20‐3; on Pv10 (10.71–10.68 and 11.09 Mb) and Pv04 (1.42 Mb) to race 63‐1; and on Pv04 (39.28 Mb) along with Pv02 (35.92 Mb) to race 31‐1. The regions on Pv04: 379 kb, 1.42 Mb and 39.28 Mb felt close to the genetic block B‐190, containing Ur‐5 and Ur‐14. Moreover, previously unreported genetic factors for bean rust resistance located on Pv02 (38.13–38.22 Mb), Pv10 (10.71–10.68 Mb), and Pv02 (35.92 Mb) were observed in this population and may prove useful for bean improvement. Using these bean rust‐resistant Guatemalan accessions as parents in a crop improvement program will help to maintain seed yield where the bean rust pathogen is present.

Abstract Introduction Cardiovascular disease (CVD) is the leading cause of mortality in people with Type 2 diabetes mellitus (T2DM). Statins reduce low‐density lipoproteins and positively affect CVD outcomes. Statin type and dose have differential effects on glycaemia and risk of incident T2DM; however, the impact of gender, and of individual drugs within the statin class, remains unclear. Aim To compare effects of simvastatin and atorvastatin on lipid and glycaemic control in men and women with and without T2DM, and their association with incident T2DM. Methods The effect of simvastatin and atorvastatin on lipid and glycaemic control was assessed in the T2DM DiaStrat cohort. Prescribed medications, gender, age, BMI, diabetes duration, blood lipid profile and HbA1c were extracted from Electronic Care Record, and compared in men and women prescribed simvastatin and atorvastatin. Analyses were replicated in the UKBiobank in those with and without T2DM. The association of simvastatin and atorvastatin with incident T2DM was also investigated in the UKBiobank. Cohorts where matched for age, BMI and diabetes duration in men and women, in the UKBioBank analysis, where possible. Results Simvastatin was associated with better LDL (1.6 ± 0.6 vs 2.1 ± 0.9 mmol/L, p

Abstract Dry bean (Phaseolus vulgaris L.) production in many regions is threatened by white mold (WM) [Sclerotinia sclerotiorum (Lib.) de Bary]. Seed yield losses can be up to 100% under conditions favorable for the pathogen. The low heritability, polygenic inheritance, and cumbersome screening protocols make it difficult to breed for improved genetic resistance. Some progress in understanding genetic resistance and germplasm improvement has been accomplished, but cultivars with high levels of resistance are yet to be released. A WM multiparent advanced generation inter‐cross (MAGIC) population (n = 1060) was developed to facilitate mapping and breeding efforts. A seedling straw test screening method provided a quick assay to phenotype the population for response to WM isolate 1980. Nineteen MAGIC lines were identified with improved resistance. For genome‐wide association studies (GWAS), the data was transformed into three phenotypic distributions—quantitative, polynomial, and binomial—and coupled with ∼52,000 single‐nucleotide polymorphisms (SNPs). The three phenotypic distributions identified 30 significant genomic intervals [−log10 (P value) ≥ 3.0]. However, across distributions, four new genomic regions as well as two regions previously reported were found to be associated with resistance. Cumulative R2 values were 57% for binomial distribution using 13 genomic intervals, 41% for polynomial using eight intervals, and 40% for quantitative using 11 intervals. New resistant germplasm as well as new genomic regions associated with resistance are now available for further investigation.

Abstract Adaptation of opportunistic pathogens to their host environment requires reprogramming of a vast array of genes to facilitate survival in the host. Burkholderia cenocepacia, a Gram‐negative bacterium with a large genome of ∼8 Mb that colonizes environmental niches, is exquisitely adaptable to the hypoxic environment of the cystic fibrosis lung and survives in macrophages. We previously identified an immunoreactive acidic protein encoded on replicon 3, BCAS0292. Deletion of the BCAS0292 gene significantly altered the abundance of 979 proteins by 1.5‐fold or more; 19 proteins became undetectable while 545 proteins showed ≥1.5‐fold reduced abundance, suggesting the BCAS0292 protein is a global regulator. Moreover, the ∆BCAS0292 mutant showed a range of pleiotropic effects: virulence and host‐cell attachment were reduced, antibiotic susceptibility was altered, and biofilm formation enhanced. Its growth and survival were impaired in 6% oxygen. In silico prediction of its three‐dimensional structure revealed BCAS0292 presents a dimeric β‐structure with a negative surface charge. The ΔBCAS0292 mutant displayed altered DNA supercoiling, implicated in global regulation of gene expression. Three proteins were identified in pull‐downs with FLAG‐tagged BCAS0292, including the Histone H1‐like protein, HctB, which is recognized as a global transcriptional regulator. We propose that BCAS0292 protein, which we have named Burkholderia negatively surface‐charged regulatory protein 1 (Bnr1), acts as a DNA‐mimic and binds to DNA‐binding proteins, altering DNA topology and regulating the expression of multiple genes, thereby enabling the adaptation of B. cenocepacia to highly diverse environments.

Abstract PD‐L1 inhibitors are part of first line treatment options for patients with advanced non‐small cell lung cancer. PD‐L1 immunohistochemistry (IHC) assays act as either a companion or a complementary diagnostic. The purpose of this study is to describe the experience of external quality assurance (EQA) provider UK NEQAS ICC and ISH with the comparison of different PD‐L1 assays used in daily practice. Three EQA rounds (pilot, run A and run B) were carried out using formalin fixed paraffin embedded samples with sample sets covering a range of epitope concentrations, including ‘critical samples’ near to clinical threshold cut‐offs. An expert panel (n = 4) evaluated all returned slides simultaneously and independently on a multi‐header microscope together with the participants own in‐house control material. The tonsil sample was evaluated as ‘acceptable’ or ‘unacceptable’, and for the other samples the percentage of PD‐L1 stained tumour cells were estimated in predetermined categories (

Abstract Introduction We assessed the association of self‐reported hearing impairment and hearing aid use with cognitive decline and progression to mild cognitive impairment (MCI). Methods We used a large referral‐based cohort of 4358 participants obtained from the National Alzheimer's Coordinating Center. The standard covariate‐adjusted Cox proportional hazards model, the marginal structural Cox model with inverse probability weighting, standardized Kaplan‐Meier curves, and linear mixed‐effects models were applied to test the hypotheses. Results Hearing impairment was associated with increased risk of MCI (standardized hazard ratio [HR] 2.58, 95% confidence interval [CI: 1.73 to 3.84], P = .004) and an accelerated rate of cognitive decline (P

Abstract The loss of huge areas of peat swamp forest in Southeast Asia and the resulting negative environmental effects, both local and global, have led to an increasing interest in peat restoration in the region. Satellite remote sensing offers the potential to provide up‐to‐date information on peat swamp forest loss across large areas, and support spatial explicit conservation and restoration planning. Fusion of optical and radar remote sensing data may be particularly valuable in this context, as most peat swamp forests are in areas with high cloud cover, which limits the use of optical data. Radar data can ‘see through’ cloud, but experience so far has shown that it doesn't discriminate well between certain types of land cover. Various approaches to fusion exist, but there is little information on how they compare. To assess this untapped potential, we compare three different classification methods with Sentinel‐1 and Sentinel‐2 images to map the remnant distribution of peat swamp forest in the area surrounding Sungai Buluh Protection Forest, Sumatra, Indonesia. Results show that data fusion increases overall accuracy in one of the three methods, compared to the use of optical data only. When data fusion was used with the pixel‐based classification using the original pixel values, overall accuracy increased by a small, but statistically significant amount. Data fusion was not beneficial in the case of object‐based classification or pixel‐based classification using principal components. This indicates optical data are still the main source of information for land cover mapping in the region. Based on our findings, we provide methodological recommendations to help those involved in peatland restoration capitalize on the potential of big data.

Abstract Introduction Hearing aid usage has been linked to improvements in cognition, communication, and socialization, but the extent to which it can affect the incidence and progression of dementia is unknown. Such research is vital given the high prevalence of dementia and hearing impairment in older adults, and the fact that both conditions often coexist. In this study, we examined for the first time the effect of the use of hearing aids on the conversion from mild cognitive impairment (MCI) to dementia and progression of dementia. Methods We used a large referral‐based cohort of 2114 hearing‐impaired patients obtained from the National Alzheimer's Coordinating Center. Survival analyses using multivariable Cox proportional hazards regression model and weighted Cox regression model with censored data were performed to assess the effect of hearing aid use on the risk of conversion from MCI to dementia and risk of death in hearing‐impaired participants. Disease progression was assessed with Clinical Dementia Rating Sum of Boxes (CDR‐SB) scores. Three types of sensitivity analyses were performed to validate the robustness of the results. Results MCI participants that used hearing aids were at significantly lower risk of developing all‐cause dementia compared to those not using hearing aids (hazard ratio [HR] 0.73, 95% confidence interval [CI], 0.61 to 0.89; false discovery rate [FDR] P = 0.004). The mean annual rate of change (standard deviation) in CDR‐SB scores for hearing aid users with MCI was 1.3 (1.45) points and significantly lower than for individuals not wearing hearing aids with a 1.7 (1.95) point increase in CDR‐SB per year (P = 0.02). No association between hearing aid use and risk of death was observed. Our findings were robust subject to sensitivity analyses. Discussion Among hearing‐impaired adults, hearing aid use was independently associated with reduced dementia risk. The causality between hearing aid use and incident dementia should be further tested.

Abstract Introduction Conflicting results on dementia risk factors have been reported across studies. We hypothesize that variation in data preparation methods may partially contribute to this issue. Methods We propose a comprehensive data preparation approach comparing individuals with stable diagnosis over time to those who progress to mild cognitive impairment (MCI)/dementia. This was compared to the often‐used “baseline” analysis. Multivariate logistic regression was used to evaluate both methods. Results The results obtained from sensitivity analyses were consistent with those from our multi‐time‐point data preparation approach, exhibiting its robustness. Compared to analysis using only baseline data, the number of significant risk factors identified in progression analyses was substantially lower. Additionally, we found that moderate depression increased healthy‐to‐MCI/dementia risk, while hypertension reduced MCI‐to‐dementia risk. Discussion Overall, multi‐time‐point–based data preparation approaches may pave the way for a better understanding of dementia risk factors, and address some of the reproducibility issues in the field.

Abstract Introduction Later‐life brain alterations in former tackle football players are poorly understood, particularly regarding their relationship with repetitive head impacts (RHIs) and clinical function. We examined white matter signal abnormalities (WMSAs) and their association with RHIs and clinical function in former National Football League (NFL) players. Methods Eighty‐six clinically symptomatic former NFL players and 23 same‐age reportedly asymptomatic controls without head trauma exposure underwent magnetic resonance imaging and neuropsychological testing. FreeSurfer calculated WMSAs. A cumulative head impact index quantified RHIs. Results In former NFL players, increased volume of WMSAs was associated with higher cumulative head impact index scores (P = .043) and worse psychomotor speed and executive function (P = .015). Although former NFL players had greater WMSA volume than controls (P = .046), these findings are inconclusive due to recruitment of controls based on lack of clinical symptoms and head trauma exposure. Discussion In former NFL players, WMSAs may reflect long‐term microvascular and nonmicrovascular pathologies from RHIs that negatively impact cognition.

Common bean ( L.) is the most consumed edible grain legume worldwide and contains a wide range of nutrients for human health including dietary fiber. Diets high in beans are associated with lower rates of chronic diseases such as obesity and type 2 diabetes, and the content of dietary fibers varies among different market classes of dry bean. In this study, we evaluated the dietary fiber content in a Middle American diversity panel (MDP) of common bean and evaluated the genetic architecture of the various dietary fiber components. The dietary fiber components included insoluble and soluble dietary fibers as well as the antinutritional raffinose family of oligosaccharides (RFOs; raffinose, stachyose, and verbascose). All variables measured differed among market classes and entries. Colored bean seeds had higher levels of insoluble dietary fibers with the black market class showing also the highest raffinose and stachyose content. Cultivars and lines released since 1997 had higher insoluble dietary fibers and RFO content in race Durango. Higher levels of RFOs were also observed in cultivars with type II growth habit that was a recent breeding target in Durango race germplasm. Candidate genes for dietary fiber traits, especially homologs to two main genes in the RFO biosynthesis pathway, were identified. The knowledge of diversity of dietary fibers in the MDP accompanied with the identification of candidate genes could effectively improve dietary fiber components in common bean.

Common bean ( L.) breeding programs aim to improve both agronomic and seed characteristics traits. However, the genetic architecture of the many traits that affect common bean production are not completely understood. Genome-wide association studies (GWAS) provide an experimental approach to identify genomic regions where important candidate genes are located. A panel of 280 modern bean genotypes from race Mesoamerica, referred to as the Middle American Diversity Panel (MDP), were grown in four US locations, and a GWAS using >150,000 single-nucleotide polymorphisms (SNPs) (minor allele frequency [MAF] ≥ 5%) was conducted for six agronomic traits. The degree of inter- and intrachromosomal linkage disequilibrium (LD) was estimated after accounting for population structure and relatedness. The LD varied between chromosomes for the entire MDP and among race Mesoamerica and Durango–Jalisco genotypes within the panel. The LD patterns reflected the breeding history of common bean. Genome-wide association studies led to the discovery of new and known genomic regions affecting the agronomic traits at the entire population, race, and location levels. We observed strong colocalized signals in a narrow genomic interval for three interrelated traits: growth habit, lodging, and canopy height. Overall, this study detected ∼30 candidate genes based on a priori and candidate gene search strategies centered on the 100-kb region surrounding a significant SNP. These results provide a framework from which further research can begin to understand the actual genes controlling important agronomic production traits in common bean.