bluuebunny/crossref_metadata_2025 huggingface dataset:
Coexpression of gene transcripts with monoamine oxidase a quantified by human in vivo positron emission tomography
Authors: Godbersen G M , Murgaš M , Gryglewski G , Klöbl M , Unterholzner J , Rischka L , Spies M , Baldinger-Melich P , Winkler D , Lanzenberger R
Published: November 2021

The monoamine oxidase A (MAO-A) is integral to monoamine metabolism and is thus relevant to the pathophysiology of various neuropsychiatric disorders; however, associated gene-enzyme relations are not well understood. This study aimed to unveil genes coexpressed with MAO-A. Therefore, 18 179 mRNA expression maps (based on the Allen Human Brain Atlas) were correlated with the cerebral distribution volume (VT) of MAO-A assessed in 36 healthy subjects (mean age ± standard deviation: 32.9 ± 8.8 years, 18 female) using [11C]harmine positron emission tomography scans. Coexpression analysis was based on Spearman’s ρ, over-representation tests on Fisher’s exact test with false discovery rate (FDR) correction. The analysis revealed 35 genes in cortex (including B-cell translocation gene family, member 3, implicated in neuroinflammation) and 247 genes in subcortex (including kallikrein-related peptidase 10, implicated in Alzheimer’s disease). Significantly over-represented Gene Ontology terms included “neuron development”, “neuron differentiation”, and “cell-cell signaling” as well as “axon” and “neuron projection”. In vivo MAO-A enzyme distribution and MAOA expression did not correlate in cortical areas (ρ = 0.08) while correlation was found in subcortical areas (ρ = 0.52), suggesting influences of region-specific post-transcriptional and -translational modifications. The herein reported information could contribute to guide future genetic studies, deepen the understanding of associated pathomechanisms and assist in the pursuit of novel therapeutic targets.
More on the invisibility of chronic kidney disease… and counting
Authors: Carriazo Sol , Villalvazo Priscila , Ortiz Alberto
Published: November 2021

Lack of awareness of a diagnosis of chronic kidney disease (CKD) in patients and physicians is a major contributor to fueling the CKD pandemic by also making it invisible to researchers and health authorities. This is an urgent matter to tackle if dire predictions of future CKD burden are to be addressed. CKD is set to become the fifth-leading global cause of death by 2040 and the second-leading cause of death before the end of the century in some countries with long life expectancy. Coronavirus disease 2019 (COVID-19) illustrated this invisibility: only after the summer of 2020 did it become clear that CKD was a major driver of COVID-19 mortality, both in terms of prevalence as a risk factor and of the risk conferred for lethal COVID-19. However, by that time the damage was done: news outlets and scientific publications continued to list diabetes and hypertension, but not CKD, as major risk factors for severe COVID-19. In a shocking recent example from Sweden, CKD was found to be diagnosed in just 23% of 57 880 persons who fulfilled diagnostic criteria for CKD. In the very same large cohort, diabetes or cancer were diagnosed in 29% of persons, hypertension in 82%, cardiovascular disease in 39% and heart failure in 28%. Thus, from the point of view of physicians, patients and health authorities, CKD was the least common comorbidity in persons with CKD, ranking sixth, after other better-known conditions. One of the consequences of this lack of awareness was that nephrotoxic medications were more commonly prescribed in patients with CKD who did not have a diagnosis of CKD. Low awareness of CKD may also fuel concepts such as the high prevalence of hypertensive nephropathy when CKD is diagnosed after the better-known condition of hypertension.
Efficient Traceable Attribute-Based Signature With Update-Free Revocation For Blockchain
Authors: Zhang Jixin , Chen Jiageng
Published: November 2021

Attribute-based signature (ABS) allows signers with a set of attributes to sign messages anonymously using a specific signing policy. However, previous schemes suffer from some efficiency issues which are not widely applied on the blockchain. In this paper, we investigate ABS regarding its features and efficiency in the blockchain setting and provide our solution correspondingly. To solve the revocation problem of ABS in a more efficient manner, we introduce the update-free revocation function. Instead of the passive attribute expiration approaches, we take the active method to ensure that no parameter updates are required by users after the execution of the revocation function. In terms of efficiency, we first address the problem that the signer has to provide proof for all attributes in the predicate for privacy, which is one of the efficiency bottlenecks for ABS. By taking advantage of the blockchain architecture, we propose a new solution which can achieve the constant signature size and verification cost, while the signing cost can be greatly reduced. The corresponding security levels are satisfied according to their strict criteria. A generic construction as well as an instantiation are provided which is provably secure in the standard model satisfying the newly defined formal security definitions. Finally, a purer primitive is discussed.
Four-dimensional flow magnetic resonance imaging visualizes reverse vortex pattern and energy loss increase in left bundle branch block
Authors: Miyajima Keisuke , Urushida Tsuyoshi , Ito Kazuki , Kin Fumihiko , Okazaki Ayako , Takashima Yasuyo , Watanabe Tomoyuki , Kawaguchi Yoshitaka , Wakabayashi Yasushi , Takehara Yasuo , Maekawa Yuichiro
Published: November 2021

Aims

This study aimed to investigate the intraventricular blood flow pattern of patients with left bundle branch block (LBBB) using four-dimensional flow magnetic resonance imaging (4D-flow MRI).

Methods and results

We performed 4D-flow MRI for 16 LBBB patients (LBBB group) and 16 propensity score-matched patients with a normal QRS duration (non-LBBB group). The energy loss (EL) in the left ventricle was evaluated. In both groups, blood flow from the mitral valve to the apex of the heart and left ventricular (LV) outflow tract during LV diastole were observed. Vortices were also observed in both groups. There were two patterns of vortices: unidirectional clockwise rotation and counterclockwise rotation taking place from the mid-diastole to the systole (reverse pattern). The reverse pattern was observed significantly more frequently in the LBBB group (LBBB 94% vs. non-LBBB 19%, P < 0.001). The interobserver agreement for the streamline analysis was good (kappa = 0.68). The maximum EL was significantly higher in the LBBB group [LBBB 12 (11–15) mW vs. non-LBBB 8.0 (6.2–9.7) mW, P < 0.001].

Conclusion

Left bundle branch block patients may suffer from inefficient LV haemodynamics reflected by non-physiological counterclockwise vortices and increased EL. Thus, the shape of the vortices and EL in the left ventricle can serve as markers of LV mechanical dyssynchrony in LBBB patients and could be investigated as predictors of response to cardiac resynchronization therapy.
Viable fructophilic lactic acid bacteria present in honeybee-based food products
Authors: Takatani Naoki , Endo Akihito
Published: November 2021

Fructophilic lactic acid bacteria (FLAB) are a group of lactic acid bacteria (LAB) with unique growth characteristics and are regarded as promising candidates for foods or food ingredients. The present study characterized levels of viable FLAB cells in honeybee-based food products, especially focusing on fresh honey. FLAB were recovered from 88% of fresh honey samples (harvested within a week) tested, and 29% of the fresh honey samples contained FLAB with levels of over 105 CFU/g. FLAB species found in the tested fresh honeys were mostly Apilactobacillus kunkeei and Fructobacillus fructosus. FLAB were not recovered from aged honey samples (aged over 2 weeks after harvest). Fresh comb honey and bee pollen samples occasionally contained low levels of FLAB. When FLAB were inoculated into honeys (linden honey and clover honey), their viability markedly reduced during a week. One of the reasons for this decrease was presence of H2O2 in the honeys, and supplementation of catalase significantly improved their survivability in linden honey. The long history of human consumption of fresh honey suggests that viable FLAB cells do not present health concerns.
A goal-oriented adaptive finite-element approach for 3-D marine controlled-source electromagnetic problems with general electrical anisotropy
Authors: Wang Feiyan , Ren Zhengyong , Zhao Lihong
Published: November 2021

We present a goal-oriented adaptive finite-element algorithm for accurately modelling marine controlled-source electromagnetic responses in 3-D media with general electrical anisotropy. We formulate the primal boundary value problem in terms of the total electric field for general applications. Following the goal-oriented adaptivity concept, the dual problem is derived from a functional designed to measure the data errors of interest in light of the data quality. We approximate the solutions to the primal and dual formulations using the edge finite-element method on tetrahedral grids for a flexible treatment of complex geological settings and survey geometries. To control the mesh adaptation, we develop a reliable residual-type a posteriori error estimation that takes account of the volumetric residual and the numerical discontinuity of the normal component of the electrical current density and that of the tangential component of the magnetic field with respect to non-smooth and anisotropic coefficients. We demonstrate the proposed modelling solver on 1-D MCSEM scenarios with varying degrees of electrical anisotropy. The comparison with goal-oriented adaptivity results obtained from other three commonly used error indicators shows that our approach is robust in dealing with both moderate and strong electrical anisotropy. After that, we constructed a 3-D hydrocarbon-bearing reservoir model with slope seafloor topography and tilted transverse isotropy in the background to examine our algorithm for the case of multiple sources. Finally, we implement a sensitivity analysis procedure to evaluate the resolution of the electrical anisotropy. The quantitative results indicate limitations and preferences of conventional MCSEM data in resolving anisotropic models, providing fundamental insights for inversion based data interpretation.
Determinants of maternal knowledge on neonatal danger signs and care-seeking practices in a rural area of southeastern Ethiopia
Authors: Getachew Tamirat , Assebe Yadeta Tesfaye , Gereziher Teklehaimanot , Eyeberu Addis , Dheresa Merga
Published: November 2021

Background

Most infants in southeastern Ethiopia are either born at home or discharged from the health facility early and families should be able to recognize signs of newborn illnesses and bring the sick newborn to a health facility to receive care. However, studies are limited and the available studies were conducted in urban areas and/or at an institution level. This study aimed to assess the determinants of maternal knowledge of neonatal danger signs and care-seeking practices.

Methods

A community-based cross-sectional study was conducted on 520 post-natal mothers using a multistage sampling method from 1 to 30 March 2019. The data were analysed using SPSS version 20 using binary logistic regression. Statistical significance was declared at p<0.05.

Results

Mothers’ level of knowledge of neonatal danger signs was 50.2% (95% confidence interval [CI] 46.3 to 54.3) and 61% of them sought healthcare when they noticed danger signs. Maternal education level (adjusted odds ratio [AOR] 2.15 [95% CI 1.11 to 4.17]), husband's education level (AOR 2.05 [95% CI 1.07 to 3.94]), residency (AOR 5.83 [95% CI 2.77 to 12.24]), antenatal visits (AOR 2.10 [95% CI 1.13 to 3.90]), antenatal care (ANC) counselling (AOR 4.33 [95% CI 1.88 to 9.98]) and knowledge about essential newborn care (AOR 3.91 [95% CI 2.05 to 7.48]) were the determining factors.

Conclusion

The mothers’ level of knowledge of neonatal danger signs was low and unsafe care-seeking practices were identified. The mothers’ education level, husbands’ education level, residence, ANC visits, counselling during ANC and knowledge about essential newborn care were found to be statistically significant determinants. Most of the mothers take their sick neonates to traditional healers and provide home remedies. Intervention modalities focusing on maternal counselling on the most common symptoms of illness in neonates are essential to increase mothers’ recognition of illness and improve care-seeking practices.
Multiple tolerance checkpoints restrain affinity maturation of B cells expressing the germline precursor of a lupus patient-derived anti-dsDNA antibody in knock-in mice
Authors: El Hussien Marwa Ali , Tsai Chao-Yuan , Satouh Yuhkoh , Motooka Daisuke , Okuzaki Daisuke , Ikawa Masahito , Kikutani Hitoshi , Sakakibara Shuhei
Published: November 2021

Anti-dsDNA antibodies are a hallmark of systemic lupus erythematosus and are highly associated with its exacerbation. Cumulative evidence has suggested that somatic hypermutation contributes to the high-affinity reactivity of anti-dsDNA antibodies. Our previous study demonstrated that these antibodies are generated from germline precursors with low-affinity ssDNA reactivity through affinity maturation and clonal expansion in patients with acute lupus. This raised the question of whether such precursors could be subjected to immune tolerance. To address this, we generated a site-directed knock-in (KI) mouse line, G9gl, which carries germline-reverted sequences of the VH–DH–JH and Vκ–Jκ regions of patient-derived, high-affinity anti-dsDNA antibodies. G9gl heterozygous mice had a reduced number of peripheral B cells, only 27% of which expressed G9gl B-cell receptor (BCR). The remaining B cells harbored non-KI allele-derived immunoglobulin heavy (IgH) chains or fusion products of upstream mouse VH and the KI gene, suggesting that receptor editing through VH replacement occurred in a large proportion of B cells in the KI mice. G9gl BCR-expressing B cells responded to ssDNA but not dsDNA, and exhibited several anergic phenotypes, including reduced surface BCR and shortened life span. Furthermore, G9gl B cells were excluded from germinal centers (GCs) induced by several conditions. In particular, following immunization with methylated bovine serum albumin-conjugated bacterial DNA, G9gl B cells occurred at a high frequency in memory B cells but not GC B cells or plasmablasts. Collectively, multiple tolerance checkpoints prevented low-affinity precursors of pathogenic anti-dsDNA B cells from undergoing clonal expansion and affinity maturation in GCs.
Management of bladder cancer in older patients
Authors: Hatakeyama Shingo , Narita Shintaro , Okita Kazutaka , Narita Takuma , Iwamura Hiromichi , Fujita Naoki , Inokuchi Junichi , Matsui Yoshiyuki , Kitamura Hiroshi , Ohyama Chikara
Published: November 2021

Evidence has shown that patients with bladder cancer are diagnosed at a much older age compared with those with other cancers. Given that co-morbidities and frailty are prevalent in older patients with advanced bladder cancer, they are easily excluded from randomized controlled trials. As little evidence has been available regarding assessment tools for frailty, the management of those patients remains challenging. This weakness is strongly manifested in muscle-invasive bladder cancer. Despite radical cystectomy is the standard of care for bladder cancer, there is an extensive undertreatment of older adult patients with potentially curative muscle-invasive bladder cancer. However, it is also true that radical cystectomy is often unsuitable for vulnerable or frail patients. Bladder preservation using trimodality therapy has been utilized as an alternative option, but the appropriate selection criteria for trimodality therapy remain unclear. Cisplatin-based regimens have been the first choice for advanced disease among eligible patients. Moreover, immunotherapy appears to have similar benefits and tolerability in both older and younger patients. Furthermore, palliative or supportive interventions need to be initiated earlier in patients with metastatic disease. Accumulating evidence suggests that frailty may play a key role in the selection of treatment modalities. Older patients should be considered for standard treatment based on frailty and not chronological age. Moreover, older patients with bladder cancer need to undergo geriatric assessment for proper decision-making.
Using Capture–Recapture Methodology to Enhance Precision of Representative Sampling-Based Case Count Estimates
Authors: Lyles Robert H , Zhang Yuzi , Ge Lin , England Cameron , Ward Kevin , Lash Timothy L , Waller Lance A
Published: November 2021

The application of serial principled sampling designs for diagnostic testing is often viewed as an ideal approach to monitoring prevalence and case counts of infectious or chronic diseases. Considering logistics and the need for timeliness and conservation of resources, surveillance efforts can generally benefit from creative designs and accompanying statistical methods to improve the precision of sampling-based estimates and reduce the size of the necessary sample. One option is to augment the analysis with available data from other surveillance streams that identify cases from the population of interest over the same timeframe, but may do so in a highly nonrepresentative manner. We consider monitoring a closed population (e.g., a long-term care facility, patient registry, or community), and encourage the use of capture–recapture methodology to produce an alternative case total estimate to the one obtained by principled sampling. With care in its implementation, even a relatively small simple or stratified random sample not only provides its own valid estimate, but provides the only fully defensible means of justifying a second estimate based on classical capture–recapture methods. We initially propose weighted averaging of the two estimators to achieve greater precision than can be obtained using either alone, and then show how a novel single capture–recapture estimator provides a unified and preferable alternative. We develop a variant on a Dirichlet-multinomial-based credible interval to accompany our hybrid design-based case count estimates, with a view toward improved coverage properties. Finally, we demonstrate the benefits of the approach through simulations designed to mimic an acute infectious disease daily monitoring program or an annual surveillance program to quantify new cases within a fixed patient registry.
Interactions between a mechanosensitive channel and cell wall integrity signaling influence pollen germination in Arabidopsis thaliana
Authors: Wang Yanbing , Coomey Joshua , Miller Kari , Jensen Gregory S , Haswell Elizabeth S
Published: November 2021

Cells employ multiple systems to maintain cellular integrity, including mechanosensitive ion channels and the cell wall integrity (CWI) pathway. Here, we use pollen as a model system to ask how these different mechanisms are interconnected at the cellular level. MscS-Like 8 (MSL8) is a mechanosensitive channel required to protect Arabidopsis thaliana pollen from osmotic challenges during in vitro rehydration, germination, and tube growth. New CRISPR/Cas9 and artificial miRNA-generated msl8 alleles produced unexpected pollen phenotypes, including the ability to germinate a tube after bursting, dramatic defects in cell wall structure, and disorganized callose deposition at the germination site. We document complex genetic interactions between MSL8 and two previously established components of the CWI pathway, MARIS and ANXUR1/2. Overexpression of MARISR240C-FP suppressed the bursting, germination, and callose deposition phenotypes of msl8 mutant pollen. Null msl8 alleles suppressed the internalized callose structures observed in MARISR240C-FP lines. Similarly, MSL8-YFP overexpression suppressed bursting in the anxur1/2 mutant background, while anxur1/2 alleles reduced the strong rings of callose around ungerminated pollen grains in MSL8-YFP overexpressors. These data show that mechanosensitive ion channels modulate callose deposition in pollen and provide evidence that cell wall and membrane surveillance systems coordinate in a complex manner to maintain cell integrity.
Rice Cell Division Cycle 20s are required for faithful chromosome segregation and cytokinesis during meiosis
Authors: Lin Ya-Nan , Jiang Chen-Kun , Cheng Zhu-Kuan , Wang Dong-Hui , Shen Li-Ping , Xu Cong , Xu Zhi-Hong , Bai Shu-Nong
Published: November 2021

Chromosome segregation must be under strict regulation to maintain chromosome euploidy and stability. Cell Division Cycle 20 (CDC20) is an essential cell cycle regulator that promotes the metaphase-to-anaphase transition and functions in the spindle assembly checkpoint, a surveillance pathway that ensures the fidelity of chromosome segregation. Plant CDC20 genes are present in multiple copies, and whether CDC20s have the same functions in plants as in yeast and animals is unclear, given the potential for divergence or redundancy among the multiple copies. Here, we studied all three CDC20 genes in rice (Oryza sativa) and constructed two triple mutants by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9-mediated genome editing to explore their roles in development. Knocking out all three CDC20 genes led to total sterility but did not affect vegetative development. Loss of the three CDC20 proteins did not alter mitotic division but severely disrupted meiosis as a result of asynchronous and unequal chromosome segregation, chromosome lagging, and premature separation of chromatids. Immunofluorescence of tubulin revealed malformed meiotic spindles in microsporocytes of the triple mutants. Furthermore, cytokinesis of meiosis I was absent or abnormal, and cytokinesis II was completely prevented in all mutant microsporocytes; thus, no tetrads or pollen formed in either cdc20 triple mutant. Finally, the subcellular structures and functions of the tapetum were disturbed by the lack of CDC20 proteins. These findings demonstrate that the three rice CDC20s play redundant roles but are indispensable for faithful meiotic chromosome segregation and cytokinesis, which are required for the production of fertile microspores.
Statistical analysis method for the worldvolume hybrid Monte Carlo algorithm
Authors: Fukuma Masafumi , Matsumoto Nobuyuki , Namekawa Yusuke
Published: November 2021

We discuss the statistical analysis method for the worldvolume hybrid Monte Carlo (WV-HMC) algorithm [M. Fukuma and N. Matsumoto, Prog. Theor. Exp. Phys. 2021, 023B08 (2021)], which was recently introduced to substantially reduce the computational cost of the tempered Lefschetz thimble method. In the WV-HMC algorithm, the configuration space is a continuous accumulation (worldvolume) of deformed integration surfaces, and sample averages are considered for various subregions in the worldvolume. We prove that, if a sample in the worldvolume is generated as a Markov chain, then the subsample in the subregion can also be regarded as a Markov chain. This ensures the application of the standard statistical techniques to the WV-HMC algorithm. We particularly investigate the autocorrelation times for the Markov chains in various subregions, and find that there is a linear relation between the probability of being in a subregion and the autocorrelation time for the corresponding subsample. We numerically confirm this scaling law for a chiral random matrix model.
Aluminum-tolerant, growth-promoting endophytic bacteria as contributors in promoting tea plant growth and alleviating aluminum stress
Authors: Jiang Xiaolan , Li Wei-Wei , Han Menglin , Chen Gao , Wu Jing , Lai Sanyan , Fu Zhouping , Zhang Shuxiang , Deng Wei-Wei , Gao Liping , Xia Tao
Published: November 2021

Unlike that of other crops, the growth of tea plants can be promoted by aluminum, but its regulation mechanism remains unclear. Some endophytes can also promote growth of plant hosts. In this paper, tea roots treated with aluminum were used to study the growth-promoting traits and aluminum tolerance of endophytes. Meta-16S rDNA analysis revealed that Burkholderia was enriched in tea roots after aluminum treatment, and it was the dominant strain for hydroponic tea roots and field tea roots. Actinomycetes constituted the dominant strains in hydroponic tea seedlings treated with aluminum. Sixteen endophytic bacteria, including 12 strains of Firmicutes, 2 strains of Proteobacteria and 2 strains of Actinomycetes, were isolated and identified from hydroponic tea roots treated with different aluminum concentrations. Growth-promoting activity analysis showed that the isolated endophytic bacteria all had more than one plant growth-promoting trait. Among them, B4 (Bacillus nealsonii), B8 (Brevibacterium frigoritolerans) and A2 (Nocardia nova) bacteria each had three growth-promoting traits. Aluminum tolerance ability analysis indicated that endophyte A1 (Leifsonia shinshuensis) had the strongest aluminum tolerance ability, up to 200 mg l−1 aluminum. Plant–bacteria interactions showed that endophytes A1, A2 and B4 and their synthetic community all had a growth-promoting effect on the growth of wheat lateral roots. Moreover, endophytes A1 and B4 alleviated aluminum stress in wheat. Endophyte A1 also promoted the growth of tea cuttings, especially lateral roots, with/without aluminum. Taken together, aluminum enhanced the distribution of aluminum-tolerant and growth-promoting bacteria, thereby promoting the growth of tea roots. This study provides a new aspect for research on the mechanism by which aluminum promotes tea plant growth.
Transcriptomic and metabolomic analyses reveal the altitude adaptability and evolution of different-colored flowers in alpine Rhododendron species
Authors: Liu Xing-Wen , Wang Yue-Hua , Shen Shi-Kang
Published: November 2021

Understanding the molecular mechanisms and evolutionary process of plant adaptation to the heterogeneous environment caused by altitude gradients in plateau mountain ecosystems can provide novel insight into species' responses to global changes. Flower color is the most conspicuous and highly diverse trait in nature. Herein, the gene expression patterns, evolutionary adaptation and metabolites changes of different-colored flowers of alpine Rhododendron L. species along altitude gradients were investigated based on a combined analysis of transcriptomics and metabolomics. Differentially expressed genes were found to be related to the biosynthesis of carbohydrates, fatty acids, amino acids and flavonoids, suggesting their important roles in the altitude adaptability of Rhododendron species. The evolution rate of high-altitude species was faster than that of low-altitude species. Genes related to DNA repair, mitogen-activated protein kinase and ABA signal transduction, and lipoic acid and propanoate metabolism were positively selected in the flowers of high-altitude Rhododendron species and those associated with carotenoid biosynthesis pathway, ABA signal transduction and ethylene signal transduction were positively selected in low-altitude species. These results indicated that the genes with differentiated expressions or functions exhibit varying evolution during the adaptive divergence of heterogeneous environment caused by altitude gradients. Flower-color variation might be attributed to the significant differences in gene expression or metabolites related to sucrose, flavonoids and carotenoids at the transcription or metabolism levels of Rhododendron species. This work suggests that Rhododendron species have multiple molecular mechanisms in their adaptation to changing environments caused by altitude gradients.
Nanopore-based genome-wide DNA methylation sequencing data of Nosema ceranae-inoculated and un-inoculated eastern honeybee workers’ midguts
Authors: Yu Kejun , Chen Dafu , Guo Rui
Published: November 2021

Apis cerana cerana is an excellent subspecies of Apis cerana, playing a vital role in pollination for wild flowers and crops as well as ecological balance. Nosema ceranae, an emergent fungal parasite infecting various bee species, originates from eastern honeybee. In this article, midguts of N. ceranae-inoculated A. c. cerana workers at 7 days post inoculation (dpi) and 10 dpi (AcT1 and AcT2) and un-inoculated workers’ midguts (AcCK1, AcCK2) were subjected to Nanopore-based genome-wide DNA methylation sequencing. Totally, 1773258, 2151476, 1927874 and 2109961 clean reads were generated from AcCK1, AcCK2, AcT1, and AcT2 groups, with the N50 lengths of 7548, 7936, 7678, and 7291 and the average quality value of 8.97, 8.95, 9.24, and 8.98, respectively. Among these, 93.85%, 94.49%, 88.69%, and 81.27% clean reads could be mapped to the reference genome of A. c. cerana. In the aforementioned four groups, 2149685, 2614513, 1637018 and 2726985 CHG sites were identified; the numbers of CHH sites were 9581990, 11801082, 7178559, and 12342423, whereas those of CpG sites were 14325356, 15703508, 14856284 and 13956849, respectively. Additionally, there were 36114, 118867, 30249, and 82984 6mA methylation sites respectively discovered. These data can be used for identifying differential 5mC methylation and 6mA methylation engaged in response of eastern honeybee workers to N. ceranae infestation, and for investigating the 5mC or 6mA methylation-mediated mechanism underlying host response.

Value of the data

The data provide enrichment for information about 5mC and 6mA methylation in eastern honeybees.

Our data contributes to clarification of the epigenetic mechanism underlying eastern honeybee worker’s response to microsporidian infestation.

This presented data offer novel insights into interaction between Apis cerana and Nosema ceranae.
Actionable absolute risk prediction of atherosclerotic cardiovascular disease: a behavior-management approach based on data from 464,547 UK Biobank participants
Authors: Kesar Ajay , Baluch Adel , Barber Omer , Hoffmann Henry , Jovanovic Milan , Renz Daniel , Stopak Bernard Leon , Wicks Paul , Gilbert Stephen
Published: November 2021

Cardiovascular diseases (CVDs) are the primary cause of all global death. Timely and accurate identification of people at risk of developing an atherosclerotic CVD and its sequelae, via risk prediction model, is a central pillar of preventive cardiology. However, currently available models only consider a limited set of risk factors and outcomes, do not focus on providing actionable advice to individuals based on their holistic medical state and lifestyle, are often not interpretable, were built with small cohort sizes or are based on lifestyle data from the 1960s, e.g. the Framingham model. The risk of developing atherosclerotic CVDs is heavily lifestyle dependent, potentially making a high percentage of occurrences preventable. Providing actionable and accurate risk prediction tools to the public could assist in atherosclerotic CVD prevention. We developed a benchmarking pipeline to find the best set of data preprocessing and algorithms to predict absolute 10-year atherosclerotic CVD risk. Based on the data of 464,547 UK Biobank participants without atherosclerotic CVD at baseline, we used a comprehensive set of 203 consolidated risk factors associated with atherosclerosis and its sequelae (e.g. heart failure).

Our two best performing absolute atherosclerotic risk prediction models provided higher performance than Framingham and QRisk3. Using a subset of 25 risk factors identified with feature selection, our reduced model achieves similar performance while being less complex. Further, it is interpretable, actionable and highly generalizable. The model could be incorporated into clinical practice and could allow continuous personalized predictions with automated intervention suggestions.
Insights from an autism imaging biomarker challenge: promises and threats to biomarker discovery
Authors: Traut Nicolas , Heuer Katja , Lemaître Guillaume , Beggiato Anita , Germanaud David , Elmaleh Monique , Bethegnies Alban , Bonnasse-Gahot Laurent , Cai Weidong , Chambon Stanislas , Cliquet Freddy , Ghriss Ayoub , Guigui Nicolas , de Pierrefeu Amicie , Wang Meng , Zantedeschi Valentina , Boucaud Alexandre , van den Bossche Joris , Kegl Balázs , Delorme Richard , Bourgeron Thomas , Toro Roberto , Varoquaux Gaël
Published: November 2021

MRI has been extensively used to identify anatomical and functional differences in Autism Spectrum Disorder (ASD). Yet, many of these findings have proven difficult to replicate because studies rely on small cohorts and are built on many complex, undisclosed, analytic choices. We conducted an international challenge to predict ASD diagnosis from MRI data, where we provided preprocessed anatomical and functional MRI data from > 2,000 individuals. Evaluation of the predictions was rigorously blinded. 146 challengers submitted prediction algorithms, which were evaluated at the end of the challenge using unseen data and an additional acquisition site. On the best algorithms, we studied the importance of MRI modalities, brain regions, and sample size. We found evidence that MRI could predict ASD diagnosis: the 10 best algorithms reliably predicted diagnosis with AUC∼0.80 – far superior to what can be currently obtained using genotyping data in cohorts 20-times larger. We observed that functional MRI was more important for prediction than anatomical MRI, and that increasing sample size steadily increased prediction accuracy, providing an efficient strategy to improve biomarkers. We also observed that despite a strong incentive to generalise to unseen data, model development on a given dataset faces the risk of overfitting: performing well in cross-validation on the data at hand, but not generalising. Finally, we were able to predict ASD diagnosis on an external sample added after the end of the challenge (EU-AIMS), although with a lower prediction accuracy (AUC=0.72). This indicates that despite being based on a large multisite cohort, our challenge still produced biomarkers fragile in the face of dataset shifts.
A Comprehensive Guide to MEGA-PRESS for GABA Measurement
Authors: Peek AL , Rebbeck TJ , Leaver AM , Puts NA , Foster SL , Refshauge KM , Oeltzschner G ,   MRS Expert Panel
Published: November 2021

Background

The aim of this guideline is to provide a series of evidence-based recommendations that allow those new to the field of MEGA-PRESS to produce high-quality data for the measurement of GABA levels using edited magnetic resonance spectroscopy with the MEGA-PRESS sequence at 3T. GABA is the main inhibitory neurotransmitter of the central nervous system and has been increasingly studied due to its relevance in many clinical disorders of the central nervous system. MEGA-PRESS is the most widely used method for quantification of GABA at 3T, but is technically challenging and operates at a low signal-to-noise ratio. Therefore, the acquisition of high-quality MRS data relies on avoiding numerous pitfalls and observing important caveats.

Methods

The guideline was developed by a working party that consisted of experts in MRS and experts in guideline development and implementation, together with key stakeholders. Strictly following a translational framework, we first identified evidence using a systematically conducted scoping literature review, then synthesised and graded the quality of evidence that formed recommendations. These recommendations were then sent to a panel of 21 world leaders in MRS for feedback and approval using a modified-Delphi process across two rounds.

Results

The final guideline consists of 23 recommendations across six domains essential for GABA MRS acquisition (Parameters, Practicalities, Data acquisition, Confounders, Quality/reporting, Post-processing). Overall, 78% of recommendations were formed from high-quality evidence, and 91% received agreement from over 80% of the expert panel.

Conclusion

These 23 expert-reviewed recommendations and accompanying extended documentation form a readily usable guideline to allow those new to the field of MEGA-PRESS to design appropriate MEGA-PRESS study protocols and generate high-quality data.
Life course traumas, phenotypic aging, and cardiovascular disease: retrospective analysis of 104,939 UKB participants
Authors: Cao Xingqi , Zhang Jingyun , Ma Chao , Li Xueqin , Kuo Chia-Ling , Levine Morgan E. , Hu Guoqing , Allore Heather , Chen Xi , Wu Xifeng , Liu Zuyun
Published: November 2021

Background

While childhood and adulthood traumatic experiences have been linked to subsequent cardiovascular disease (CVD), the relationship between life course traumas and CVD and the underpinning pathways are poorly understood. This study aimed to: (1) examine the associations of childhood, adulthood, and lifetime traumas with CVD; (2) examine the associations between diverse life course traumatic profiles and CVD; and (3) examine the extent to which Phenotypic Age (PhenoAge), a well-developed phenotypic aging measure, mediates these associations.

Methods

We included 104,939 participants from the UK Biobank who completed the 2016 online mental health questionnaire. CVD outcomes including ischemic heart disease, myocardial infarction, and stroke were ascertained. Childhood, adulthood, and lifetime traumas were categorized into three subgroups (mild, moderate, and severe), respectively. Four life course traumatic profiles were defined as non-severe traumas across life course, non-severe childhood and severe adulthood traumas, severe childhood and non-severe adulthood traumas, and severe traumas across life course based on both childhood and adulthood traumas. PhenoAge was measured using an equation previously developed. Multivariable logistic models and formal mediation analyses were performed.

Results

Of 104,939 participants, 7,398 (7.0%) were diagnosed with CVD. Subgroups of childhood, adulthood, and lifetime traumas were associated with CVD, respectively. Furthermore, life course traumatic profiles were significantly associated with CVD. For instance, compared with subgroups experiencing non-severe traumas across life course, those who experienced non-severe childhood and severe adulthood traumas, severe childhood and non-severe adulthood traumas, and severe traumas across life course had higher odd of CVD, with odds ratios of 1.07 (95% confidence interval [CI]: 1.00, 1.15), 1.17 (95% CI: 1.09, 1.25), and 1.33 (95% CI: 1.24, 1.43), respectively. Formal mediation analyses suggested that PhenoAge partially mediated the above associations. For instance, PhenoAge mediated 5.8% of increased CVD events in subgroups who experienced severe childhood traumas, relative to those experiencing mild childhood traumas.

Conclusions

Childhood, adulthood, and lifetime traumas, as well as diverse life course traumatic profiles, were associated with CVD. Furthermore, phenotypic aging partially mediated these associations. These findings suggest a potential pathway from life course traumas to CVD through phenotypic aging, and underscore the importance of policy programs targeting traumatic events over the life course in ameliorating inequalities in cardiovascular health.
Transcriptomic-based clustering of advanced atherosclerotic plaques identifies subgroups of plaques with differential underlying biology that associate with clinical presentation
Authors: Mokry Michal , Boltjes Arjan , Cui Kai , Slenders Lotte , Mekke Joost M. , Depuydt Marie A.C. , Timmerman Nathalie , Waissi Farahnaz , Verwer Maarten C , Turner Adam W. , Khan Mohammad Daud , Hodonsky Chani J. , Benavente Ernest Diez , Hartman Robin J.G. , van den Dungen Noortje A M , Lansu Nico , Nagyova Emilia , Prange Koen H.M. , Pavlos Eleftherios , Andreakos Evangelos , Schunkert Heribert , Owens Gary K. , Monaco Claudia , Finn Aloke V , Virmani Renu , Leeper Nicholas J. , de Winther Menno P.J. , Kuiper Johan , de Borst Gert J. , Stroes Erik S.G. , Civelek Mete , de Kleijn Dominique P.V. , den Ruijter Hester M. , Asselbergs Folkert W. , van der Laan Sander W. , Miller Clint L. , Pasterkamp Gerard
Published: November 2021

Histopathological studies have revealed key processes of atherosclerotic plaque thrombosis. However, the diversity and complexity of lesion types highlight the need for improved sub- phenotyping. We hypothesized that unbiased clustering of plaques based on gene expression results in an alternative categorization of late-stage atherosclerotic lesions.

We analyzed the gene expression profiles of 654 advanced human carotid plaques. The unsupervised, transcriptome-driven clustering revealed five dominant plaque types. These novel plaque phenotypes associated with clinical presentation (p<0.001) and showed differences in cellular compositions. Validation in coronary segments showed that the molecular signature of these plaques was linked to coronary ischemia. One of the plaque types with most severe clinical symptoms pointed to both inflammatory and fibrotic cell lineages. This highlighted plaque phenotype showed high expression of genes involved in active inflammatory processes, neutrophil degranulation, matrix turnover, and metabolism. For clinical translation, we did a first promising attempt to identify circulating biomarkers that mark these newly identified plaque phenotypes.

In conclusion, the definition of the plaque at risk for a thrombotic event can be fine-tuned by in- depth transcriptomic based phenotyping. These differential plaque phenotypes prove clinically relevant for both carotid and coronary artery plaques and point to differential underlying biology of symptomatic lesions.
The COVID-19 pandemic and temporal change in metabolic risk factors for cardiovascular disease: a natural experiment within the HELIUS study
Authors: Hummel Bryn , Yerkes Mara A , Harskamp Ralf E , Galenkamp Henrike , Kunst Anton E , Lok Anja , van Valkengoed Irene GM
Published: November 2021

Objective

We studied the association between the coronavirus disease 2019 (COVID-19) pandemic, including the restrictive measures, and metabolic risk factors for cardiovascular disease (CVD) in women and men. Next, we analysed whether changes in these metabolic risk factors were mediated by psychological and behavioural mechanisms.

Design

In this natural experiment, we assessed changes from baseline in metabolic CVD risk factors in the exposed group (whose follow-up measurements were taken during the pandemic), and compared these to the changes in the control group (whose follow-up measurements were taken before the pandemic).

Participants

This study used data from 6962 participants from six different ethnic groups (Dutch, South-Asian Surinamese, African Surinamese, Ghanaian, Turkish and Moroccan) of the HELIUS study, based in Amsterdam, the Netherlands. We included women and men without prior CVD, who participated in both the baseline (2011-2015) and follow-up measurements (2019-2021).

Outcome measures

Changes between baseline and follow-up measurements in six metabolic CVD risk factors were calculated for systolic and diastolic blood pressure (SBP, DBP), total cholesterol (TC), fasting plasma glucose (FPG), haemoglobin A1c (HbA1c), and estimated glomerular filtration rate (eGFR).

Results

The exposed group experienced somewhat less favourable changes over time in SBP, DBP and FPG (the latter only in women) than the control group, while temporal changes in HbA1c and eGFR were more favourable among the control group. For instance, SBP was 1.119 mmHg [0.046, 2.193] higher in exposed than non-exposed women, and 1.380 [0.288, 2.471] in men. Changes in SBP and DBP were partially mediated by changes in behavioural factors, most notably BMI and alcohol consumption.

Conclusions

The COVID-19 pandemic, including the restrictive lockdown measures, is associated with a deterioration of several CVD risk factors in women and men. These findings may aid in decision making concerning the management of and the recovery following the pandemic.

Article Summary

Strengths and limitations of this study

The COVID19 pandemic lockdown measures led to a pause in the data collection for the prospective, population-based HELIUS study, which shaped a natural experiment.

Natural experiments, as quasi-experimental designs, are generally considered stronger than cross-sectional studies.

Through inverse-probability weighting, this study aimed to account for baseline differences between the control and exposed group.

We could not adjust for differences in follow-up time that occurred as a result of the restrictive measures, which may have affected estimates of variables that change with age.

The effects of certain mediators may be underestimated, as the data available for defining these variables were largely based on self-reports.
Prophylactic Magnesium Supplementation and New-Onset Atrial Fibrillation in a General Critical Care Population: A Prescribing Preference Instrumental Variable Analysis
Authors: Wilson Matthew G. , Rashan Aasiyah , Klapaukh Roman , Asselbergs Folkert W. , Harris Stephen K.
Published: November 2021

Aims

Atrial fibrillation is frequently encountered in critical illness and causes adverse effects including haemodynamic decompensation, stroke and longer hospital stay. It is common to supplement serum magnesium for the purpose of preventing new-onset atrial fibrillation. However, no randomised studies support this practice in the non-cardiac surgery critical care population, and its effectiveness is unclear. We sought to investigate the effectiveness of magnesium supplementation in preventing new-onset atrial fibrillation in a mixed critical care population.

Methods

We conducted a single centre retrospective observational study of adult critical care patients. We employed a natural experiment design, using the supplementation preference of the bedside critical care nurse as an instrumental variable.

Using the electronic patient record, magnesium supplementation opportunities were defined and linked to the bedside nurse. Nurse preference for administering magnesium was obtained using multilevel modelling. The results were used to define ‘pro’ and ‘anti’ supplementation groups, which were inputted into an instrumental variable regression to obtain an estimate of the effect of magnesium supplementation.

Results

9,114 magnesium supplementation opportunities were analysed, representing 2,137 critical care admissions for 1,914 patients. There was significant variation in magnesium supplementation practices attributable to the individual nurse, after accounting for covariates. The instrumental variable analysis showed magnesium supplementation was associated with a 3% decreased chance of experiencing new-onset atrial fibrillation (95% CI −0.06 to −0.04, p = 0.03).

Conclusions

This study supports the strategy of routine magnesium supplementation, but further work is required to identify optimal serum magnesium targets for prophylaxis of atrial fibrillation.

What’s New?

Routine administration of supplemental magnesium sulphate is associated with a reduced chance of developing new-onset Atrial Fibrillation, in a general critical care cohort.

This finding agrees with previous Randomised Controlled Trial results which are limited to the cardiac critical care population.

This finding disagrees with previously published observational studies, which is likely due to better control of unmeasured confounding.

There is significant variation in serum magnesium supplementation attributable to the individual bedside critical care nurse.

Electronic health records offer the ability to evaluate the effectiveness of routinely administered treatments which lack evidence in an affordable way.

Natural experiments and instrumental variable analysis offer the opportunity to derive causally robust estimations of treatment effectiveness by better accounting for unobserved confounding.