bluuebunny/crossref_metadata_2025 huggingface dataset:
Machine learning identifies six genetic variants and alterations in the Heart Atrial Appendage as key contributors to PD risk predictivity
Authors: Ho Daniel , Schierding William , Farrow Sophie , Cooper Antony A. , Kempa-Liehr Andreas W. , O’Sullivan Justin M.
Published: July 2021

Parkinson’s disease (PD) is a complex neurodegenerative disease with a range of causes and clinical presentations. Over 76 genetic loci (comprising 90 SNPs) have been associated with PD by the most recent GWAS meta-analysis. Most of these PD-associated variants are located in non-coding regions of the genome and it is difficult to understand what they are doing and how they contribute to the aetiology of PD. We hypothesised that PD-associated genetic variants modulate disease risk through tissue-specific expression quantitative trait loci (eQTL) effects. We developed and validated a machine learning approach that integrated tissue-specific eQTL data on known PD-associated genetic variants with PD case and control genotypes from the Wellcome Trust Case Control Consortium, the UK Biobank, and NeuroX. In so doing, our analysis ranked the tissue-specific transcription effects for PD-associated genetic variants and estimated their relative contributions to PD risk. We identified roles for SNPs that are connected with INPP5P, CNTN1, GBA and SNCA in PD. Ranking the variants and tissue-specific eQTL effects contributing most to the machine learning model suggested a key role in the risk of developing PD for two variants (rs7617877 and rs6808178) and eQTL associated transcriptional changes of EAF1-AS1 within the heart atrial appendage. Similarly, effects associated with eQTLs located within the brain cerebellum were also recognized to confer major PD risk. These findings warrant further mechanistic investigations to determine if these transcriptional changes could act as early contributors to PD risk and disease development.
Feeding Activated Bifidobacterium infantis EVC001 to Very Low Birth Weight Infants is Associated with Significant Reduction in Rates of Necrotizing Enterocolitis
Authors: Tobias Joseph , Olyaei Amy , Laraway Bryan , Jordan Brian K. , Dickinson Stephanie , Arroyo Lilian G. , Fialkowski Elizabeth , Owora Arthur , Scottoline Brian
Published: July 2021

Objectives

To assess the effects of Bifidobacterium infantis EVC001 administration on the rate of necrotizing enterocolitis (NEC) in preterm infants in a single Level IV NICU.

Study Design

This was a retrospective observational analysis of 2 cohorts of VLBW infants (+/-B. infantis EVC001 probiotic) at OHSU from 2014 to 2020. Outcomes included NEC rates and NEC-associated mortality, including subgroup analysis of ELBW infants. Fisher’s exact test and log binomial models were used to determine differences between cohorts and risk reduction of NEC. Adjusted number needed to treat was calculated from the cohort coefficient of the model.

Results

In this analysis of 483 infants, the difference in rates of NEC between cohorts was statistically significant (11.0% vs. 2.7%, P = 0.0008). The EVC001-fed cohort had a 73% risk reduction of NEC compared to the No EVC001 cohort (adjusted risk ratio 0.270, 95% CI 0.094, 0.614, P = 0.0054) resulting in an adjusted number needed to treat of 12.4 (95% CI 10.0, 23.5) for B. infantis EVC001. There was no NEC-related mortality in the EVC001-fed cohort, yielding statistically significant differences from the No EVC001 cohort overall (0% vs. 2.7%, P = 0.0274) and the ELBW subgroup (0% vs. 5.6%, P = 0.0468).

Conclusion(s)

B. infantis EVC001 feeding was associated with a significant reduction in the rate of NEC and NEC-related mortality in an observational study of 483 VLBW infants. B. infantis EVC001 supplementation may be considered safe and effective for reducing morbidity and mortality in the NICU.
Perceptions and acceptance of COVID-19 vaccine among pregnant and lactating women in Singapore: A cross-sectional study
Authors: Jayagobi Pooja A , Ong Chengsi , Thai Yeo Kee , Lim Caleb CW , Jiun Seet Meei , Koon Kwek Lee , Wai Ku Chee , Chan Jerry KY , Mathur Manisha , Chien Chua Mei
Published: July 2021

Introduction

Vaccination is critical in controlling the coronavirus disease 19 (COVID-19) pandemic. However, vaccine perception and acceptance among pregnant and lactating women is unknown in Singapore. We aimed to determine the acceptance of COVID-19 vaccination among these two groups of women in Singapore, and factors associated with vaccine acceptance.

Methods

We conducted an anonymous, online survey on the perception and acceptance of the COVID-19 vaccine in pregnant and lactating women at a tertiary hospital in Singapore from 1st March to 31st May 2021. Information on demographics and knowledge were collected, and these factors were assessed for their relationship with vaccine acceptance.

Results

A total of 201 pregnant and 207 lactating women participated. Vaccine acceptance rates in pregnant and lactating women were 30.3% and 16.9% respectively. Pregnant women who were unsure or unwilling to take the vaccine cited concerns about safety of the vaccine during pregnancy (92.9%), while lactating women were concerned about potential long-term negative effects on the breastfeeding child (75.6%). Other factors significantly associated with vaccine acceptance included a lower monthly household income or education level, appropriate knowledge regarding vaccine mechanism and higher perceived maternal risk of COVID-19. Most pregnant (70.0%) and lactating women (83.7%) were willing to take the vaccine only when more safety data during pregnancy and breastfeeding were available.

Conclusions

COVID-19 vaccine acceptance was low among pregnant and lactating women in Singapore. Addressing safety concerns when more data is available and education on mechanism of vaccine action will likely improve acceptance among these women.
Gestational diabetes mellitus in women born small or premature: Systematic review and meta-analysis
Authors: Tsujimoto Yasushi , Kataoka Yuki , Banno Masahiro , Taito Shunsuke , Kokubo Masayo , Masuzawa Yuko , Yamamoto Yoshiko
Published: July 2021

Background

Women born preterm or with low birthweight (LBW) have an increased future risk of gestational diabetes mellitus (GDM) during pregnancy; however, a quantitative summary of evidence is lacking.

In this study, we aimed to investigate whether being born preterm, or with LBW or small for gestational age (SGA) are associated with GDM risk.

Methods

We searched the MEDLINE, Embase, and CINAHL databases and study registries, including ClinicalTrials.gov and ICTRP, from launch until 29 October 2020 for observational studies examining the association between birth weight or gestational age and GDM were eligible. We pooled the odds ratios and 95% confidence intervals using the DerSimonian and Laird random-effects model.

Results

Eighteen studies were included (N = 827,382). The meta-analysis showed that being born preterm, with LBW or SGA was associated with increased risk of GDM (pooled odds ratio = 1.84; 95% confidence interval: 1.54 to 2.20; I2 = 78.3%; τ2 = 0.07). Given a GDM prevalence of 2.0%, 10%, and 20%, the absolute risk differences were 1.6%, 7.0%, and 11.5%, respectively. The certainty of evidence was low due to serious concerns of risk of bias and publication bias.

Conclusion

Women born prematurely, with LBW or SGA status, may be at increased risk for GDM. However, whether this should be considered in clinical decision-making depends on the prevalence of GDM.

What is already known on this subject?

Approximately 10–15% of infants are born small or premature worldwide, and these children are at high risk of diseases, such as type 1 and 2 diabetes mellitus, hypertension, obesity, and kidney disease, in adulthood. A narrative review reported in 2007 that women born with LBW are at risk of gestational diabetes mellitus, but included a small number of studies. Several subsequent studies have been published since then, but there is no quantitative summary of the relevant evidence to date.

What this study adds?

This is the first systematic review and meta-analysis of observational studies that provides a comprehensive summary of evidence on the association between birth size or premature birth and future GDM risk including previously unpublished data and a large sample size. LBW, preterm birth, and SGA status may be prognostic factors for GDM.
Combining Attention-based Multiple Instance Learning and Gaussian Processes for CT Hemorrhage Detection
Authors: Wu Yunan , Schmidt Arne , Hernández-Sánchez Enrique , Molina Rafael , Katsaggelos Aggelos K.
Published: July 2021

Intracranial hemorrhage (ICH) is a life-threatening emergency with high rates of mortality and morbidity. Rapid and accurate detection of ICH is crucial for patients to get a timely treatment. In order to achieve the automatic diagnosis of ICH, most deep learning models rely on huge amounts of slice labels for training. Unfortunately, the manual annotation of CT slices by radiologists is time-consuming and costly. To diagnose ICH, in this work, we propose to use an attention-based multiple instance learning (Att-MIL) approach implemented through the combination of an attention-based convolutional neural network (Att-CNN) and a variational Gaussian process for multiple instance learning (VGP-MIL). Only labels at scan-level are necessary for training. Our method trains the model using scan labels and assigns each slice with an attention weight, which can be used to provide slice-level predictions, and uses the VGPMIL model based on low-dimensional features extracted by the Att-CNN to obtain improved predictions both at slice and scan levels. To analyze the performance of the proposed approach, our model has been trained on 1150 scans from an RSNA dataset and evaluated on 490 scans from an external CQ500 dataset. Our method outperforms other methods using the same scan-level training and is able to achieve comparable or even better results than other methods relying on slicelevel annotations.
Healthcare experience affects pain-specific responses to others’ suffering in the anterior insula
Authors: Corradi-Dell’Acqua Corrado , Hofstetter Christoph , Sharvit Gil , Hugli Olivier , Vuilleumier Patrik
Published: July 2021

Medical students and professional healthcare providers often underestimate patients’ pain, together with decreased neural responses to pain information in the anterior insula (AI), a brain region implicated in self-pain processing and negative affect. However, the functional significance and specificity of these neural changes remains debated. Across two experiments, we recruited university medical students and emergency nurses to test the role of healthcare experience on the brain reactivity to other’s pain, emotions, and beliefs, using both pictorial and verbal cues. Brain responses to self-pain was also assessed and compared with those to observed pain. Our results confirmed that healthcare experience decreased the activity in AI in response to others’ suffering. This effect was independent from stimulus modality (pictures or texts), but specific for pain, as it did not generalize to inferences about other mental or affective states. Furthermore, representational similarity and multivariate pattern analysis revealed that healthcare experience impacted specifically a component of the neural representation of others’ pain that is shared with that of first-hand nociception, and related more to AI than to other pain-responsive regions. Taken together, our study suggests a decreased propensity to appraise others’ suffering as one’s own, associated with a reduced recruitment of pain-specific information in AI. These findings provide new insights into neural mechanisms leading to pain underestimation by caregivers in clinical settings.
Plakoglobin and HMGB1 mediate intestinal epithelial cell apoptosis induced by Clostridioides difficile TcdB
Authors: Li Yingxue , Xu Wei , Ren Yutian , Cheung Hung-Chi , Huang Panpan , Kaur Guneet , Kuo Chih-Jung , McDonough Sean P. , Fubini Susan L. , Lipkin Stephen M. , Deng Xin , Chang Yung-Fu , Huang Linfeng
Published: July 2021

Clostridioides difficile infection (CDI) is the leading cause of antibiotic-associated intestinal disease, resulting in severe diarrhea and fatal pseudomembranous colitis. TcdB, one of the essential virulence factors secreted by this bacterium, induces host cell apoptosis through a poorly understood mechanism. Here, we performed an RNAi screen customized to Caco-2 cells, a cell line model of the intestinal epithelium, to discover host factors involved in TcdB-induced apoptosis. We identified plakoglobin, also known as junction plakoglobin (JUP) or γ-catenin, a member of the catenin family, as a novel host factor, and a previously known cell death-related chromatin factor, high mobility group box 1 (HMGB1). Disruption of those host factors by RNAi and CRISPR resulted in resistance of cells to TcdB-mediated and mitochondria-dependent apoptosis. JUP was redistributed from adherens junctions to the mitochondria and colocalized with Bcl-XL after stimulation by TcdB, suggesting a role of JUP in cell death signaling through mitochondria. Treatment with glycyrrhizin, an HMGB1 inhibitor, resulted in significantly increased resistance to TcdB-induced epithelial damage in cultured cells and a mouse ligated colon loop model. These findings demonstrate the critical roles of JUP and HMGB1 in TcdB-induced epithelial cell apoptosis.
Reward and expectancy effects on neural signals of motor preparation and execution
Authors: Chen Xing-Jie , van den Berg Berry , Kwak Youngbin
Published: July 2021

The prospect of rewards can have strong modulatory effects on response preparation. Importantly, selection and execution of movements in real life happens under an environment characterized by uncertainty and dynamic changes. The current study investigated how the brain’s motor system adapts to the dynamic changes in the environment in pursuit of rewards. In addition, we studied how the prefrontal cognitive control system contributes in this adaptive control of motor behavior. To this end, we tested the effect of rewards and expectancy on the hallmark neural signals that reflect activity in motor and prefrontal systems, the lateralized readiness potential (LRP) and the mediofrontal (mPFC) theta oscillations, while participants performed an expected and unexpected action to retrieve rewards. To better capture the dynamic changes in neural processes represented in the LRP waveform, we decomposed the LRP into the preparation (LRPprep) and execution (LRPexec) components. The overall pattern of LRPprepand LRPexecconfirmed that they each reflect motor preparation based on the expectancy and motor execution when making a response that is either or not in line with the expectations. In the comparison of LRP magnitude across task conditions, we found a greater LRPprepwhen large rewards were more likely, reflecting a greater motor preparation to obtain larger rewards. We also found a greater LRPexecwhen large rewards were presented unexpectedly, suggesting a greater motor effort placed for executing a correct movement when presented with large rewards. In the analysis of mPFC theta, we found a greater theta power prior to performing an unexpected than expected response, indicating its contribution in response conflict resolution. Collectively, these results demonstrate an optimized motor control to maximize rewards under the dynamic changes of real-life environment.
Economic costs of biological invasions in the United States
Authors: Fantle-Lepczyk Jean E. , Haubrock Phillip J. , Kramer Andrew M. , Cuthbert Ross N. , Turbelin Anna J. , Crystal-Ornelas Robert , Diagne Christophe , Courchamp Franck
Published: July 2021

The United States has thousands of invasive species, representing a sizable, but unknown burden to the national economy. Given the potential economic repercussions of invasive species, quantifying these costs is of paramount importance both for national economies and invasion management. Here, we used a novel global database of invasion costs (InvaCost) to quantify the overall costs of invasive species in the United States across spatiotemporal, taxonomic, and socioeconomic scales. From 1960 to 2020, reported invasion costs totaled $4.52 trillion (USD 2017). Considering only observed, highly reliable costs, this total cost reached $1.22 trillion with an average annual cost of $19.94 billion/year. These costs increased from $2.00 billion annually between 1960-1969 to $21.08 billion annually between 2010-2020. Most costs (73%) were related to resource damages and losses ($896.22 billion), as opposed to management expenditures ($46.54 billion). Moreover, the majority of costs were reported from invaders from terrestrial habitats ($643.51 billion, 53%) and agriculture was the most impacted sector ($509.55 billion). From a taxonomic perspective, mammals ($234.71 billion) and insects ($126.42 billion) were the taxonomic groups responsible for the greatest costs. Considering the apparent rising costs of invasions, coupled with increasing numbers of invasive species and the current lack of cost information for most known invaders, our findings provide critical information for policymakers and managers.
Single nucleus transcriptomic analysis of human dorsal root ganglion neurons
Authors: Nguyen Minh Q. , von Buchholtz Lars J. , Reker Ashlie N. , Ryba Nicholas J. P. , Davidson Steve
Published: July 2021

Somatosensory neurons with cell bodies in the dorsal root ganglia (DRG) project to the skin, muscles, bones, and viscera to detect touch and temperature as well as to mediate proprioception and many types of interoception. In addition, the somatosensory system conveys the clinically relevant noxious sensations of pain and itch. Here we used single nuclear transcriptomics to characterize the classes of human DRG neurons that detect these diverse types of stimuli. Notably, multiple types of human DRG neurons have transcriptomic features that resemble their mouse counterparts although expression of genes considered important for sensory function often differed between species. More unexpectedly, we demonstrated that several classes of mouse neurons have no direct equivalents in humans and human specific cell-types were also identified. This dataset should serve as a valuable resource for the community, for example as means of focusing translational efforts on molecules with conserved expression across species.
Single-domain antibodies for targeting, detection andin vivoimaging of human CD4+cells
Authors: Traenkle Bjoern , Kaiser Philipp D. , Pezzana Stefania , Richardson Jennifer , Gramlich Marius , Wagner Teresa R. , Seyfried Dominik , Weldle Melissa , Holz Stefanie , Parfyonova Yana , Nueske Stefan , Scholz Armin M. , Zeck Anne , Jakobi Meike , Schneiderhan-Marra Nicole , Schaller Martin , Maurer Andreas , Gouttefangeas Cécile , Kneilling Manfred , Pichler Bernd J. , Sonanini Dominik , Rothbauer Ulrich
Published: July 2021

The advancement of new immunotherapies necessitates appropriate probes to monitor the presence and distribution of distinct immune cell populations. Considering the key role of CD4+T cells in regulating immunological processes, we generated novel single-domain antibodies (nanobodies, Nbs) that specifically recognize human CD4. After in depth analysis of their binding properties, recognized epitopes, and effects on T cell proliferation, activation and cytokine release, we selected CD4 Nbs that did not interfere with crucial T cell processesin vitroand converted them into immune tracers for non-invasive molecular imaging.

By optical imaging, we demonstrate the ability of a high-affinity CD4-Nb to specifically visualize CD4+cellsin vivousing a xenograft model. Furthermore, time-resolved immune positron emission tomography (immunoPET) of a human CD4 knock-in mouse model showed rapid accumulation of64Cu-radiolabeled CD4-Nb in CD4+T cell-rich tissues. We propose that the CD4 Nbs presented here could serve as versatile probes for stratifying patients and monitoring individual immune responses during personalized immunotherapy in both cancer and inflammatory diseases.
Hundreds of viral families in the healthy infant gut
Authors: Shah Shiraz A. , Deng Ling , Thorsen Jonathan , Pedersen Anders G. , Dion Moïra B. , Castro-Mejía Josué L. , Silins Ronalds , Romme Fie O. , Sausset Romain , Ndela Eric Olo , Hjemlsø Mathis , Rasmussen Morten A. , Redgwell Tamsin A. , Vestergaard Gisle , Zhang Yichang , Sørensen Søren J. , Bisgaard Hans , Enault Francois , Stokholm Jakob , Moineau Sylvain , Petit Marie-Agnès , Nielsen Dennis S.
Published: July 2021

The gut microbiome (GM) is shaped through infancy and plays a major role in determining susceptibility to chronic inflammatory diseases later in life. Bacteriophages (phages) are known to modulate bacterial populations in numerous ecosystems, including the gut. However, virome data is difficult to analyse because it mostly consists of unknown viruses, i.e. viral dark matter. Here, we manually resolved the viral dark matter in the largest human virome study published to date. Fecal viromes from a cohort of 647 infants at 1 year of age were deeply sequenced and analysed through successive rounds of clustering and curation. We uncovered more than ten thousand viral species distributed over 248 viral families falling within 17 viral order-level clades. Most of the defined viral families and orders were novel and belonged to theCaudoviricetesviral class. Bacterial hosts were predicted for 79% of the viral species using CRISPR spacers, including those in metagenomes from the same fecal samples. WhileBacteroides-infecting Crassphages were present, novel viral families were more predominant, including phages infecting Clostridiales andBifidobacterium. Phage lifestyles were determined for more than three thousand caudoviral species. Lifestyles were homogeneous at the family level for 149Caudoviricetesfamilies, including 32 families that were found to be virulent, while 117 were temperate. Virulent phage families were more abundant but temperate ones were more diverse and widespread. Together, the viral families found in this study represent a major expansion of existing bacteriophage taxonomy.
A genome-wide association study of serum proteins reveals shared loci with common diseases
Authors: Gudjonsson Alexander , Gudmundsdottir Valborg , Axelsson Gisli T , Gudmundsson Elias F , Jonsson Brynjolfur G , Launer Lenore J , Lamb John R , Jennings Lori L , Aspelund Thor , Emilsson Valur , Gudnason Vilmundur
Published: July 2021

With the growing number of genetic association studies, the genotype-phenotype atlas has become increasingly more complex, yet the functional consequences of most disease associated alleles is not understood. The measurement of protein level variation in solid tissues and biofluids integrated with genetic variants offers a path to deeper functional insights. Here we present a large-scale proteogenomic study in 5,368 individuals, revealing 4,113 independent associations between genetic variants and 2,099 serum proteins, of which 37% are previously unreported. The majority of bothcis- andtrans-acting genetic signals are unique for a single protein, although our results also highlight numerous highly pleiotropic genetic effects on protein levels and demonstrate that a protein’s genetic association profile reflects certain characteristics of the protein, including its location in protein networks, tissue specificity and intolerance to loss of function mutations. Integrating protein measurements with deep phenotyping of the cohort, we observe substantial enrichment of phenotype associations for serum proteins regulated by established GWAS loci, and offer new insights into the interplay between genetics, serum protein levels and complex disease.
Extrachromosomal DNA is associated with chromothripsis events and diverse prognoses in gastric cardia adenocarcinoma
Authors: Zhao Xue-Ke , Xing Pengwei , Song Xin , Zhao Miao , Zhao Linxuan , Dang Yonglong , Lei Ling-Ling , Xu Rui-Hua , Han Wen-Li , Wang Pan-Pan , Yang Miao-Miao , Hu Jing-Feng , Zhong Kan , Zhou Fu-You , Han Xue-Na , Meng Chao-Long , Ji Jia-Jia , Chen Xingqi , Wang Li-Dong
Published: July 2021

Extrachromosomal DNA plays an important role in oncogene amplification in tumour cells and poor outcomes across multiple cancers. However, the function of extrachromosomal DNA in gastric cardia adenocarcinoma (GCA) is very limited. Here, we investigated the availability and function of extrachromosomal DNA in GCA from a Chinese cohort of GCA using whole-genome sequencing (WGS), whole-exome sequencing (WES), and immunohistochemistry. For the first time, we identified the ecDNA amplicons present in most GCA patients, and found that some oncogenes are present as ecDNA amplicons in these patients. We found that oncogene ecDNA amplicons in the GCA cohort were associated with the chromothripsis process and may be induced by accumulated DNA damage due to local dietary habits in the geographic region. Strikingly, we observed diverse correlations between the presence of ecDNA oncogene amplicons and prognosis, where ERBB2 ecDNA amplicons correlated with good prognosis, EGFR ecDNA amplicons correlated with poor prognosis, and CCNE1 ecDNA amplicons did not correlate with prognosis. Large-scale ERBB2 immunohistochemistry results from 1668 GCA patients revealed that there was a positive correlation between the presence of ERBB2 and prognosis in 2-7-year survival; however, there was a negative correlation between the presence of ERBB2 and prognosis in 0-2-year survival. Our observations indicate that the presence of ERBB2 ecDNA in GCA patients may represent a good prognosis marker.
The first observation of osmotically neutral sodium accumulation in the myocardial interstitium
Authors: Artyukov I. , Arutyunov G. , Bobrov M. , Bukreeva I. , Cedola A. , Dragunov D. , Feshchenko R. , Fratini M. , Mitrokhin V. , Sokolova A. , Vinogradov A. , Gianoncelli A.
Published: July 2021

The aim of this study was the detection and quantification of the Na+ depositions in the extracellular matrix of myocardial tissue, which are suggested to be bound by negatively charged glycosaminoglycan (GAG) structures. The presented experimental results are based on high resolution X-ray fluorescence (XRF) spectromicroscopy technique used to perform a comparative analysis of sodium containment in intracellular and interstitial spaces of cardiac tissues taken from animals selected by low and high sodium intake rates. The experimental results obtained show that high sodium daily intake can result in a remarkable increase of sodium concentration in the myocardial interstitium.
Longitudinal Changes in Auditory and Reward Systems Following Receptive Music-Based Intervention in Older Adults
Authors: Quinci Milena Aiello , Belden Alexander , Goutama Valerie , Gong Dayang , Hanser Suzanne , Donovan Nancy J. , Geddes Maiya , Loui Psyche
Published: July 2021

Listening to pleasurable music is known to engage the brain’s reward system. This has motivated many cognitive-behavioral interventions for healthy aging, but little is known about the effects of music-based intervention (MBI) on activity and connectivity of the brain’s auditory and reward systems. Here we show preliminary evidence that brain network connectivity can change after receptive MBI in cognitively unimpaired older adults. Using a combination of whole-brain regression, seed-based connectivity analysis, and representational similarity analysis (RSA), we examined fMRI responses during music listening in older adults before and after an eight-week personalized MBI. Participants rated self-selected and researcher-selected musical excerpts on liking and familiarity. Parametric effects of liking, familiarity, and selection showed simultaneous activation in auditory, reward, and default mode network (DMN) areas. Functional connectivity within and between auditory and reward networks was modulated by participant liking and familiarity ratings. RSA showed significant representations of selection and novelty at both time-points, and an increase in striatal representation of musical stimuli following intervention. An exploratory seed-based connectivity analysis comparing pre- and post-intervention showed significant increase in functional connectivity between auditory regions and medial prefrontal cortex (mPFC). Taken together, results show how regular music listening can provide an auditory channel towards the mPFC, thus offering a potential neural mechanism for MBI supporting healthy aging.
Atherosis of trophoblast type: A specific form of decidual vasculopathy distinct from atherosis of macrophage type
Authors: Zhang Peilin
Published: July 2021

Background

There are three types of decidual vasculopathy, namely, acute atherosis, fibrinoid medial necrosis and mural arterial hyerptrophy. Persistence of vascular trophoblasts is also known to be related to maternal vascular malperfusion, but detailed study is lacking.

Material and methods

A total 1017 placentas from 2021 were collected with clinical, neonatal and placental information, and routine placental pathology examination was performed. Decidual vasculopathy was classified based on the new classification scheme including atherosis of macrophage type atherosis of trophoblast type, fibrinoid medial necrosis, mural arterial hypertrophy and mixed type vasculopathy. The significance of these morphologic changes were examined based on the clinical, neonatal and placental pathology features.

Results

Decidual vasculopathy is classified as classic type, mural hypertrophy and mixed type. Classic type vasculopathy is further separated as atherosis and fibrinoid medial necrosis. Atherosis is defined as atherosis of macrophage type and atherosis of trophoblast type. Each category of decidual vasculopathy was evaluated in association with maternal, neonatal and placental pathologic findings. Atherosis of macrophage type and mixed type vasculopathy showed statistically significant association with preeclampsia/pregnancy induced hypertension, low birth weight and low placental weight. Atherosis of trophoblast type was associated with lower placental weight but not with specific clinical features. There is no neonatal sex dimorphism in decidual vasculopathy.

Conclusion

Atherosis of trophoblast type is a distinct pathologic feature in late pregnancy, and it is associated with lower placental weight. New classification of decidual vasculopathy helps with better stratification and categorization of placental maternal vascular abnormalities.
The VersaLive platform enables pipette-compatible microfluidic mammalian cell culture for versatile applications
Authors: Nocera G. M. , Viscido G. , Brillante S. , Carrella S. , di Bernardo D.
Published: July 2021

Microfluidic-based cell culture allows for precise spatio-temporal regulation of microenvironment, live cell imaging and better recapitulation of physiological conditions, while minimizing reagents consumption. Despite their usefulness, most microfluidic systems are designed with one specific application in mind and require specialized equipment and expertise for their operation. All these requirements prevent microfluidic-based cell culture to be widely adopted. Here, we designed and implemented a versatile and easy-to-use perfusion cell culture microfluidic platform for multiple application (VersaLive) requiring only standard pipettes. Here, we showcase the multiple uses of VersaLive (e.g., time-lapse live cell imaging, immunostaining, cell recovery, cell lysis) on mammalian cell lines and primary cells. VersaLive can replace standard cell culture formats in several applications, thus decreasing costs and increasing reproducibility across laboratories. The layout, documentation and protocols are open-source and available online at https://versalive.tigem.it/.
Comparative Analysis of non-coding smallRNAs in Pseudomonas aeruginosa Keratitis Strains with Different Antibiotic Susceptibility
Authors: Kandasamy Kathirvel , Lalitha Prajna , Devarajan Bharanidharan
Published: July 2021

Pseudomonas aeruginosa, is a gram-negative bacterium causes opportunistic or nosocomial infections in immunocompromised individuals. In recent years, a steady increase in human corneal infections of P. aeruginosa has been reported with increased multi-drug resistance (MDR) or extensively drug resistance (XDR). Several non-coding sRNAs, has been identified to regulate various physiological processes in P. aeruginosa, including biofilm formation, quorum sensing. However, the regulatory mechanism of sRNAs in MDR/XDR pathways of P. aeruginosa keratitis strains is not yet studied. In this study, we identified bacterial sRNAs in publicly available P. aeruginosa keratitis genomes and investigated their regulatory role in MDR/XDR pathways using bioinformatic analysis. Totally, 46 P. aeruginosa keratitis strains from different geographical regions were included. Of 46, Eight (30%) out of Twenty-seven and Nine (52) out of Nineteen P. aeruginosa strains from India and Australia were identified as not-MDR. Whereas, 10 (38%) Indian and 9 (47%) Australian strains were identified as MDR. Eight Indian strains were identified as XDR. Out of 46 strains, 23 (50%) carried ExoU, 21(45%) carried ExoS and two (5%) strains carried both ExoU and ExoS, exotoxins for their virulence. The sRNA, SPA0021 was identified in 18 MDR/XDR and 6 not-MDR strains along with UCBPP-PA14. Interestingly, majority of the imipenem resistant P. aeruginosa keratitis strains from the present study was found to be carried SPA0023 sRNA (18 out of 30 strains). The outer membrane porin protein OprD, identified as binding target of SPA0023. Negative regulation or inactivation of OprD, reported in increased imipenem resistance in P. aeruginosa. Mutation analysis revealed that SPA0023 carrying P. aeruginosa keratitis strains contains a lesser number of amino acid changes in OprD protein than other strains. These findings indicate, imipenem resistance in SPA0023 carried strains might arose from the negative regulation or inhibition of OprD by SPA0023. However, functional studies are warranted with large number of P. aeruginosa keratitis strains to confirm the negative regulation of OprD by SPA0023 and imipenem resistance.
Mammalian UPF3A and UPF3B activate NMD independently of their EJC binding
Authors: Yi Zhongxia , Arvola René M , Myers Sean , Dilsavor Corinne N , Alhasan Rabab Abu , Carter Bayley N , Patton Robert D , Bundschuh Ralf , Singh Guramrit
Published: July 2021

Nonsense-mediated mRNA decay (NMD) is governed by the three conserved factors - UPF1, UPF2 and UPF3. While all three are required for NMD in yeast, UPF3B is dispensable for NMD in mammals, with its paralog UPF3A suggested to only weakly activate or even repress NMD due to its weaker binding to the exon junction complex (EJC). Here we characterize the UPF3B-dependent and -independent NMD in human cell lines knocked-out of one or bothUPF3paralogs. We show that in human colorectal cancer HCT116 cells, EJC-mediated NMD can operate in UPF3B-dependent and -independent manner. While UPF3A is almost completely dispensable for NMD in wild-type cells, it strongly activates EJC-mediated NMD in cells lacking UPF3B. Surprisingly, this major NMD branch can operate in UPF3-independent manner questioning the idea that UPF3 is needed to bridge UPF proteins to the EJC during NMD. Complementation studies in UPF3 knockout cells further show that EJC-binding domain of UPF3 paralogs is not essential for NMD. Instead, the conserved mid domain of UPF3B, previously shown to engage with ribosome release factors, is required for its full NMD activity. Altogether, UPF3 plays a more active role in NMD than simply being a bridge between the EJC and the UPF complex.
Entorhinal cortex epigenome-wide association study highlights four novel loci showing differential methylation in Alzheimer’s disease
Authors: Sommerer Yasmine , Dobricic Valerija , Schilling Marcel , Ohlei Olena , Sabet Sanaz Sedghpour , Wesse Tanja , Fuß Janina , Franzenburg Sören , Franke Andre , Parkkinen Laura , Lill Christina M. , Bertram Lars
Published: July 2021

Background

Studies on DNA methylation (DNAm) in Alzheimer’s disease (AD) have recently highlighted several genomic loci showing association with disease onset and progression.

Methods

Here, we conducted an epigenome-wide association study (EWAS) using DNAm profiles in entorhinal cortex (EC) from 149 AD patients and control brains and combined these with two previously published EC datasets by meta-analysis (total n=337).

Results

We identified 12 cytosine-phosphate-guanine (CpG) sites showing epigenome-wide significant association with either case-control status or Braak’s tau-staging. Four of these CpGs, located in proximity toCNFN/LIPE, TENT5A, PALD1/PRF1, andDIRAS1, represent novel findings. Integrating DNAm levels with RNA sequencing-based mRNA expression data generated in the same individuals showed significant DNAm-mRNA correlations for 6 of the 12 significant CpGs. Lastly, by calculating rates of epigenetic age acceleration using two recently proposed “epigenetic clock” estimators we found a significant association with accelerated epigenetic aging in AD patients vs. controls.

Conclusion

In summary, our study represents the hitherto most comprehensive EWAS in AD using EC and highlights several novel differentially methylated loci with potential effects on gene expression.
phasebook: haplotype-aware de novo assembly of diploid genomes from long reads
Authors: Luo Xiao , Kang Xiongbin , Schönhuth Alexander
Published: July 2021

Haplotype-aware diploid genome assembly is crucial in genomics, precision medicine, and many other disciplines. Long-read sequencing technologies have greatly improved genome assembly thanks to advantages of read length. However, current long-read assemblers usually introduce disturbing biases or fail to capture the haplotype diversity of the diploid genome. Here, we present phasebook, a novel approach for reconstructing the haplotypes of diploid genomes from long reads de novo.

Benchmarking experiments demonstrate that our method outperforms other approaches in terms of haplotype coverage by large margins, while preserving competitive performance or even achieving advantages in terms of all other aspects relevant for genome assembly.
RNA modification mapping with JACUSA2
Authors: Piechotta Michael , Wang Qi , Altmüller Janine , Dieterich Christoph
Published: July 2021

A whole series of high-throughput antibody-free methods for RNA modification detection from sequencing data emerged lately. We present JACUSA2 as a versatile software solution and comprehensive analysis framework for RNA modification detection assays that are based on either the Illumina or Nanopore platform. Importantly, JACUSA2 can integrate information from multiple experiments (e.g. replicates and different conditions) and different library types (e.g. first- or secondstrand libraries). We demonstrate its utility by example, showing three analysis workflows for m6A detection on published data sets: 1) MazF m6a-sensitive RNA digestion (FTO+ vs FTO-), 2) DART-seq (YTHwt vs YTHmut) and 3) Nanopore profiling (METTL3 +/+ vs -/-). All assays have been conducted in HEK293 cells and complement one another.
Strainline: full-length de novo viral haplotype reconstruction from noisy long reads
Authors: Luo Xiao , Kang Xiongbin , Schönhuth Alexander
Published: July 2021

Haplotype-resolved de novo assembly of highly diverse virus genomes is critical in prevention, control and treatment of viral diseases. Current methods either can handle only relatively accurate short read data, or collapse haplotype-specific variations into consensus sequence. Here, we present Strainline, a novel approach to assemble viral haplotypes from noisy long reads without a reference genome. As a crucial consequence, Strainline is the first approach to provide strain-resolved, full-length de novo assemblies of viral quasispecies from noisy third-generation sequencing data. Benchmarking experiments on both simulated and real datasets of varying complexity and diversity confirm this novelty, by demonstrating the superiority of Strainline in terms of relevant criteria in comparison with the state of the art.
mGluR5 Negative Modulators for Fragile X: Resistance and Persistence
Authors: Stoppel David C , McCamphill Patrick K , Senter Rebecca K , Heynen Arnold J , Bear Mark F
Published: July 2021

Fragile X syndrome (FXS) is caused by silencing of the human FMR1 gene and is the leading monogenic cause of intellectual disability and autism. Abundant preclinical data indicated that negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGluR5) might be efficacious in treating FXS in humans. Initial attempts to translate these findings in clinical trials have failed, but these failures provide the opportunity for new discoveries that will improve future trials. The emergence of acquired treatment resistance (“tolerance”) after chronic administration of mGluR5 NAMs is a potential factor in the lack of success. Here we confirm that FXS model mice display acquired treatment resistance after chronic treatment with the mGluR5 NAM CTEP in three assays commonly examined in the mouse model of FXS: (1) audiogenic seizure susceptibility, (2) sensory cortex hyperexcitability, and (3) hippocampal protein synthesis. Cross-tolerance experiments suggest that the mechanism of treatment resistance likely occurs at signaling nodes downstream of glycogen synthase kinase 3α (GSK3α), but upstream of protein synthesis. The rapid emergence of tolerance to CTEP begs the question of how previous studies showed an improvement in inhibitory avoidance (IA) cognitive performance after chronic treatment. We show here that this observation was likely explained by timely inhibition of mGluR5 during a critical period, as brief CTEP treatment in juvenile mice is sufficient to provide a persistent improvement of IA behavior measured many weeks later. These data will be important to consider when designing future fragile X clinical trials using compounds that target the mGluR5-to-protein synthesis signaling cascade.
Novel canine high-quality metagenome-assembled genomes, prophages, and host-associated plasmids by long-read metagenomics together with Hi-C proximity ligation
Authors: Cuscó Anna , Pérez Daniel , Viñes Joaquim , Fàbregas Norma , Francino Olga
Published: July 2021

Long-read metagenomics facilitates the assembly of high-quality metagenome-assembled genomes (HQ MAGs) out of complex microbiomes. It provides highly contiguous assemblies by spanning repetitive regions, complete ribosomal genes, and mobile genetic elements. Hi-C proximity ligation data bins the long contigs and their associated extra-chromosomal elements to their bacterial host. Here, we characterized a canine fecal sample combining a long-read metagenomics assembly with Hi-C data, and further correcting frameshift errors.

We retrieved 27 HQ MAGs and seven medium-quality (MQ) MAGs considering MIMAG criteria. All the long-read canine MAGs improved previous short-read MAGs from public datasets regarding contiguity of the assembly, presence, and completeness of the ribosomal operons, and presence of canonical tRNAs. This trend was also observed when comparing to representative genomes from a pure culture (short-read assemblies). Moreover, Hi-C data linked six potential plasmids to their bacterial hosts. Finally, we identified 51 bacteriophages integrated into their bacterial host, providing novel host information for eight viral clusters that included Gut Phage Database viral genomes. Even though three viral clusters were species-specific, most of them presented a broader host range.

In conclusion, long-read metagenomics retrieved long contigs harboring complete assembled ribosomal operons, prophages, and other mobile genetic elements. Hi-C binned together the long contigs into HQ and MQ MAGs, some of them representing closely related species. Long-read metagenomics and Hi-C proximity ligation are likely to become a comprehensive approach to HQ MAGs discovery and assignment of extra-chromosomal elements to their bacterial host.
Plasmodium falciparum GBP2 is a telomere-associated protein that binds to G-quadruplex DNA and RNA
Authors: Edwards-Smallbone James , Jensen Anders L. , Roberts Lydia E. , Totanes Francis Isidore G. , Hart Sarah R. , Merrick Catherine J.
Published: July 2021

In the early-diverging protozoan parasite Plasmodium, few telomere-binding proteins have been identified and several are unique. Plasmodium telomeres, like those of most eukaryotes, contain guanine-rich repeats that can form G-quadruplex structures. In model systems, quadruplex-binding drugs can disrupt telomere maintenance and some quadruplex-binding drugs are potent anti-plasmodial agents. Therefore, telomere-interacting and quadruplex-interacting proteins may offer new targets for anti-malarial therapy. Here, we report that P. falciparum GBP2 is such a protein. It was identified via ‘Proteomics of Isolated Chromatin fragments’, applied here for the first time in Plasmodium. In vitro, PfGBP2 binds specifically to G-rich telomere repeats in quadruplex form and it can also bind to G-rich RNA. In vivo, PfGBP2 partially colocalises with the known telomeric protein HP1 but is also found in the cytoplasm, probably due to its affinity for RNA. Consistently, its interactome includes numerous RNA-associated proteins. PfGBP2 is evidently a multifunctional DNA/RNA-binding factor in Plasmodium.
Deep learning the arrow of time in brain activity: characterising brain-environment behavioural interactions in health and disease
Authors: Deco Gustavo , Perl Yonatan Sanz , Sitt Jacobo D. , Tagliazucchi Enzo , Kringelbach Morten L.
Published: July 2021

The complex intrinsic and extrinsic forces from the body and environment push the brain into non-equilibrium. The arrow of time, central to thermodynamics in physics, is a hallmark of non-equilibrium and serves to distinguish between reversible and non-reversible dynamics in any system. Here, we use a deep learning Temporal Evolution NETwork (TENET) framework to discover the asymmetry in the flow of events, ‘arrow of time’, in human brain signals, which provides a quantification of how the brain is driven by the interplay of the environment and internal processes. Specifically, we show in large-scale HCP neuroimaging data from a thousand participants that the levels of non-reversibility/non-equilibrium change across time and cognitive state with higher levels during tasks than when resting. The level of non-equilibrium also differentiates brain activity during the seven different cognitive tasks. Furthermore, using the large-scale UCLA neuroimaging dataset of 265 participants, we show that the TENET framework can distinguish with high specificity and sensitivity resting state in control and different neuropsychiatric diseases (schizophrenia, bipolar disorders and ADHD) with higher levels of non-equilibrium found in health. Overall, the present thermodynamics-based machine learning framework provides vital new insights into the fundamental tenets of brain dynamics for orchestrating the interactions between behaviour and brain in complex environments.