bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of epigenetic and cell cycle-related targets in glioblastoma cell lines: onametostat reduces proliferation and viability in both normoxic and hypoxic conditions
Authors: Lavogina Darja , Krõlov Mattias Kaspar , Vellama Hans , Modhukur Vijayachitra , Di Nisio Valentina , Lust Helen , Eskla Kattri-Liis , Salumets Andres , Jaal Jana
Published: November 2023

The choice of targeted therapies for treatment of glioblastoma patients is currently limited, and most glioblastoma patients die from the disease recurrence. Thus, systematic studies in simplified model systems are required to pinpoint the choice of targets for further exploration in clinical settings. Here, we report screening of 5 compounds targeting epigenetic writers or erasers and 6 compounds targeting cell cycle-regulating protein kinases against 3 glioblastoma cell lines following incubation under normoxic or hypoxic conditions. The viability assay indicated that PRMT5 inhibitor onametostat was endowed with high potency under both normoxic and hypoxic conditions in both MGMT-positive and MGMT-negative cell lines. In U-251 MG and U-87 MG cells, onametostat also affected the spheroid formation at concentrations lower than the currently used chemotherapeutic drug lomustine. Furthermore, in T98-G cell line, treatment with onametostat led to dramatic changes in the transcriptome profile by inducing the cell cycle arrest, suppressing RNA splicing, and down-regulating several major glioblastoma cell survival pathways. In this way, we confirmed that inhibition of epigenetic targets might represent a viable strategy for glioblastoma treatment even in the case of decreased chemo- and radiation sensitivity, although further studies in clinically more relevant models are required.
A Comprehensive Targeted Panel of 295 Genes: Unveiling Key Disease Initiating and Transformative Biomarkers in Multiple Myeloma
Authors: Ruhela Vivek , Oberoi Rupin , Gupta Ritu , Gupta Anubha
Published: November 2023

Multiple myeloma (MM) is a haematological cancer that evolves from the benign precursor stage termed monoclonal gammopathy of undetermined significance (MGUS). Understanding the pivotal biomarkers, genomic events, and gene interactions distinguishing MM from MGUS can significantly contribute to early detection and an improved understanding of MM’s pathogenesis. This study presents a curated, comprehensive, targeted sequencing panel focusing on 295 MM-relevant genes and employing clinically oriented NGS-targeted sequencing approaches. To identify these genes, an innovative AI-powered attention model, theBio-Inspired Graph Network Learning-based Gene-Gene Interaction(BIO-DGI) model, was devised for identifyingDisease-InitiatingandDisease-Transformativegenes using the genomic profiles of MM and MGUS samples. The BIO-DGI model leverages gene interactions from nine protein-protein interaction (PPI) networks and analyzes the genomic features from 1154 MM and 61 MGUS samples. The proposed model outperformed base-line machine learning (ML) and deep learning (DL) models on quantitative performance metrics. Additionally, the BIO-DGI model identified the highest number of MM-relevant genes in the post-hoc analysis, demonstrating its superior qualitative performance. Pathway analysis highlighted the significance of top-ranked genes, emphasizing their role in MM-related pathways. Encompassing 9417 coding regions with a length of 2.630 Mb, the 295-gene panel exhibited superior performance, surpassing previously published panels in detecting genomic disease-initiating and disease-transformative events. The panel also revealed highly influential genes and their interactions within MM gene communities. Clinical relevance was confirmed through a two-fold univariate survival analysis, affirming the significance of the proposed gene panel in understanding disease progression. The study’s findings offer crucial insights into essential gene biomarkers and interactions, shaping our understanding of MM pathophysiology.
Long-termin vivothree-photon imaging reveals region-specific differences in healthy and regenerative oligodendrogenesis
Authors: Thornton Michael A. , Futia Gregory L. , Stockton Michael E. , Budoff Samuel A. , Ramirez Alexandra N , Ozbay Baris , Tzang Omer , Kilborn Karl , Poleg-Polsky Alon , Restrepo Diego , Gibson Emily A. , Hughes Ethan G.
Published: November 2023

The generation of new myelin-forming oligodendrocytes in the adult CNS is critical for cognitive function and regeneration following injury. Oligodendrogenesis varies between gray and white matter regions suggesting that local cues drive regional differences in myelination and the capacity for regeneration. Yet, the determination of regional variability in oligodendrocyte cell behavior is limited by the inability to monitor the dynamics of oligodendrocytes and their transcriptional subpopulations in white matter of the living brain. Here, we harnessed the superior imaging depth of three-photon microscopy to permit long-term, longitudinalin vivothree-photon imaging of an entire cortical column and underlying subcortical white matter without cellular damage or reactivity. Using this approach, we found that the white matter generated substantially more new oligodendrocytes per volume compared to the gray matter, yet the rate of population growth was proportionally higher in the gray matter. Following demyelination, the white matter had an enhanced population growth that resulted in higher oligodendrocyte replacement compared to the gray matter. Finally, deep cortical layers had pronounced deficits in regenerative oligodendrogenesis and restoration of the MOL5/6-positive oligodendrocyte subpopulation following demyelinating injury. Together, our findings demonstrate that regional microenvironments regulate oligodendrocyte population dynamics and heterogeneity in the healthy and diseased brain.
Withdrawn: Hypertension increases PPV for polycystic kidney disease inPKD1andPKD2variant carriers
Authors: Telis Natalie , McEwen Lisa , Bolze Alexandre , Judge Daniel P. , Pawloski Pamala A. , Grzymski Joseph J. , Hajek Catherine , Schiabor Barrett Kelly M. , Washington Nicole L. , Cirulli Elizabeth T.
Published: November 2023

Withdrawal Statement

This version of the manuscript and associated files have been removed owing to concerns of data privacy.
The modified elevated gap interaction test: A novel paradigm to assess social preference
Authors: De Zeeuw Chris I. , Yu Si-yang , Chen Jiawei , van Hoogstraten Willem S. , van den Maagdenberg Arn M.J.M. , Bosman Laurens W.J. , Kros Lieke
Published: November 2023

Social deficits play a role in numerous psychiatric, neurological and neurodevelopmental disorders. Relating complex behavior, such as social interaction, to brain activity remains one of the biggest goals and challenges in neuroscience. Availability of standardized behavioral tests that assess social preference is however, limited. Here, we present a novel behavioral set-up and paradigm that we developed to measure social behavior, the modified elevated gap interaction test (MEGIT). In this test, animals are placed on one of two elevated platforms separated by a gap, in which they can engage in whisker-interaction with either a conspecific or an object. This allows quantification of social preference in real interaction rather than just proximity and forms an ideal setup for social behavior-related neuronal recordings. We provide a detailed description of the paradigm and its highly reliable, deep-learning based analysis, and show test results obtained from wild-type animals as well as genetic mouse models for disorders characterized by either hyposocial (autism spectrum disorder; ASD) or hypersocial (Williams Beuren syndrome; WBS) behavior. Wild-type animals show a clear preference for whisker interaction with another mouse rather than an inanimate object. This preference proved to be significantly smaller in mice carrying a mutation that can cause ASD in humans, whereas it is larger in WBS murine models. Differences in social preference became even more pronounced when corrected for hyperactive or repetitive behavior. The results indicate that MEGIT is a sensitive and reliable test for detecting and investigating social phenotypes.
Mechanical Resistance to Micro-Heart Tissue Contractility unveils early Structural and Functional Pathology in iPSC Models of Hypertrophic Cardiomyopathy
Authors: Guo Jingxuan , Jiang Huanzhu , Schuftan David , Moreno Jonathan D , Ramahdita Ghiska , Aryan Lavanya , Bhagavan Druv , Silva Jonathan , Huebsch Nathaniel
Published: November 2023

Hypertrophic cardiomyopathy is the most common cause of sudden death in the young. Because the disease exhibits variable penetrance, there are likely nongenetic factors that contribute to the manifestation of the disease phenotype. Clinically, hypertension is a major cause of morbidity and mortality in patients with HCM, suggesting a potential synergistic role for the sarcomeric mutations associated with HCM and mechanical stress on the heart. We developed anin vitrophysiological model to investigate how the afterload that the heart muscle works against during contraction acts together with HCM-linked MYBPC3 mutations to trigger a disease phenotype. Micro-heart muscle arrays (μHM) were engineered from iPSC-derived cardiomyocytes bearing MYBPC3 loss-of-function mutations and challenged to contract against mechanical resistance with substrates stiffnesses ranging from the of embryonic hearts (0.4 kPa) up to the stiffness of fibrotic adult hearts (114 kPa). Whereas MYBPC3+/-iPSC-cardiomyocytes showed little signs of disease pathology in standard 2D culture, μHMs that included components of afterload revealed several hallmarks of HCM, including cellular hypertrophy, impaired contractile energetics, and maladaptive calcium handling. Remarkably, we discovered changes in troponin C and T localization in the MYBPC3+/-μHM that were entirely absent in 2D culture. Pharmacologic studies suggested that excessive Ca2+intake through membrane-embedded channels, rather than sarcoplasmic reticulum Ca2+ATPase (SERCA) dysfunction or Ca2+buffering at myofilaments underlie the observed electrophysiological abnormalities. These results illustrate the power of physiologically relevant engineered tissue models to study inherited disease mechanisms with iPSC technology.
LIFE: A Deep Learning Framework for Laboratory Data Imputation in Electronic Health Records
Authors: Heilbroner Samuel P. , Carter Curtis , Vidmar David M. , Mueller Erik T. , Stumpe Martin C. , Miotto Riccardo
Published: November 2023

Laboratory data in electronic health records (EHRs) is an effective source of information to characterize patient populations, inform accurate diagnostics and treatment decisions, and fuel research studies. However, despite their value, laboratory values are underutilized due to high levels of missingness. Existing imputation methods fall short, as they do not fully leverage patient clinical histories and are commonly not scalable to the large number of tests available in real-world data (RWD). To address these shortcomings, we present Laboratory Imputation Framework using EHRs (LIFE), a deep learning framework based on multi-head attention that is trained to impute any laboratory test value at any point in time in the patient’s journey using their complete EHRs. This architecture (1) eliminates the need to train a different model for each laboratory test by jointly modeling all laboratory data of interest; and (2) better clinically contextualizes the predictions by leveraging additional EHR variables, such as diagnosis, medications, and discrete laboratory results. We validate our framework using a large-scale, real-world dataset encompassing over 1 million oncology patients. Our results demonstrate that LIFE obtains superior or equivalent results compared to state-of-the-art baselines in 23 out of 25 evaluated laboratory tests and better enhances a downstream adverse event detection task in 7 out of 9 cases, showcasing its potential in efficiently estimating missing laboratory values and, consequently, in transforming the utilization of RWD in healthcare.
Muscle mass, strength, power and physical performance and their association with quality of life in older adults, the Study of Muscle, Mobility and Aging (SOMMA)
Authors: Petnehazy Nora , Barnes Haley N. , Newman Anne B. , Kritchevsky Stephen B. , Cummings Steven R. , Hepple Russel T. , Cawthon Peggy M.
Published: November 2023

Background

Sarcopenia negatively impacts quality of life. It is unclear whether different measures of muscle size, strength, physical performance, and fitness have similar associations with quality of life.

Objective

To describe associations of sarcopenia metrics with quality of life outcomes.

Participants

Community-dwelling adults aged 70+ years participating in the SOMMA (Study of Muscle, Mobility and Aging) study.

Design and settings

Two academic medical centers.

Measurements

Measures included muscle size (MRI-muscle volume. D3Cr muscle mass); strength and power (grip strength, leg extension power and strength); walking and physical performance (4m and 400m walk, SPPB (Short Physical Performance Battery), stair climb, chair stand); fitness (VO2peak); health related quality of life (EQ-5D); and anthropometrics (weight, height, and body mass index).

Results were stratified by sex. Correlations, scatterplots and linear regression models described the association between various measures of sarcopenia and fitness with overall quality of life score (EQ5D VAS) as a continuous variable. We also quantified differences between sarcopenia and fitness measures by overall QOL (Quality of Life) as a categorical variable (low, medium, high) and by QOL subcomponents (pain and discomfort, problems with usual activities, mobility, anxiety and depression, and problems with self-care) using distributionally appropriate methods.

Results

Walking tests and physical performance were most consistently (but modestly) associated with overall quality of life (r∼0.2, p<.001) and its subcomponents. Both men and women several sarcopenia and fitness measures were more strongly associated with pain and usual activity than other QOL components.

Conclusions

Poor performance, lower fitness and lower strength are related to worse quality of life, particularly pain, in older adults. Future studies should quantify these relationships longitudinally.
Human mobility impacts the transmission of common respiratory viruses: A modeling study of the Seattle metropolitan area
Authors: Perofsky Amanda C. , Hansen Chelsea , Burstein Roy , Boyle Shanda , Prentice Robin , Marshall Cooper , Reinhart David , Capodanno Ben , Truong Melissa , Schwabe-Fry Kristen , Kuchta Kayla , Pfau Brian , Acker Zack , Lee Jover , Sibley Thomas R. , McDermot Evan , Rodriguez-Salas Leslie , Stone Jeremy , Gamboa Luis , Han Peter D. , Adler Amanda , Waghmare Alpana , Jackson Michael L. , Famulare Mike , Shendure Jay , Bedford Trevor , Chu Helen Y. , Englund Janet A. , Starita Lea M. , Viboud Cécile
Published: November 2023

Many studies have used mobile device location data to model SARS-CoV-2 dynamics, yet relationships between mobility behavior and endemic respiratory pathogens are less understood. We studied the impacts of human mobility on the transmission of SARS-CoV-2 and 16 endemic viruses in Seattle over a 4-year period, 2018-2022. Before 2020, school-related foot traffic and large-scale population movements preceded seasonal outbreaks of endemic viruses. Pathogen circulation dropped substantially after the initiation of stay-at-home orders in March 2020. During this period, mobility was a positive, leading indicator of transmission of all endemic viruses and lagged SARS-CoV-2 activity. Mobility was briefly predictive of SARS-CoV-2 transmission when restrictions relaxed in summer 2020 but associations weakened in subsequent waves. The rebound of endemic viruses was heterogeneously timed but exhibited stronger relationships with mobility than SARS-CoV-2. Mobility is most predictive of respiratory virus transmission during periods of dramatic behavioral change, and, to a lesser extent, at the beginning of epidemic waves.

Teaser:Human mobility patterns predict the transmission dynamics of common respiratory viruses in pre- and post-pandemic years.
Breathing exercises for the management of gastrointestinal conditions: protocol for a scoping review
Authors: Gholamrezaei Ali , Guadagnoli Livia , Teugels Anouk , Peluso Natalie , Fung Asta , Van Oudenhove Lukas , Van Diest Ilse , Vlaeyen Johan , Tack Jan , Vanuytsel Tim , Aziz Qasim , Talley Nicholas J , Keefer Laurie
Published: November 2023

1.

Objectives

This scoping review will identify and map the literature on breathing exercises for the management of gastrointestinal conditions.

Introduction

Emerging evidence suggests the potential benefits of breathing exercises for gastrointestinal conditions. However, there is a lack of a comprehensive review to systematically map the research done in this area, as well as to identify existing gaps in knowledge and guide future research.

Inclusion criteria

The review will consider any study that describes or evaluates a breathing exercise to manage a gastrointestinal condition or symptom in a patient population. Original studies including controlled clinical trials and observational studies (e.g., on patient’s experience), systematic reviews, scoping reviews, meta-analyses or any other form of systematic evidence synthesis, and case series will be sourced from published literature, gray literature, and the references of retrieved articles. Case reports, narrative reviews, letters, comments, editorials, and experimental studies including a healthy population only will be excluded.

Methods

The review will follow the Joanna Briggs Institute Reviewer’s Manual for the conduct and reporting of scoping reviews. Databases to be searched will include PubMed, EMBASE, PsycINFO, Web of Science, Scopus, Cochrane Database of Systematic Reviews, CINAHL, JBI Evidence Synthesis, and databases for gray literature. All databases will be searched from inception till the present. Retrieved citations will be independently reviewed, relevant studies will be included, and data will be extracted using a data extraction form. The results will be presented in tabular format, accompanied by a narrative summary and figures.
A STING-CASM-GABARAP Pathway Activates LRRK2 at Lysosomes
Authors: Bentley-DeSousa Amanda , Roczniak-Ferguson Agnes , Ferguson Shawn M.
Published: November 2023

Mutations that increase LRRK2 kinase activity have been linked to Parkinson’s disease and Crohn’s disease. LRRK2 is also activated by lysosome damage. However, the endogenous cellular mechanisms that control LRRK2 kinase activity are not well understood. In this study, we identify signaling through Stimulator of Interferon Genes (STING) as an activator of LRRK2 via the Conjugation of ATG8 to Single Membranes (CASM) pathway. We furthermore establish that multiple chemical stimuli that perturb lysosomal homeostasis also converge on CASM to activate LRRK2. Although CASM results in the lipidation of multiple ATG8 protein family members, we establish that LRRK2 lysosome recruitment and kinase activation is highly dependent on interactions with the GABARAP member of this family. Collectively these results define a pathway that integrates multiple stimuli at lysosomes to control the kinase activity of LRRK2. Aberrant activation of LRRK2 via this pathway may be of relevance in both Parkinson’s and Crohn’s diseases.
Chloroplasts lacking class I glutaredoxins are functional but show a delayed recovery of protein cysteinyl redox state after oxidative challenge
Authors: Bohle Finja , Rossi Jacopo , Tamanna Sadia S. , Jansohn Hannah , Schlosser Marlene , Reinhardt Frank , Brox Alexa , Bethmann Stephanie , Kopriva Stanislav , Trentmann Oliver , Jahns Peter , Deponte Marcel , Schwarzländer Markus , Trost Paolo , Zaffagnini Mirko , Meyer Andreas J. , Müller-Schüssele Stefanie J.
Published: November 2023

Redox status of protein cysteinyl residues is mediated via glutathione (GSH)/glutaredoxin (GRX) and thioredoxin (TRX)-dependent redox cascades. An oxidative challenge can induce post-translational protein modifications on thiols, such as proteinS-glutathionylation. Class I GRX are small thiol-disulfide oxidoreductases that reversibly catalyseS-glutathionylation and protein disulfide formation. TRX and GSH/GRX redox systems can provide partial backup for each other in several subcellular compartments, but not in the plastid stroma where TRX/light-dependent redox regulation of primary metabolism takes place. While the stromal TRX system has been studied at detail, the role of class I GRX on plastid redox processesin vivois still unknown. We generate knockout lines ofGRXC5as the only chloroplast class I GRX of the mossPhyscomitrium patens.

While we find that class I PpGRXC5 has high activities in glutathione-dependent oxidoreductase assays using hydroxyethyl disulfide or redox-sensitive GFP2 (roGFP2) as substratesin vitro, Δgrxc5plants show no detectable growth defect or stress sensitivity, in contrast to mutants with a less negative stromalEGSH(Δgr1). Using stroma-targeted roGFP2, we show increased protein Cys oxidation and decreased reduction rates after oxidative challenge in Δgrxc5plantsin vivo, indicating kinetic uncoupling of the protein Cys redox state from glutathione redox potential. Protein Cys disulfide andS-glutathionylation formation rates after H2O2treatment remained unchanged. Lack of class I GRX function in the stroma did not result in impaired carbon fixation.

Our observations suggest specific roles for class I GRX in the efficient redox equilibration betweenEGSHand protein Cys in the plastid stroma as well as negligible cross-talk with metabolic regulation via the TRX system. We propose a model for stromal class I GRX function as efficient kinetic couplers of protein Cys redox state to the dynamic stromalEGSHand highlight the importance of identifyingin vivotarget proteins of GRXC5.

One sentence summary

Removal of class I GRX activity in the chloroplast stroma ofP. patenskinetically uncouples GRX-dependent cysteine redox changes from the local glutathione redox potential, without an effect on NPQ or photosynthetic carbon reactions.
Nanometer-scale views of visual cortex reveal anatomical features of primary cilia poised to detect synaptic spillover
Authors: Ott Carolyn M. , Torres Russel , Kuan Tung-Sheng , Kuan Aaron , Buchanan JoAnn , Elabbady Leila , Seshamani Sharmishtaa , Bodor Agnes L. , Collman Forrest , Bock Davi D. , Lee Wei Chung , Maçarico da Costa Nuno , Lippincott-Schwartz Jennifer
Published: November 2023

A primary cilium is a thin membrane-bound extension off a cell surface that contains receptors for perceiving and transmitting signals that modulate cell state and activity. While many cell types have a primary cilium, little is known about primary cilia in the brain, where they are less accessible than cilia on cultured cells or epithelial tissues and protrude from cell bodies into a deep, dense network of glial and neuronal processes. Here, we investigated cilia frequency, internal structure, shape, and position in large, high-resolution transmission electron microscopy volumes of mouse primary visual cortex. Cilia extended from the cell bodies of nearly all excitatory and inhibitory neurons, astrocytes, and oligodendrocyte precursor cells (OPCs), but were absent from oligodendrocytes and microglia. Structural comparisons revealed that the membrane structure at the base of the cilium and the microtubule organization differed between neurons and glia. OPC cilia were distinct in that they were the shortest and contained pervasive internal vesicles only occasionally observed in neuron and astrocyte cilia. Investigating cilia-proximal features revealed that many cilia were directly adjacent to synapses, suggesting cilia are well poised to encounter locally released signaling molecules. Cilia proximity to synapses was random, not enriched, in the synapse-rich neuropil. The internal anatomy, including microtubule changes and centriole location, defined key structural features including cilium placement and shape. Together, the anatomical insights both within and around neuron and glia cilia provide new insights into cilia formation and function across cell types in the brain.
Semantic composition in experimental and naturalistic paradigms
Authors: Li Jixing , Lai Marco , Pylkkänen Liina
Published: November 2023

Naturalistic paradigms using movies or audiobooks have become increasingly popular in cognitive neuroscience, but connecting them to findings from controlled experiments remains rare. Here, we aim to bridge this gap in the context of semantic composition in language processing, which is typically examined using a “minimal” two-word paradigm. Using magnetoencephalography (MEG), we investigated whether the neural signatures of semantic composition observed in an auditory two-word paradigm can extend to naturalistic story listening, and vice versa. Our results demonstrate consistent differentiation between phrases and single nouns in the left anterior and middle temporal lobe, regardless of the context. Notably, this distinction emerged later during naturalistic listening. Yet this latency difference disappeared when accounting for various factors in the naturalistic data, such as prosody, word rate, word frequency, surprisal, and emotional content. These findings suggest the presence of a unified compositional process underlying both isolated and connected speech comprehension.
Chromosome-scale assembly of the African yam bean genome
Authors: Waweru Bernice , Njaci Isaac , Murungi Edwin , Paliwal Rajneesh , Mulli Collins , Maranga Mary , Kaimenyi Davies , Lyimo Beatus , Nigussie Helen , Ahadi Bwihangane Birindwa , Assefa Ermias , Ishag Hassan , Olomitutu Oluwaseyi , Abberton Michael , Darby Christopher , Uauy Cristobal , Yao Nasser , Adewale Daniel , Emmrich Peter , Domelevo Entfellner Jean-Baka , Shorinola Oluwaseyi
Published: November 2023

Genomics-informed breeding of locally adapted, nutritious, albeit underutilised African crops can help mitigate food and nutrition insecurity challenges in Africa, particularly against the backdrop of climate change. However, utilisation of modern crop improvement tools including genomic selection and genome editing for many African indigenous crops is hampered by the scarcity of genetic and genomic resources. Here we report on the assembly of the genome of African yam bean (Sphenostylis stenocarpa), a tuberous legume crop that is indigenous to Africa. By combining long and short read sequencing with Hi-C scaffolding, we produced a chromosome-scale assembly with an N50 of 69.5 Mbp and totalling 649 Mbp in length (77 - 81% of the estimated genome size based on flow cytometry). Using transcriptome evidence from Nanopore RNA-Seq and homology evidence from related crops, we annotated 31,614 putative protein coding genes. We further show how this resource improves anchoring of markers, genome-wide association analysis and candidate gene analyses in Africa yam bean. This genome assembly provides a valuable resource for genetic research in Africa yam bean.
A Simple Bias Reduction Algorithm for RNA Sequencing Datasets
Authors: Thron Christopher , Bergom Hannah , Boytim Ella , Roberts Mienie , Hwang Justin , Jafari Farhad
Published: November 2023

RNA sequencing (RNA-seq) is the conventional genome-scale approach used to capture the expression levels of all detectable genes in a biological sample. This is now regularly used in the clinical diagnostic space for cancer patients. While the information gained is intended to impact treatment decisions, numerous technical and quality issues remain. This includes inaccuracies in the dissemination of gene-gene relationships. For such reasons, clinical decisions are still mostly driven by DNA biomarkers, such as gene mutations or fusions. In this study, we aimed to correct for systemic bias based on RNA-sequencing platforms in order to improve our understanding of the gene-gene relationships. To do so, we examined standard pre-processed RNA-seq datasets obtained from three studies conducted by two consortium efforts including The Cancer Genome Atlas (TCGA) and Stand Up 2 Cancer (SU2C). We particularly examined the TCGA Bladder Cancer (n = 408) and Prostate Cancer (n = 498) studies as well as the SU2C Prostate Cancer study (n = 208). Using various statistical tests, we detected expression-level dependent, per-sample biases in all datasets. Using simulations, we show that these biases corrupt the results oft-tests designed to identify expression level differences between subpopulations. Importantly, these biases introduce large errors into estimates of gene-gene correlations. To mitigate these biases, we introduceLocal Levelingas a novel mathematical approach that transforms count level data and corrects these observed biases. Local Leveling specifically corrects for the bias due to the inherent differential detection of transcripts that is driven by differential expression levels. Based on standard forms of count data (Raw counts, transcripts per million, fragments per kilobase of exon per million), we demonstrate that local leveling effectively removes the observed per-sample biases, and improves the accuracy in simulated statistical tests. Importantly, this led to systemic changes of gene-gene relationships when examining the correlation of key oncogenes, such as the Androgen Receptor, with all other detectable genes. Altogether, Local Leveling improves our capacity towards understanding gene-gene relationships, which may lead to novel ways to utilize the information derived from clinical tests.
Inferring the proportion of undetected cholera infections from serological and clinical surveillance in an immunologically naive population
Authors: Finger Flavio , Lemaitre Joseph , Juin Stanley , Jackson Brendan , Funk Sebastian , Lessler Justin , Mintz Eric , Dely Patrick , Boncy Jacques , Azman Andrew S
Published: November 2023

Most infections with pandemic Vibrio cholerae are thought to result in subclinical disease and are not captured by surveillance. Previous estimates of the ratio of infections to clinical cases have varied widely (2 to 100). Understanding cholera epidemiology and immunity relies on the ability to translate between numbers of clinical cases and the underlying number of infections in the population. We estimated the infection incidence during the first months of an outbreak in a cholera-naive population using a Bayesian vibriocidal antibody titer decay model combining measurements from a representative serosurvey and clinical surveillance data. 3,880 suspected cases were reported in Grande Saline, Haiti, between 20 October 2010 and 6 April 2011 (clinical attack rate 18.4%). We found that more than 52.6% (95% Credible Interval (CrI) 49.4-55.7) of the population ≥2 years showed serologic evidence of infection, with a lower infection rate among children aged 2-4 years (35.5%; 95%CrI 24.2-51.6) compared with people ≥5 years (53.1%; 95%CrI 49.4-56.4). This estimated infection rate, nearly three times the clinical attack rate, with underdetection mainly seen in those ≥5 years, has likely impacted subsequent outbreak dynamics. Our findings show how seroincidence estimates improve understanding of links between cholera burden, transmission dynamics and immunity.

Key Results

We combine serological and clinical cholera incidence in an outbreak in a naive population in Grande Saline, Haiti.

The rate of infection withVibrio choleraewas several times the clinical attack rate.

Half of the population ≥2 years showed serological evidence of infection.

For every reported clinical case ≥5 years old, 3.2 (95% CrI 3.0-3.4) people were infected.

Children 2-4 years old had a lower infection rate, which was not significantly different from the clinical attack rate.
Negative association between higher maternal body mass index and breastfeeding outcomes is not mediated by DNA methylation
Authors: Elliott Hannah R. , Bennett Chloe L. , Caramaschi Doretta , English Sinead
Published: November 2023

The benefits of breastfeeding for the health and wellbeing of both infants and mothers are well documented, yet global breastfeeding rates are low. One factor associated with low breastfeeding is maternal body mass index (BMI), which is used as a measure of obesity. The negative relationship between maternal obesity and breastfeeding is likely caused by a variety of social, psychological, and physiological factors. Maternal obesity may also have a direct biological association with breastfeeding through changes in maternal DNA methylation. Here, we investigate this potential biological association using data from a UK-based cohort study, the Avon Longitudinal Study of Parents and Children (ALSPAC). We find that pre-pregnancy body mass index (BMI) is associated with lower initiation to breastfeed and shorter breastfeeding duration. We conduct epigenome-wide association studies (EWAS) of maternal BMI and breastfeeding outcomes and candidate-gene analysis of methylation sites associated with BMI identified via previous meta-EWAS. We find that DNA methylation at cg11453712, annotated to PHTP1, is associated with maternal BMI. From our results, neither this association nor those at candidate-gene sites are likely to mediate the link between maternal BMI and breastfeeding.
Systemic immune markers and infection risk in preterm infants fed human milk fortified with bovine colostrum or conventional fortifier, a secondary analysis of theFortiColostrial
Authors: Bæk Ole , Muk Tik , Aunsholt Lise , Zachariassen Gitte , Sangild Per Torp , Nguyen Duc Ninh
Published: November 2023

Background

For very preterm infants, human milk is often fortified with formula products based on processed bovine milk. Intact bovine colostrum (BC) is rich in anti-inflammatory milk factors and considered an alternative. Our objective was to investigate if BC affects anti-inflammatory/TH2 immunity and infection risk in very preterm infants.

Methods

In a secondary analysis of a multicenter, randomized controlled trial (NCT03537365), very preterm infants (26-31 weeks gestation, 23% small for gestational age, SGA) were randomized to receive BC (ColoDan, Biofiber, Denmark, n=113) or a conventional fortifier (PreNAN, Nestlé, Switzerland, n=116). Infection was defined as antibiotic treatment for five or more consecutive days. Levels of 29 cytokines and chemokines were measured in plasma before and after start of fortification.

Results

Infants fortified with BC showed more infection episodes (20 vs. 12%, P<0.05) and tendency to higher cumulative infection risk (hazard ratio, HR 1.9, P=0.06), particularly for SGA infants (HR 3.6, P<0.05). Additionally, BC-fortified infants had higher levels of TH2 related cytokines and chemokines (IL-10, MDC, MCP4) and reduced levels of cytokines related to TH1/TH17 responses (IL-15, IL-17, GM-CSF). The differences were most pronounced in SGA infants, displaying higher levels of TH2-related IL-4, IL-6, and IL-13, and lower interferon-γ and IL-1α levels in the BC group

Conclusion

Infants fortified with BC show delayed transition from TH2-to TH1-biased systemic immunity, especially for SGA infants. This was associated with more frequent antibiotic use, indicating elevated sensitivity to infection. Thus, an anti-inflammatory milk supplement like BC may delay systemic immune development in preterm infants with effects depending on weight at birth.
Analysis of root volatiles and functional characterization of a root-specific germacrene A synthase inArtemisia pallens
Authors: Kiran N.R. , Narayanan Ananth Krishna , Mohapatra Soumyajit , Gupta Priyanka , Nagegowda Dinesh A.
Published: November 2023

Davana (Artemisia pallens) is a valuable aromatic herb within the Asteraceae family, highly prized for its essential oil (EO) produced in the aerial parts. However, the root volatiles and their specific composition, and genes responsible for root volatiles have remained unexplored until now. Here, we show thatA. pallensroots possess distinct oil bodies and yields ∼0.05% of EO, which is primarily composed of sesquiterpenes β-elemene, neryl isovalerate, β-selinene, and α-selinene, and trace amounts of monoterpenes β-myrcene, D-limonene. This shows that, besides aerial parts, roots of davana can also be a source of unique EO. Moreover, we functionally characterized a terpene synthase (ApTPS1) that exhibited highin silicoexpression in the root transcriptome. The recombinant ApTPS1 showed the formation of β-elemene and germacrene A withE,E-farnesyl diphosphate (FPP) as a substrate. Further, detailed analysis of assay products revealed that β-elemene was the thermal rearrangement product of germacrene A. Furthermore, the functional expression of ApTPS1 inSaccharomyces cerevisiaeconfirmed thein vivoβ-elemene/germacrene A synthase activity of ApTPS1. At the transcript level,ApTPS1displayed predominant expression in root, with significantly lower level of expression in other tissues. This expression pattern ofApTPS1positively correlated with the tissue-specific accumulation level of β-elemene. Overall, these findings provide fundamental insights into the EO profile of davana roots, and the contribution of ApTPS1 in the formation of a major root volatile.

Main conclusion

The study demonstrated thatArtemisia pallensroots can be a source of terpene-rich essential oil and root-specific ApTPS1 forms germacrene-A contributing to major root volatiles.
Sperm Cryopreservation of the African Turquoise KillifishNothobranchius furzeri
Authors: Dolfi Luca , Suen Tsz Kin , Medelbekova Danel , Ripa Roberto , Symmons Orsolya , Antebi Adam
Published: November 2023

Sperm cryopreservation is an essential method for the genetic preservation and long-term storage of wild-type and transgenic animal stocks. In addition, it allows for the synchronization of gamete availability and the transport and sharing of lines between different laboratories. Here, we describe a protocol developed in our laboratory for the extraction and cryopreservation of killifish (Nothobranchius furzeri) sperm.
Agar Plate–Based Method for the Selection of Antibiotic-Resistant Bacterial Strains
Authors: Zeden Merve S. , Gründling Angelika
Published: November 2023

Identifying the molecular mechanisms underlying antibiotic resistance is important, as it can reveal key information on the mode of action of a drug and provide insights for the development of novel or improved antimicrobials. Here, we describe an agar-based method for the selection of bacterial strains with increased antibiotic resistance, and how the increase in resistance can be confirmed by a spot-plating assay. As a specific example, we describe the selection ofStaphylococcus aureusstrains with increased resistance to oxacillin; however, the protocol can be easily adapted and used with other bacteria and antibiotics.
Selection of Antibiotic-Resistant Bacterial Strains and Identification of Genomic Alterations by Whole-Genome Sequencing: UsingStaphylococcus aureusand Oxacillin Resistance as an Example
Authors: Zeden Merve S. , Gründling Angelika
Published: November 2023

Here, we discuss methods for the selection of antibiotic-resistant bacteria and the use of high-throughput whole-genome sequencing for the identification of the underlying mutations. We comment on sample requirements and the choice of specific DNA preparation methods depending on the strain used and briefly introduce a workflow we use for the selection ofStaphylococcus aureusstrains with increased oxacillin resistance and identification of genomic alterations.
Correlation between the initial aging of epoxy coatings and the typical marine atmospheric environmental factors
Authors: Song Dongdong , Qin Wenxiang , Zhou Qian , Xu Dong , Zhang Bo
Published: November 2023

Purpose

The anticorrosion coatings used in marine and atmospheric environment are subjected to many environmental factors. And the aging failure has been puzzling researchers. The purpose of this study is to find the correlation between the initial aging of epoxy coatings and the typical marine atmospheric environmental factors.

Design/methodology/approach

The epoxy coatings were subjected to a one-year exposure in three typical marine atmospheres. Meanwhile, principal component analysis, linear regression and Spearman and gray correlation analysis were applied to quantify the environmental characteristics and establish correlations with the coating aging.

Findings

The results indicate that the coating will undergo macroscopic fading and chalking upon exposure to the marine atmosphere, while microscopic examination reveals holes, cracks and partial peeling. The adhesion performance and electrochemical properties of the coating deteriorated with prolonged exposure, coating aging mainly occurs with the generation of O-H bonds and the breakage of molecular chains such as C-N and C-O-C. The coating was most deeply aged after exposure to the Xisha, followed by Zhoushan and finally Qingdao. Environmental factors affect the photooxidative aging and hydrolytic degradation processes of coatings and thus coating aging. To further demonstrate the correlation between environmental factors and coating aging, principal component analysis was used. The correlation model between environmental factors and coating aging was subsequently obtained. The correlation model between the rate of coating adhesion loss (E) and the comprehensive evaluation parameter of environmental factors (Z) is expressed as E = 0.142 + 0.028Z. Meanwhile, the Spearman correlation analysis and gray correlation method were used to investigate the impact of each environmental factor on coating aging. Solar irradiation, relative humidity and wetting time have the highest correlation with coating aging, which are all above 0.8 and have the greatest influence on coating aging; wind speed and temperature have the smallest correlation with coating aging, which are about 0.6 and have the least influence on coating aging.

Originality/value

This paper establishes a correlation between typical marine environmental factors and coating aging performance, which is crucial for predicting the service life of other coatings in diverse environments.
Impact of circular economy practices on supply chain capability, flexibility and sustainable supply chain performance
Authors: Malhotra Gunjan
Published: November 2023

Purpose

This paper analyses the effect of circular economy practices on sustainable supply chain performance. The study explores the impact of mediating variables such as supply chain flexibility and capabilities and the moderating role of supply chain integration in the relationship between circular economy practices and sustainable supply chain performance in Indian manufacturing firms. The study builds on the stimulus-organism-response (S-O-R) model to conceptualise circular economy practices that influence supply chain capabilities, integration and flexibility, impacting sustainable supply chain performance.

Design/methodology/approach

This study adopted an online survey questionnaire distributed to managers of Indian manufacturing firms adopting circular economy practices. The data were analysed using SPSS Amos 25 and PROCESS macros.

Findings

The results suggest a positive impact of circular economy practices on sustainable supply chain performance in manufacturing firms. In addition, a supply chain manager's relationship with retailers is improved in the presence of supply chain capabilities and flexibility. Supply chain integration further strengthens this relationship as a moderating variable.

Originality/value

By examining the literature on circular economy practices and sustainable supply chain management, this study contributes to bridging the gap between supply chain capabilities, integration and flexibility using the S-O-R model. This study is possibly among the first to explore and provide empirical evidence on how circular economy practices in manufacturing firms can impact supply chain managers' experiences and thus help to improve environmental well-being. Both academics and business professionals might find these contributions interesting.
The impact of financial assets’ classification according to IFRS 9 on firm value: the case of MENA region’s banks
Authors: Ben Ltaief Khouloud , Moalla Hanen
Published: November 2023

Purpose

The purpose of this study is twofold. On the one hand, it studies the impact of IFRS 9 adoption on the firm value; and on the other hand, it investigates the impact of the classification of financial assets on the firm value.

Design/methodology/approach

The study covers a sample of 55 listed banks in the Middle Eastern and North African (MENA) region. Data is collected for three years (2017–2019).

Findings

The findings show that banks’ value is not impacted by IFRS 9 adoption but by financial assets’ classification. Firm value is positively affected by fair value through other comprehensive income assets, while it is negatively affected by amortized cost and fair value through profit or loss assets. The results of the additional analysis show consistent outcomes.

Practical implications

This research reveals important managerial implications. Priority should be given to the financial assets’ classification strategy following the adoption of IFRS 9 to boost the market valuation of banks. It may be useful for investors, managers and regulators in their decision-making.

Originality/value

This study enriches previous research as IFRS 9 is a new standard, and its adoption consequences need to be investigated. A few recent studies have focused on IFRS 9 as a whole or on other parts of IFRS 9, namely, the impairment regime and hedge accounting and concern developed contexts. However, this research adds to the knowledge of capital market studies by investigating the application of IFRS 9 in terms of classification in the MENA region.
The development of China's online livestreaming industry and comparative analysis between China and other countries
Authors: Shi Yupeng , Wang Xinyu , Zhang Siyu
Published: November 2023

Purpose

The purpose of this study is to discover the uniqueness of China's online livestreaming industry and to make preliminary predictions about its future.

Design/methodology/approach

Providing a panoramic description of China's online livestreaming industry and a comparative analysis with other countries' online livestreaming industries.

Findings

China's online livestreaming industry is world leader in general. In terms of user size and age structure, although China has a high proportion of online livestreaming users, the proportion of anchors is not high, while the age structure of users in both China and other countries shows the characteristics of younger users. In terms of policy, the difference between China and foreign support in online livestreaming is small, but developed countries have stricter regulations.

Originality/value

The research in this paper has great significance in gaining an in-depth understanding of the development status and trends of China's online livestreaming industry and in designing accurate support policies.