bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural Insights into Regulation of Insulin Expression Involving i-Motif DNA Structures in the Insulin-Linked Polymorphic Region
Authors: Guneri Dilek , Alexandrou Effrosyni , El Omari Kamel , Dvořáková Zuzana , Chikhale Rupesh V. , Pike Daniel , Waudby Christopher A. , Morris Christopher J. , Haider Shozeb , Parkinson Gary N. , Waller Zoë A. E.
Published: June 2023

The insulin linked polymorphic region (ILPR) is a variable number of tandem repeats (VNTR) region of DNA in the promoter of the insulin gene that regulates transcription of insulin. This region is known to form the alternative DNA structures, i-motifs and G-quadruplexes. Individuals have different sequence variants of VNTR repeats and although previous work investigated the effects of some variants on G-quadruplex formation, there is not a clear picture of the relationship between the sequence diversity, the DNA structures formed, and the functional effects on insulin gene expression. Here we show that different sequence variants of the ILPR form different DNA secondary structures and insulin expression is dependent on formation of i-motif and G-quadruplex structures. The first crystal structure and dynamics of an intramolecular i-motif also reveal sequences within the loop regions forming additional stabilising interactions, which are critical to formation of the stable i-motif structures that modulate insulin expression. The outcomes of this work reveal the detail in formation of stable i-motif DNA structures, with potential for rational based drug design for compounds to alter insulin gene expression.
Insulin-like Growth Factot-1 Supplementation Promotes Kidney Development and Alleviate Renal Inflammation in Preterm Pigs
Authors: Zhong Jingren , Thymann Thomas , Sangild Per Torp , Nguyen Duc Ninh , Muk Tik
Published: June 2023

Background

Preterm birth and its associated complications cause disruption of normal prenatal renal development, leading to postnatal kidney injury and failure. Preterm infants are deficient in insulin-like growth factor 1 (IGF-1), a critical growth factor that stimulates tissue perfusion and development. Using necrotizing enterocolitis-sensitive preterm pigs as a model for preterm infants, we investigated whether IGF-1 supplementation during early life could improve kidney development and health.

Methods

Caesarean-delivered preterm pigs were allocated into two groups, either consistently receiving vehicle or IGF-1 immediately after birth for 5, 9 or 19 days. Postnatal age-matched term pigs were selected and served as term control on postnatal day (PND) 5, 9, and 19. Blood, urine and kidney tissue were collected for biochemical, histological and gene expression analyses.

Results

Preterm pigs showed impaired kidney development and increased kidney insults, as indicated by reduced average glomerular area, increased abnormal glomeruli percentage and increased markers of renal injury and inflammation compared to term pigs. IGF-1 supplementation significantly reduced the abnormal glomeruli percentage, renal injury and inflammation related markers, and up-regulated certain maturation-related genes on PND5.

Conclusion

IGF-1 supplementation supports kidney maturation and restoration of kidney insults after preterm birth in the early life of newborns.

Impact

Preterm birth disrupts kidney development in preterm pigs.

Preterm birth leads to kidney injury and inflammation in preterm pigs.

IGF-1 supplementation might promote kidney maturation and alleviate preterm birth associated kidney injury and inflammation in preterm pigs.
Modeling of lung-liver interaction during infection in a human microfluidic organ-on-a-chip
Authors: Reinhold Susanne , Herr Christian , Yao Yiwen , Pourrostami Mehdi , Ritzmann Felix , Lehr Thorsten , Selzer Dominik , Kohl Yvonne , Yildiz Daniela , Slevogt Hortense , Beisswenger Christoph , Bals Robert
Published: June 2023

Background

Infections of the respiratory tract such as pneumonia or COVID-19 cause high mortality and morbidity worldwide. Organ-on-a-chip (OC) technologies have been developed in the last years to establish human-based disease models, to study basic disease mechanisms and to provide a tool to speed up drug development. The aim of this study was to establish a lung-liver microfluidic system to study the interaction of both organ modules during infection.

Methods

A two organ (lung / liver) microfluidic system was established using primary human bronchial (HBECs) or alveolar type epithelial cells (ATC) for the lung module and Huh-7 cells for the liver module. Inactivated non typeableHaemophilus influenzae(NTHi) andPseudomonas aeruginosaPAO1 (PAO1) were applied to the lung module. Secreted mediators were screened by dot-blot analysis and quantified. The effect of lung epithelial bacterial stimulation on the liver cell transcriptome was analyzed by mRNA sequencing.

Results

Lung and liver cells established stable cultures in a circulatory microfluidic system. Activation of HBECs or ATCs with NTHi or PAO1 resulted in the secretion of multiple inflammatory mediators into the microfluidic medium including TNF-α, monocyte chemotactic protein-1 (MCP-1) and macrophage inflammatory protein-3 (MIP-3). Addition of lung cells and application of bacterial onto the HBECs module resulted in the gross change of the transcriptome of the liver cell module. Gene ontology enrichment analysis showed the induction of various pathways involved in host defense, metabolisms, repair, and acute phase response.

Interpretation

In conclusion, a two-organ lung/liver microfluidic system was established to study the interaction of the organ modules during infection. Mediators released from epithelial culture modules into the microfluidic circulation after exposure to bacterial pathogens significantly modify the gene expression patterns of liver cells.

Funding

This research was funded by the German Federal Ministry of Education and Research (BMBF), 031L0153 VISION “Alternativmethoden zum Tierversuch” and the Dr. Rolf M. Schwiete Stiftung.
pi_tailtrack: A compact, inexpensive, and open-source behaviour-tracking system for head-restrained zebrafish
Authors: Randlett Owen
Published: June 2023

Quantifying animal behavior during microscopy is crucial to associate optically recorded neural activity with behavioural outputs and states. Here I describe an imaging and tracking system for head-restrained larval zebrafish compatible with functional microscopy. This system is based on the Raspberry Pi computer, Pi NoIR camera, and open-source software for the real-time tail segmentation and skeletonization of the zebrafish tail at over 100hz. This allows for precise and long-term analyses of swimming behaviour, that can be related to functional signals recorded in individual neurons. This system offers a simple but performant solution for quantifying the behavior of head-restrained larval zebrafish, which can be built for 340€.
Predicting drug response from single-cell expression profiles of tumours
Authors: Pellecchia Simona , Viscido Gaetano , Franchini Melania , Gambardella Gennaro
Published: June 2023

Drug response prediction at the single cell level is an emerging field of research that aims to improve the efficacy and precision of cancer treatments. Here, we introduce DREEP (Drug Response Estimation from single-cell Expression Profiles), a computational method that leverages publicly available pharmacogenomic screens and functional enrichment analysis to predict single cell drug sensitivity from transcriptomic data. We validated DREEP extensivelyin vitrousing several independent single-cell datasets with over 200 cancer cell lines and showed its accuracy and robustness. Additionally, we also applied DREEP to molecularly barcoded breast cancer cells and identified drugs that can selectively target specific cell populations. DREEP provides an in-silico framework to prioritize drugs from single-cell transcriptional profiles of tumours and thus helps in designing personalized treatment strategies and accelerate drug repurposing studies. DREEP is available athttps://github.com/gambalab/DREEP.
Influence of traffic and weather on carcass persistence time of small wildlife on roads
Authors: Bénard Annaëlle , Bonenfant Christophe , Lengagne Thierry
Published: June 2023

The rapidly expanding road network threatens the persistence of many terrestrial species through habitat loss, fragmentation, chemical, light and noise pollution and mortality associated with wildlife-vehicle collisions. Roadkill monitoring under-estimate actual collision numbers as the time during which roadkill carcasses remain visible on the road is often shorter than the frequency of road monitoring. By placing passerines (< 20 g) and amphibian carcasses on stretches of roads we surveyed every 2 hours, we fine-tuned existing persistence estimates for these species. We found median disappearance times (time for half of the carcasses to disappear) of less than 30 minutes for birds and 1-18 hours for amphibians depending on the volume of traffic, which is much shorter than previous estimates. Rainfall did not impact carcass persistence. We show the implications of these results by (1) correcting the results of roadkill surveys performed on common toads in reproductive migration for the number of removed carcasses and (2) estimating the number of passerine-vehicle collisions in the Auvergne-Rhône-Alpes (AuRA) region of France using the citizen-science database Faune-AuRA. We estimate that a road survey conducted 3 hours after amphibian road crossing under-estimates the number of roadkill by half, and that about 6800 passerine collisions were missed in 2022 by contributors because of short carcass persistence on the road. Small-bodied carcasses are hard to detect for drivers, and for a collision-report rate of 1%, total collision numbers for passerines could be as high as 700 000 individuals from 21 reported passerine species in 2022 in AuRA.
A population-averaged structural connectomic brain atlas of 422 HCP-Aging subjects
Authors: Xiao Yiming , Lau Jonathan C. , Peters Terry , Khan Ali R.
Published: June 2023

Population-averaged brain atlases, that are represented in a standard space with anatomical labels, are instrumental tools in neurosurgical planning and the study of neurodegenerative conditions. Traditional brain atlases are primarily derived from anatomical scans and contain limited information regarding the axonal organization of the white matter. With the advance of diffusion MRI that allows the modelling of fiber orientation distribution (FOD) in the brain tissue, there is an increasing interest for a population-averaged FOD template, especially based on a large healthy aging cohort, to offer structural connectivity information for connectomic surgery and analysis of neurodegeneration. The dataset described in this article contains a set of multi-contrast structural connectomic MRI atlases, including T1w, T2w, and FOD templates, along with the associated whole brain tractograms. The templates were made using multi-contrast group-wise registration based on 3T MRIs of 422 Human Connectome Project in Aging (HCP-A) subjects. To enhance the usability, probabilistic tissue maps and segmentation of 22 subcortical structures are provided. Finally, the subthalamic nucleus shown in the atlas is parcellated into sensorimotor, limbic, and associative sub-regions based on their structural connectivity to facilitate the analysis and planning of deep brain stimulation procedures. The dataset is available on the OSF Repository:https://osf.io/p7syt.

Specifications table

Value of the data

These publicly available templates were created using 422 HCP-Aging subjects, representing averaged anatomical and structural connectivity features of the healthy aging brain.

Matching T1w, T2w, and fiber orientation distribution (FOD) templates are provided, together with the associated tractograms that contain 20K and 2 million streamlines.

Segmentation of 22 subcortical structures and probabilistic tissue maps are provided to enhance the usability of the templates.

Parcellation of the subthalamic nucleus, based on structural connectivity of the included cohort at 0.3 × 0.3 × 0.3 mm3resolution, is provided.
The 3D modules of enzyme catalysis: deconstructing active sites into distinct functional entities
Authors: Riziotis Ioannis G. , Ribeiro António J. M. , Borkakoti Neera , Thornton Janet M.
Published: June 2023

Enzyme catalysis is governed by a limited toolkit of residues and organic or inorganic co-factors. Therefore, it is expected that recurring residue arrangements will be found across the enzyme space, which perform a defined catalytic function, are structurally similar and occur in unrelated enzymes. Leveraging the integrated information in the Mechanism and Catalytic Site Atlas (M-CSA) (enzyme structure, sequence, catalytic residue annotations, catalysed reaction, detailed mechanism description), 3D templates were derived to represent compact groups of catalytic residues. A fuzzy template-template search, allowed us to identify those recurring motifs, which are conserved or convergent, that we define as the “modules of enzyme catalysis”. We show that a large fraction of these modules facilitate binding of metal ions, co-factors and substrates, and are frequently the result of convergent evolution. A smaller number of convergent modules perform a well-defined catalytic role, such as the variants of the catalytic triad (i.e. Ser-His-Asp/Cys-His-Asp) and the saccharide-cleaving Asp/Glu triad. It is also shown that enzymes whose functions have diverged during evolution preserve regions of their active site unaltered, as shown by modules performing similar or identical steps of the catalytic mechanism. We have compiled a comprehensive library of catalytic modules, that characterise a broad spectrum of enzymes. These modules can be used as templates in enzyme design and for better understanding catalysis in 3D.
The pharmacoepigenomic landscape of cancer cell lines reveals the epigenetic component of drug sensitivity
Authors: Ohnmacht AJ , Rajamani A , Avar G , Kutkaite G , Gonçalves E , Saur D , Menden MP
Published: June 2023

Aberrant DNA methylation accompanies genetic alterations during oncogenesis and tumour homeostasis and contributes to the transcriptional deregulation of key signalling pathways in cancer. Despite increasing efforts in DNA methylation profiling of cancer patients, there is still a lack of epigenetic biomarkers to predict treatment efficacy. To address this, we analysed 721 cancer cell lines across 22 cancer types treated with 453 anti-cancer compounds. We systematically detected the predictive component of DNA methylation in the context of transcriptional and mutational patterns, i.e., in total 19 DNA methylation biomarkers across 17 drugs and five cancer types. DNA methylation constituted drug sensitivity biomarkers by mediating the expression of proximal genes, thereby enhancing biological signals across multi-omics data modalities. Our method reproduced anticipated associations, and in addition, we found that theNEK9promoter hypermethylation may confer sensitivity to the NEDD8-activating enzyme (NAE) inhibitor pevonedistat in melanoma through downregulation ofNEK9. In summary, we envision that epigenomics will refine existing patient stratification, thus empowering the next generation of precision oncology.
BrainBeats, an Open-Source EEGLAB Plugin to Jointly Analyze EEG and Cardiovascular Signals
Authors: Cannard Cédric , Wahbeh Helané , Delorme Arnaud
Published: June 2023

The interplay between the brain and the cardiovascular systems is garnering increased attention for its potential to advance our understanding of human physiology and improve health outcomes. However, the multimodal analysis of these signals is challenging due to the lack of guidelines, standardized signal processing and statistical tools, graphical user interfaces (GUIs), and automation for processing large datasets and increasing reproducibility. A further void exists in standardized quantitative EEG (qEEG) and heart-rate variability (HRV) feature extraction methods, undermining clinical diagnostics or the robustness of machine learning (ML) models. In response to these limitations, we introduce the BrainBeats toolbox. Implemented as an open-source EEGLAB plugin, BrainBeats integrates three main protocols: 1) Heartbeat-evoked potentials (HEP) and oscillations (HEO) for assessing time-locked brain-heart interplay at the millisecond accuracy; 2) qEEG and HRV feature extraction for examining associations/differences between various brain and heart metrics or for building robust feature-based ML models; 3) Automated extraction of heart artifacts from EEG signals to remove any potential cardiovascular contamination while conducting EEG analysis. We provide a step-by-step tutorial for performing these three methods on an open-source dataset containing simultaneous 64-channel EEG, ECG, and PPG signals. Users can easily fine-tune parameters to tailor their unique research needs via the graphical user interface (GUI) or the command line. BrainBeats should make brain-heart interplay research more accessible and reproducible.

The BrainBeats toolbox is an open-source EEGLAB plugin designed to jointly analyze EEG and cardiovascular (ECG/PPG) signals. It offers three main protocols: heartbeat-evoked potentials (HEP) assessment, feature-based analysis, and heart artifact extraction from EEG signals. It should aid researchers and clinicians in studying brain-heart interplay through two lenses (HEP and features), enhancing reproducibility and accessibility.
A semiconductor 96-microplate platform for electrical-imaging based high-throughput phenotypic screening
Authors: Chitale Shalaka , Wu Wenxuan , Mukherjee Avik , Lannon Herbert , Suresh Pooja , Nag Ishan , Ambrosi Christina M. , Gertner Rona S. , Melo Hendrick , Powers Brendan , Wilkins Hollin , Hinton Henry , Cheah Mickey , Boynton Zachariah , Alexeyev Alexander , Sword Duane , Basan Markus , Park Hongkun , Ham Donhee , Abbott Jeffrey
Published: June 2023

Profiling compounds and genetic perturbations via high-content imaging has become increasingly popular for drug discovery, but the technique is limited to endpoint images of fixed cells. In contrast, electronic-based devices offer label-free, functional information of live cells, yet current approaches suffer from low-spatial resolution or single-well throughput. Here, we report a semiconductor 96-microplate platform designed for high-resolution real-time impedance “imaging” at scale. Each well features 4,096 electrodes at 25 µm spatial resolution while a miniaturized data interface allows 8× parallel plate operation (768 total wells) within each incubator for enhanced throughputs. New electric field-based, multi-frequency measurement techniques capture >20 parameter images including tissue barrier, cell-surface attachment, cell flatness, and motility every 15 min throughout experiments. Using these real-time readouts, we characterized 16 cell types, ranging from primary epithelial to suspension, and quantified heterogeneity in mixed epithelial and mesenchymal co-cultures. A proof-of-concept screen of 904 diverse compounds using 13 semiconductor microplates demonstrates the platform’s capability for mechanism of action (MOA) profiling with 25 distinct responses identified. The scalability of the semiconductor platform combined with the translatability of the high dimensional live-cell functional parameters expands high-throughput MOA profiling and phenotypic drug discovery applications.
Eosinophils exert direct and indirect anti-tumorigenic effects in the development of esophageal squamous cell carcinoma
Authors: Jacobse Justin , Aziz Zaryab , Sun Lili , Chaparro Jasmine , Pilat Jennifer M. , Kwag Aaron , Buendia Matthew , Wimbiscus Mae , Nasu Motomi , Saito Tsuyoshi , Mine Shinji , Orita Hajime , Revetta Frank , Short Sarah P. , Washington M. Kay , Hiremath Girish , Gibson Michael K. , Coburn Lori , Koyama Tatsuki , Goettel Jeremy A. , Williams Christopher S. , Choksi Yash A.
Published: June 2023

Background/Aims

Eosinophils are present in several solid tumors and have context-dependent function. Our aim is to define the contribution of eosinophils in esophageal squamous cell carcinoma (ESCC), since their role in ESCC is unknown.

Methods

Eosinophils were enumerated in tissues from two ESCC cohorts. Mice were treated with 4-nitroquinolone-1-oxide (4-NQO) for 8 weeks to induce pre-cancer or 16 weeks to induce carcinoma. Eosinophil number was modified by monoclonal antibody to IL-5 (IL5mAb), recombinant IL-5 (rIL-5), or genetically with eosinophil-deficient (ΔdblGATA) mice or mice deficient in eosinophil chemoattractant eotaxin-1 (Ccl11-/-). Esophageal tissue and eosinophil specific RNA-sequencing was performed to understand eosinophil function. 3-D co-culturing of eosinophils with pre-cancer or cancer cells was done to ascertain direct effects of eosinophils.

Results

Activated eosinophils are present in higher numbers in early stage versus late stage ESCC. Mice treated with 4-NQO exhibit more esophageal eosinophils in pre-cancer versus cancer. Correspondingly, epithelial cellCcl11expression is higher in mice with pre-cancer. Eosinophil depletion using three mouse models (Ccl11-/-mice, ΔdblGATA mice, IL5mAb treatment) all display exacerbated 4-NQO tumorigenesis. Conversely, treatment with rIL-5 increases esophageal eosinophilia and protects against pre-cancer and carcinoma. Tissue and eosinophil RNA-sequencing revealed eosinophils drive oxidative stress in pre-cancer.In vitroco-culturing of eosinophils with pre-cancer or cancer cells resulted in increased apoptosis in the presence of a degranulating agent, which is reversed with N-acetylcysteine, a reactive oxygen species (ROS) scavenger. ΔdblGATA mice exhibited increased CD4 T cell infiltration, IL-17, and enrichment of IL-17 pro-tumorigenic pathways.

Conclusion

Eosinophils likely protect against ESCC through ROS release during degranulation and suppression of IL-17.
Learning Peptide Properties with Positive Examples Only
Authors: Ansari Mehrad , White Andrew D.
Published: June 2023

Abstract

Deep learning can create accurate predictive models by exploiting existing large-scale experimental data, and guide the design of molecules. However, a major barrier is the requirement of both positive and negative examples in the classical supervised learning frameworks. Notably, most peptide databases come with missing information and low number of observations on negative examples, as such sequences are hard to obtain using high-throughput screening methods. To address this challenge, we solely exploit the limited known positive examples in a semi-supervised setting, and discover peptide sequences that are likely to map to certain antimicrobial properties via positive-unlabeled learning (PU). In particular, we use the two learning strategies of adapting base classifier and reliable negative identification to build deep learning models for inferring solubility, hemolysis, binding against SHP-2, and non-fouling activity of peptides, given their sequence. We evaluate the predictive performance of our PU learning method and show that by only using the positive data, it can achieve competitive performance when compared with the classical positive-negative (PN) classification approach, where there is access to both positive and negative examples.
Can Quantum Chemistry Improve the understanding of Protein-Ligand Interactions? Implications for Structure Based Drug Discovery
Authors: Menezes Filipe , Fröhlich Tony , Popowicz Grzegorz M.
Published: June 2023

We introduce an Energy Decomposition Analysis suitable for understanding the nature of non-covalent binding in large chemical systems, like those of drug-protein complexes. The method is atom specific, thus allowing rationalization of the role that each atom or functional group plays for the interaction. Visual representations are constructed in the form of interaction maps, depicting the different contributions for electrostatics, polarization, dispersion (lipophilicity),etc. This marks the departure from atomistic models towards electronic interaction ones, that better correlate with experimental data. The maps provide a quick access to the driving forces behind the formation of intermolecular complexes, and the key contributors for each interaction. This allows constructing quantum mechanical models of binding. The presented method is validated against experimental binding data for the difficult to target protein-protein interface for PEX14-PEX5 and its inhibitors.
scATAnno: Automated Cell Type Annotation for single-cell ATAC Sequencing Data
Authors: Jiang Yijia , Hu Zhirui , Lynch Allen W. , Jiang Junchen , Zhu Alexander , Zeng Ziqi , Zhang Yi , Wu Gongwei , Xie Yingtian , Li Rong , Zhou Ningxuan , Meyer Cliff , Cejas Paloma , Brown Myles , Long Henry W. , Qiu Xintao
Published: June 2023

Recent advances in single-cell epigenomic techniques have created a growing demand for scATAC-seq analysis. One key analysis task is to determine cell type identity based on the epigenetic data. We introduce scATAnno, a python package designed to automatically annotate scATAC-seq data using large-scale scATAC-seq reference atlases. This workflow generates the reference atlases from publicly available datasets enabling accurate cell type annotation by integrating query data with reference atlases, without the use of scRNA-seq data. To enhance annotation accuracy, we have incorporated KNN-based and weighted distance-based uncertainty scores to effectively detect cell populations within the query data that are distinct from all cell types in the reference data. We compare and benchmark scATAnno against 7 other published approaches for cell annotation and show superior performance in multiple data sets and metrics. We showcase the utility of scATAnno across multiple datasets, including peripheral blood mononuclear cell (PBMC), Triple Negative Breast Cancer (TNBC), and basal cell carcinoma (BCC), and demonstrate that scATAnno accurately annotates cell types across conditions. Overall, scATAnno is a useful tool for scATAC-seq reference building and cell type annotation in scATAC-seq data and can aid in the interpretation of new scATAC-seq datasets in complex biological systems.
Catalytic activity of the Bin3/MEPCE methyltransferase domain is dispensable for 7SK snRNP function inDrosophila melanogaster
Authors: Palumbo Ryan J , Hanes Steven D
Published: June 2023

Methylphosphate Capping Enzyme (MEPCE) monomethylates the gamma phosphate at the 5’ end of the 7SK noncoding RNA, a modification thought to protect 7SK from degradation. 7SK serves as a scaffold for assembly of a snRNP complex that inhibits transcription by sequestering the positive elongation factor P-TEFb. While much is known about the biochemical activity of MEPCEin vitro, little is known about its functionsin vivo, or what roles— if any—there are for regions outside the conserved methyltransferase domain. Here, we investigated the role of Bin3, theDrosophilaortholog of MEPCE, and its conserved functional domains inDrosophiladevelopment. We found thatbin3mutant females had strongly reduced rates of egg-laying, which was rescued by genetic reduction of P-TEFb activity, suggesting that Bin3 promotes fecundity by repressing P-TEFb.bin3mutants also exhibited neuromuscular defects, analogous to a patient withMEPCEhaploinsufficiency. These defects were also rescued by genetic reduction of P-TEFb activity, suggesting that Bin3 and MEPCE have conserved roles in promoting neuromuscular function by repressing P-TEFb. Unexpectedly, we found that a Bin3 catalytic mutant (Bin3Y795A) could still bind and stabilize 7SK and rescue allbin3mutant phenotypes, indicating that Bin3 catalytic activity is dispensable for 7SK stability and snRNP functionin vivo. Finally, we identified a metazoan-specific motif (MSM) outside of the methyltransferase domain and generated mutant flies lacking this motif (Bin3ΔMSM). Bin3ΔMSMmutant flies exhibited some—but not all—bin3mutant phenotypes, suggesting that the MSM is required for a 7SK-independent, tissue-specific function of Bin3.
Zoledronic acid improves bone quality and muscle function in a high bone turnover state
Authors: Trivedi Trupti , Manaa Mohamed , John Sutha , Reiken Steven , Murthy Sreemala , Pagnotti Gabriel M. , Dole Neha S. , She Yun , Suresh Sukanya , Hain Brian A. , Regan Jenna , Ofer Rachel , Wright Laura , Robling Alex , Cao Xu , Alliston Tamara , Marks Andrew R. , Waning David L. , Mohammad Khalid S. , Guise Theresa A.
Published: June 2023

Zoledronic acid (ZA) prevents muscle weakness in mice with bone metastases; however, its role in muscle weakness in non-tumor-associated metabolic bone diseases and as an effective treatment modality for the prevention of muscle weakness associated with bone disorders, is unknown. We demonstrate the role of ZA-treatment on bone and muscle using a mouse model of accelerated bone remodeling, which represents the clinical manifestation of non-tumor associated metabolic bone disease. ZA increased bone mass and strength and rescued osteocyte lacunocanalicular organization. Short-term ZA treatment increased muscle mass, whereas prolonged, preventive treatment improved muscle mass and function. In these mice, muscle fiber-type shifted from oxidative to glycolytic and ZA restored normal muscle fiber distribution. By blocking TGFβ release from bone, ZA improved muscle function, promoted myoblast differentiation and stabilized Ryanodine Receptor-1 calcium channel. These data demonstrate the beneficial effects of ZA in maintaining bone health and preserving muscle mass and function in a model of metabolic bone disease.

Context and significance

TGFβ is a bone regulatory molecule which is stored in bone matrix, released during bone remodeling, and must be maintained at an optimal level for the good health of the bone. Excess TGFβ causes several bone disorders and skeletal muscle weakness. Reducing excess TGFβ release from bone using zoledronic acid in mice not only improved bone volume and strength but also increased muscle mass, and muscle function. Progressive muscle weakness coexists with bone disorders, decreasing quality of life and increasing morbidity and mortality. Currently, there is a critical need for treatments improving muscle mass and function in patients with debilitating weakness. Zoledronic acid’s benefit extends beyond bone and could also be useful in treating muscle weakness associated with bone disorders.
Mapping theArabidopsis thalianaproteome in PeptideAtlas and the nature of the unobserved (dark) proteome; strategies towards a complete proteome
Authors: van Wijk Klaas J. , Leppert Tami , Sun Zhi , Kearly Alyssa , Li Margaret , Mendoza Luis , Guzchenko Isabell , Debley Erica , Sauermann Georgia , Routray Pratyush , Malhotra Sagunya , Nelson Andrew , Sun Qi , Deutsch Eric W.
Published: June 2023

This study describes a new release of theArabidopsis thalianaPeptideAtlas proteomics resource providing protein sequence coverage, matched mass spectrometry (MS) spectra, selected PTMs, and metadata. 70 million MS/MS spectra were matched to the Araport11 annotation, identifying ∼0.6 million unique peptides and 18267 proteins at the highest confidence level and 3396 lower confidence proteins, together representing 78.6% of the predicted proteome. Additional identified proteins not predicted in Araport11 should be considered for building the next Arabidopsis genome annotation. This release identified 5198 phosphorylated proteins, 668 ubiquitinated proteins, 3050 N-terminally acetylated proteins and 864 lysine-acetylated proteins and mapped their PTM sites. MS support was lacking for 21.4% (5896 proteins) of the predicted Araport11 proteome – the ‘dark’ proteome. This dark proteome is highly enriched for certain (e.g.CLE, CEP, IDA, PSY) but not other (e.g.THIONIN, CAP,) signaling peptides families, E3 ligases, TFs, and other proteins with unfavorable physicochemical properties. A machine learning model trained on RNA expression data and protein properties predicts the probability for proteins to be detected. The model aids in discovery of proteins with short-half life (e.g.SIG1,3 and ERF-VII TFs) and completing the proteome. PeptideAtlas is linked to TAIR, JBrowse, PPDB, SUBA, UniProtKB and Plant PTM Viewer.
Combining Procedural and Behavioral Treatments for Chronic Low Back Pain: A Pilot Feasibility Randomized Controlled Trial
Authors: Tanus Adrienne D. , Nishio Isuta , Williams Rhonda , Friedly Janna , Soares Bosco , Anderson Derek , Bambara Jennifer , Dawson Timothy , Hsu Amy , Kim Peggy Y. , Krashin Daniel , Piero Larissa Del , Korpak Anna , Timmons Andrew , Suri Pradeep
Published: June 2023

Individual treatments for chronic low back pain (CLBP) have small magnitude effects. Combining different types of treatments may produce larger effects. This study used a 2×2 factorial randomized controlled trial (RCT) design to combine procedural and behavioral treatments for CLBP. The study aims were to: (1) assess feasibility of conducting a factorial RCT of these treatments; and (2) estimate individual and combined treatment effects of (a) lumbar radiofrequency ablation (LRFA) of the dorsal ramus medial branch nerves (vs. a simulated LRFA control procedure) and (b) Activity Tracker-Informed Video-Enabled Cognitive Behavioral Therapy program for CLBP (AcTIVE-CBT) (vs. an educational control treatment) on back-related disability at 3 months post-randomization. Participants (n=13) were randomized in a 1:1:1:1 ratio. Feasibility goals included an enrollment proportion ≥30%, a randomization proportion ≥80%, and a ≥80% proportion of randomized participants completing the 3-month Roland-Morris Disability Questionnaire (RMDQ) primary outcome endpoint. An intent-to-treat analysis was used. The enrollment proportion was 62%, the randomization proportion was 81%, and all randomized participants completed the primary outcome. Though not statistically significant, there was a beneficial, moderate-magnitude effect of LRFA vs. control on 3-month RMDQ (−3.25 RMDQ points; 95% CI: -10.18, 3.67). There was a significant, beneficial, large-magnitude effect of AcTIVE-CBT vs. control (−6.29, 95% CI: -10.97, -1.60). Though not statistically significant, there was a beneficial, large effect of LRFA+AcTIVE-CBT vs. control (−8.37; 95% CI: -21.47, 4.74). We conclude that it is feasible to conduct an RCT combining procedural and behavioral treatments for CLBP.

ClinicalTrials.gov Registration:https://clinicaltrials.gov/ct2/show/NCT03520387
Awareness and use of Tranexamic Acid in the management of Postpartum Haemorrhage among health care providers in Enugu, Nigeria
Authors: Onwujekwe Ogochukwu , Mosanya Adaobi Uchenna , Ekwuazi Kingsley , Iyoke Chukwuemeka
Published: June 2023

Objectives

This study was carried out to determine the knowledge, practice and barriers regarding the use of Tranexamic acid for the prevention and treatment of postpartum hemorrhage among health care providers in Enugu, Nigeria.

Methods

A cross sectional study was carried out among health professionals (Doctors, Pharmacists and Nurses) in two Nigerian tertiary teaching hospitals. One is Federal and the other is State. A total of 220 questionnaires were distributed, 207 were collected back (response rate: 94%) and analyzed using SPSS for inferential statistics with level of significance at p < 0.05.

Results

Only 23.7% of the respondents had good Knowledge (p<0.001). Good awareness of the recent WHO recommendation on the use of Tranexamic acid for Postpartum Haemorrhage was low (19.8%, <0.001). Majority of the respondents have neither prescribed nor dispensed it (30%; <0.001). Very few respondents use it for all cases of Postpartum Haemorrhage (16.4%; p<0.001). Barriers against its use include non-awareness of the latest WHO recommendation, preference for other utero-tonics and cost of the drug.

Conclusions

There was poor knowledge of Tranexamic acid, poor awareness of its recommendation and low use for Postpartum Haemorrhage among different cadres of health care providers.

Synopsis

There was poor knowledge of Tranexamic acid, poor awareness of its recommendation and low use for Postpartum Haemorrhage among different cadres of health care providers.
A NEW PERSPECTIVE ON ISOTRETINOIN IN PREGNANCY: PREGNANCY OUTCOMES, EVALUATION OF COMPLEX PHENOTYPES, AND IMPORTANCE OF TERATOLOGICAL COUNSELLING
Authors: Alay Mustafa Tarık , Yiğin Aysel Kalaycı , Seven Mehmet
Published: June 2023

Background

Teratogens are responsible for 5% of all known causes of congenital anomalies. Isotretinoin, a retinoic acid–derived agent, leads to congenital anomalies in 21-52% of cases when exposure occurs during pregnancy according to studies conducted before 2006. However, rates of congenital anomalies were much lower in later studies.

Objectives

To investigate the rates of congenital anomalies in isotretinoin exposure during pregnancy, isotretinoin exposure before pregnancy, and a control group unexposed to any teratogenic agents.

Methods

In this cohort study, we divided pregnant women admitted to our center between 2009 and 2020 into two groups: isotretinoin exposure during the pregnancy (n=77) and isotretinoin exposure before the pregnancy (n=75). We selected the control group from among the non-teratogen exposed pregnant women with a simple random sampling method. Obstetricians calculated the ages of all pregnancies via ultrasound (USG) (crown-rump diameter for the first trimester; biparietal diameter and femur length for the second trimester). After birth, a pediatric genetics specialist examined all babies.

Results

Among the isotretinoin exposure during the pregnancy, isotretinoin exposure before the pregnancy, and the control groups, there were statistically significant differences in live births (respectively, 64.3%, 88%, 93.3%), congenital anomalies (respectively, 28.6%, 6.1%, 1.4%), miscarriages (respectively, 13%, 2.7%, 4%), terminations (respectively, 32.5%, 9.3%, 2.7%), prematurities (11.9%, 16.7%, 2.9%) (respectively, p < 0.001, p<0.001, p=0.014, p<0.001). We detected novel phenotypical features in five patients.

Conclusions

Our study demonstrated that study design, long-term follow-up, teratological counseling, and implementing advanced molecular analysis in complex phenotypes with novel phenotypical features are beneficial for understanding the association of congenital anomalies with isotretinoin exposure. While evaluating congenital anomalies, we detected statistically significant differences between isotretinoin exposure vs control, but we did not detect any statistical differences between isotretinoin exposure before the pregnancy and controls. This conflict between our study and previous studies might be caused by no evident differentiation between isotretinoin exposure before the pregnancy and during the pregnancy and higher termination rates in previous studies.
Tafenoquine following G6PD screening versus primaquine for the treatment of vivax malaria in Brazil: a cost-effectiveness analysis using a transmission model
Authors: Price David J , Nekkab Narimane , Monteiro Wuelton M , Villela Daniel AM , Simpson Julie A. , Lacerda Marcus VG , White Michael T , Devine Angela
Published: June 2023

Background

Malaria transmission modelling has demonstrated the potential impact of semi-quantitative glucose-6-phosphate dehydrogenase (G6PD) testing and treatment with single-dose tafenoquine forPlasmodium vivaxradical cure. This modelling has focused on predicting the number of vivax cases averted, rather than its cost-effectiveness.

Methods

We explored the cost-effectiveness of using tafenoquine after G6PD screening as compared to usual practice (7-day low-dose primaquine (0.5 mg/kg/day) without G6PD screening) in Brazil using a 10-year time horizon with 5% discounting considering four scenarios: 1) tafenoquine for adults only assuming 66.7% primaquine treatment adherence, 2) tafenoquine for adults and children aged >2 years assuming 66.7% primaquine adherence, 3) tafenoquine for adults only assuming 90% primaquine adherence, 4) tafenoquine for adults only assuming 30% primaquine adherence. The incremental cost-effectiveness ratios (ICERs) were estimated by dividing the incremental costs by the disability-adjusted life-years (DALYs) averted. These were compared to a willingness to pay threshold of US$7,800 for Brazil, and one-way and probabilistic sensitivity analyses were performed.

Results

All four scenarios were cost-effective using this willingness to pay threshold with ICERs ranging from US$154–1836. One-way sensitivity analyses showed that the results were most sensitive to severity and mortality due to vivax malaria, the lifetime and number of semi-quantitative G6PD analysers needed, cost per malaria episode and per G6PD test strips, and life expectancy. All scenarios had a 100% likelihood of being cost-effective at the willingness to pay threshold.

Conclusions

Tafenoquine prescribed after a semi-quantitative G6PD testing is highly likely to be cost-effective in Brazil.
Comparative Analysis of Decision Trees on Two COVID-19 Symptom Datasets
Authors: Saengamnatdej Somchai , Molee Phuangphet Waree , Warnnissorn Prateep
Published: June 2023

Objective

This study compares decision trees on two COVID-19 symptom datasets to assess their performance and feature importance in predicting and understanding infection patterns.

Methods

We created decision trees on Israeli and Swedish COVID-19 infection datasets. Performance metrics were used to assess their predictive capabilities, and feature importance analysis identified significant variables in the decision-making process.

Results

The study observed different performance levels of decision trees on the COVID-19 datasets. The Swedish dataset achieved high accuracy and F1-score without hyperparameter tuning, while the Israeli dataset improved significantly with Extreme Gradient Boosting. Dataset characteristics impact the selection of an optimal decision tree algorithm. The key variable in both datasets was sore throat.

Conclusion

This study compares decision trees on COVID-19 infection datasets, emphasizing the importance of dataset characteristics in selecting an optimal algorithm. Identifying significant features enhances understanding of infection patterns, benefiting decision-making and prediction accuracy in infectious disease analysis.
Estimation of introduction and transmission rates of SARS-CoV-2 in a prospective household study
Authors: van Boven Michiel , van Dorp Christiaan H. , Westerhof Ilse , Jaddoe Vincent , Heuvelman Valerie , Duijts Liesbeth , Fourie Elandri , Sluiter-Post Judith , van Houten Marlies A. , Badoux Paul , Euser Sjoerd , Herpers Bjorn , Eggink Dirk , de Hoog Marieke , Boom Trisja , Wildenbeest Joanne , Bont Louis , Rozhnova Ganna , Bonten Marc J. , Kretzschmar Mirjam E. , Bruijning-Verhagen Patricia
Published: June 2023

Household studies provide an efficient means to study transmission of infectious diseases, enabling estimation of individual susceptibility and infectivity. A main inclusion criterion in such studies is often the presence of an infected person. This precludes estimation of the hazards of pathogen introduction into the household. Here we use data from a prospective household-based study to estimate SARS-CoV-2 age- and time-dependent household introduction hazards together with within household transmission rates in the Netherlands from August 2020 to August 2021. Introduction hazards and within-household transmission rates are estimated with penalized splines and stochastic epidemic models, respectively. The estimated hazard of introduction of SARS-CoV-2 in the households was lower for children (0-12 years) than for adults (relative hazard: 0.62; 95%CrI: 0.34-1.0). Estimated introduction hazards peaked in mid October 2020, mid December 2020, and mid April 2021, preceding peaks in hospital admissions by 1-2 weeks. The best fitting transmission models include increased infectivity of children relative to adults and adolescents, such that the estimated child-to-child transmission probability (0.62; 95%CrI: 0.40-0.81) was considerably higher than the adult-to-adult transmission probability (0.12; 95%CrI: 0.057-0.19). Scenario analyses show that vaccination of adults could have strongly reduced infection attack rates in households and that adding adolescent vaccination would have offered limited added benefit.
Tau accumulation and its spatial progression across the Alzheimer’s disease spectrum
Authors: St-Onge Frédéric , Chapleau Marianne , Breitner John CS , Villeneuve Sylvia , Binette Alexa Pichet ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: June 2023

The spread of tau abnormality in sporadic Alzheimer’s disease is believed typically to follow neuropathologically defined Braak staging. Recentin-vivopositron emission tomography (PET) evidence challenges this belief, however, as spreading patterns for tau appear heterogenous among individuals with varying clinical expression of Alzheimer’s disease. We therefore sought better understanding of the spatial distribution of tau in the preclinical and clinical phases of sporadic Alzheimer’s disease and its association with cognitive decline.

Longitudinal tau-PET data (1,370 scans) from 832 participants (463 cognitively unimpaired, 277 with mild cognitive impairment (MCI) and 92 with Alzheimer’s disease dementia) were obtained from the Alzheimer’s Disease Neuroimaging Initiative. Among these, we defined thresholds of abnormal tau deposition in 70 brain regions from the Desikan atlas, and for each group of regions characteristic of Braak staging. We summed each scan’s number of regions with abnormal tau deposition to form a spatial extent index. We then examined patterns of tau pathology cross-sectionally and longitudinally and assessed their heterogeneity. Finally, we compared our spatial extent index of tau uptake with a temporal meta region of interest—a commonly used proxy of tau burden—assessing their association with cognitive scores and clinical progression.

More than 80% of amyloid-beta positive participants across diagnostic groups followed typical Braak staging, both cross-sectionally and longitudinally. Within each Braak stage, however, the pattern of abnormality demonstrated significant heterogeneity such that overlap of abnormal regions across participants averaged less than 50%. The annual rate of change in number of abnormal tau-PET regions was similar among individuals without cognitive impairment and those with Alzheimer’s disease dementia. Spread of disease progressed more rapidly, however, among participants with MCI. The latter’s change on our spatial extent measure amounted to 2.5 newly abnormal regions per year, as contrasted with 1 region/year among the other groups. Comparing the association of tau pathology and cognitive performance in MCI and Alzheimer’s disease dementia, our spatial extent index was superior to the temporal meta-ROI for measures of executive function.

Thus, while participants broadly followed Braak stages, significant individual regional heterogeneity of tau binding was observed at each clinical stage. Progression of spatial extent of tau pathology appears to be fastest in persons with MCI. Exploring the spatial distribution of tau deposits throughout the entire brain may uncover further pathological variations and their correlation with impairments in cognitive functions beyond memory.