bluuebunny/crossref_metadata_2025 huggingface dataset:
DLL4-Notch3-WNT5B axis is a novel mediator of bi-directional pro-metastatic crosstalk between melanoma and lymphatic endothelial cells
Authors: Alve Sanni , Gramolelli Silvia , Jukonen Joonas , Juteau Susanna , Pink Anne , Manninen Atte , Monto Elisa , Lackman Madeleine H. , Carpén Olli , Karaman Sinem , Saharinen Pipsa , Vaahtomeri Kari , Ojala Päivi M.
Published: April 2023

Despite strong indications that melanoma interaction with lymphatic vessels actively promotes melanoma progression, the molecular mechanisms are not yet completely understood. To characterize molecular factors of this crosstalk we established human primary lymphatic endothelial cell (LEC) co-cultures with human melanoma cell lines. Here, we show that co-culture with melanoma cells induced transcriptomic changes in LECs and led to multiple alterations in their function. WNT5B, a paracrine signaling molecule upregulated in melanoma cells upon LEC interaction, was found contributing to the functional changes in LECs. Moreover,WNT5Btranscription was regulated by Notch3 in melanoma cells following the co-culture with LECs, and Notch3 and WNT5B were co-expressed in melanoma patient primary tumor and metastasis samples. Moreover, melanoma cells derived from LEC co-culture escaped efficiently from the primary site to the proximal tumor draining lymph nodes, which was impaired upon WNT5B depletion. This supports the role of WNT5B in promoting the metastatic potential of melanoma cells through its effects on LECs. Finally, DLL4, a Notch ligand expressed in LECs, was identified as an upstream inducer of the Notch3-WNT5B axis in melanoma. This study elucidates WNT5B as a novel molecular factor mediating bi-directional crosstalk between melanoma cells and lymphatic endothelium and promoting melanoma metastasis.
Contribution of the IGCR1 regulatory element and the 3’IghCBEs to Regulation ofIghV(D)J Recombination
Authors: Liang Zhuoyi , Zhao Lijuan , Yongxin Ye Adam , Lin Sherry G. , Zhang Yiwen , Guo Chunguang , Dai Hai-Qiang , Ba Zhaoqing , Alt Frederick W.
Published: April 2023

Immunoglobulin heavy chain variable region exons are assembled in progenitor-B cells, from VH, D, and JHgene segments located in separate clusters across theIghlocus. RAG endonuclease initiates V(D)J recombination from a JH-based recombination center (RC). Cohesin-mediated extrusion of upstream chromatin past RC-bound RAG presents Ds for joining to JHs to form a DJH-RC.Ighhas a provocative number and organization of CTCF-binding-elements (CBEs) that can impede loop extrusion. Thus,Ighhas two divergently oriented CBEs (CBE1 and CBE2) in the IGCR1 element between the VHand D/JHdomains, over 100 CBEs across the VHdomain convergent to CBE1, and 10 clustered 3’Igh-CBEs convergent to CBE2 and VHCBEs. IGCR1 CBEs segregate D/JHand VHdomains by impeding loop extrusion-mediated RAG-scanning. Down-regulation of WAPL, a cohesin unloader, in progenitor-B cells neutralizes CBEs, allowing DJH-RC-bound RAG to scan the VH domain and perform VH-to-DJH rearrangements. To elucidate potential roles of IGCR1-based CBEs and 3’Igh-CBEs in regulating RAG-scanning and elucidate the mechanism of the “ordered” transition from D-to-JHto VH-to-DJHrecombination, we tested effects of deleting or inverting IGCR1 or 3’Igh-CBEs in mice and/or progenitor-B cell lines. These studies revealed that normal IGCR1 CBE orientation augments RAG-scanning impediment activity and suggest that 3’Igh-CBEs reinforce ability of the RC to function as a dynamic loop extrusion impediment to promote optimal RAG scanning activity. Finally, our findings indicate that ordered V(D)J recombination can be explained by a gradual WAPL down-regulation mechanism in progenitor B cells as opposed to a strict developmental switch.

SIGNIFICANCE STATEMENT

To counteract diverse pathogens, vertebrates evolved adaptive immunity to generate diverse antibody repertoires through a B lymphocyte-specific somatic gene rearrangement process termed V(D)J recombination. Tight regulation of the V(D)J recombination process is vital to generating antibody diversity and preventing off-target activities that can predispose the oncogenic translocations. Recent studies have demonstrated V(D)J rearrangement is driven by cohesin-mediated chromatin loop extrusion, a process that establishes genomic loop domains by extruding chromatin, predominantly, between convergently-oriented CTCF looping factor-binding elements (CBEs). By deleting and inverting CBEs within a critical antibody heavy chain gene locus developmental control region and a loop extrusion chromatin-anchor at the downstream end of this locus, we reveal how these elements developmentally contribute to generation of diverse antibody repertoires.
PEELing: an integrated and user-centric platform for spatially-resolved proteomics data analysis
Authors: Peng Xi , Clements Jody , Jiang Zuzhi , Han Shuo , Preibisch Stephan , Li Jiefu
Published: April 2023

Molecular compartmentalization is vital for cellular physiology. Spatially-resolved proteomics allows biologists to survey protein composition and dynamics with subcellular resolution. Here we present PEELing, an integrated package and user-friendly web service for analyzing spatially- resolved proteomics data. PEELing assesses data quality using curated or user-defined references, performs cutoff analysis to remove contaminants, connects to databases for functional annotation, and generates data visualizations—providing a streamlined and reproducible workflow to explore spatially-resolved proteomics data.

Availability and Implementation

PEELing and its tutorial are publicly available athttps://peeling.janelia.org/. A Python package of PEELing is available athttps://github.com/JaneliaSciComp/peeling/.

Contact

Technical support for PEELing:peeling@janelia.hhmi.org.
CoSIA: an R Bioconductor package for CrOss Species Investigation and Analysis
Authors: Haldar Anisha , Oza Vishal H. , DeVoss Nathaniel S. , Clark Amanda D. , Lasseigne Brittany N.
Published: April 2023

High throughput sequencing technologies have enabled cross-species comparative transcriptomic studies; however, there are numerous challenges for these studies due to biological and technical factors. We developed CoSIA (Cross-Species Investigation and Analysis), an Bioconductor R package and Shiny app that provides an alternative framework for cross-species transcriptomic comparison of non-diseased wild-type RNA sequencing gene expression data from Bgee across tissues and species (human, mouse, rat, zebrafish, fly, and nematode) through visualization of variability, diversity, and specificity metrics.

Availability and Implementation

https://github.com/lasseignelab/CoSIA

Contact

Brittany Lasseigne (bnp0001@uab.edu)

Supplementary information

See Supplementary Files
Genomic mechanisms and consequences of diverse postzygotic barriers between monkeyflower species
Authors: Sotola V. Alex , Berg Colette S. , Samuli Matt , Chen Hongfei , Mantel Samuel J. , Beardsley Paul A. , Yuan Yao-Wu , Sweigart Andrea L. , Fishman Lila
Published: April 2023

The evolution of genomic incompatibilities causing postzygotic barriers to hybridization is a key step in species divergence. Incompatibilities take two general forms – structural divergence between chromosomes leading to severe hybrid sterility in F1hybrids and epistatic interactions between genes causing reduced fitness of hybrid gametes or zygotes (Dobzhansky-Muller incompatibilities). Despite substantial recent progress in understanding the molecular mechanisms and evolutionary origins of both types of incompatibility, how each behaves across multiple generations of hybridization remains relatively unexplored. Here, we use genetic mapping in F2and RIL hybrid populations between the phenotypically divergent but naturally hybridizing monkeyflowersMimulus cardinalisandM. parishiito characterize the genetic basis of hybrid incompatibility and examine its changing effects over multiple generations of experimental hybridization. In F2s, we found severe hybrid pollen inviability (< 50% reduction vs. parental genotypes) and pseudolinkage caused by a reciprocal translocation between Chromosomes 6 and 7 in the parental species. RILs retained excess heterozygosity around the translocation breakpoints, which caused substantial pollen inviability when interstitial crossovers had not created compatible heterokaryotypic configurations. Strong transmission ratio distortion and inter-chromosomal linkage disequilibrium in both F2s and RILs identified a novel two-locus genic incompatibility causing sex-independent gametophytic (haploid) lethality. The latter interaction eliminated three of the expected nine F2genotypic classes via F1gamete loss without detectable effects on the pollen number or viability of F2double heterozygotes. Along with the mapping of numerous milder incompatibilities, these key findings illuminate the complex genetics of plant hybrid breakdown and are an important step toward understanding the genomic consequences of natural hybridization in this model system.
Non-canonical D1-D2 recombination produces two types of rearrangements and represents a conservative hidden stage of T-cell receptor beta chain generation
Authors: Smirnova Anastasia O. , Miroshnichenkova Anna M. , Belyaeva Laima D. , Kelmanson Ilya V. , Lebedev Yuri B. , Mamedov Ilgar Z. , Chudakov Dmitriy M. , Komkov Alexander Y.
Published: April 2023

T-cell receptor (TCR) diversity is generated by VDJ recombination. The classical course of TCR beta (TRB) chain production starts with D and J segment recombination and finishes with subsequent recombination between the resulting DJ junction and V segment. In this study, we performed deep sequencing of poorly explored incomplete TRBD1 to TRBD2 rearrangements in T-cell genomic DNA. We reconstructed full repertoires of human incomplete TRB DD rearrangements and validated its authenticity by detecting excision circles with RSS (recombination signal sequence) junctions for the first time. The identified rearrangements generated in compliance with the classical 12/23 rule are common for humans, rats, and mice and contain typical VDJ recombination footprints. Detected bimodal distribution of DD junctions indicates two active recombination sites producing long and short DD rearrangements. Unlike long DD rearrangements, the short ones have unusual origin resulting from non-canonical intrachromosomal RSSs’ junctions formation. Identified DD rearrangements lead to deleting J1 and C1 segments and creating diverse hybrid D segments, which recombine further with J2 and V segments. Resulting functional TRB VDDJ rearrangements are present in the memory T-cells subset proving its participation in antigen recognition.
Single cell analyses of cancer cells identified two regulatorily and functionally distinct categories in differentially expressed genes among tumor subclones
Authors: Cao Wei , Wang Xuefei , Luo Kaiwen , Li Yang , Sun Jiahong , Fu Ruqing , Zhang Qi , Hong Ni , Cheung Edwin , Jin Wenfei
Published: April 2023

To explore the feature of cancer cells and tumor subclones, we analyzed 101,065 single-cell transcriptomes from 12 colorectal cancer (CRC) patients and 92 single cell genomes from one of these patients. We found cancer cells, endothelial cells and stromal cells in tumor tissue expressed much more genes and had stronger cell-cell interactions than their counterparts in normal tissue. We identified copy number variations (CNVs) in each cancer cell and found correlation between gene copy number and expression level in cancer cells at single cell resolution. Analysis of tumor subclones inferred by CNVs showed accumulation of mutations in each tumor subclone along lineage trajectories. We found differentially expressed genes (DEGs) between tumor subclones had two populations: DEGCNVand DEGreg. DEGCNV, showing high CNV-expression correlation and whose expression differences depend on the differences of CNV level, enriched in housekeeping genes and cell adhesion associated genes. DEGreg, showing low CNV-expression correlation and mainly in low CNV variation regions and regions without CNVs, enriched in cytokine signaling genes. Furthermore, cell-cell communication analyses showed that DEGCNVtends to involve in cell-cell contact while DEGregtends to involve in secreted signaling, which further support that DEGCNVand DEGregare two regulatorily and functionally distinct categories.
Chromatin condensation delays human mesenchymal stem cells senescence by safeguarding nuclear damages during long termin vitroexpansion
Authors: Joshi Rohit , Suryawanshi Tejas , Mukherjee Sourav , Shukla Shobha , Majumder Abhijit
Published: April 2023

Human mesenchymal stem cells (hMSCs) are multipotent cells that can differentiate into adipocytes, chondrocytes and osteoblasts. Due to their differentiation potential, hMSCs are among the most frequently used cells for therapeutic applications in tissue engineering and regenerative medicine. However, the number of cells obtained through isolation alone is insufficient for hMSC-based therapies and basic research, necessitating theirin-vitroexpansion. Conventionally, this is often carried out on rigid surfaces such as tissue culture petriplates (TCPs). However, duringin-vitroexpansion, hMSCs lose their proliferative ability and multilineage differentiation potential, making them unsuitable for clinical use. Although multiple approaches have been tried to maintain hMSC stemness over prolonged expansion, finding a suitable culture system to achieve this remains an unmet need. Recently, few research groups including ours have shown that hMSCs maintain their stemness over long passages when cultured on soft substrate. In addition, it has been shown that hMSCs cultured on soft substrates have more condensed chromatin and lower levels of histone acetylation compared to those cultured on stiff substrates. It has also been shown that condensing/decondensing chromatin by deacetylation/acetylation can delay/hasten replicative senescence in hMSCs during long-term expansion on TCPs. However, how chromatin condensation/decondensation influences nuclear morphology and DNA damage - which are strongly related to the onset of senescence and cancer - is still not known.

To answer this question, here we cultured hMSCs for long duration (P4-P11) in presence of epigenetic modifiers histone acetyltransferase inhibitor (HATi) which promotes chromatin condensation by preventing histone acetylation and histone deacetylase inhibitor (HDACi) which promotes chromatin decondensation and investigated their effect on various nuclear markers related to senescence and cancer. We have found that consistent acetylation causes severe nuclear abnormalities whereas chromatin condensation by deacetylation helps in safeguarding nucleus from damages caused byin-vitroexpansion.
SARS-CoV-2 Nonstructural Proteins 3 and 4 tune the Unfolded Protein Response
Authors: Davies Jonathan P. , Sivadas Athira , Keller Katherine R. , Wojcikiewicz Richard J.H. , Plate Lars
Published: April 2023

Coronaviruses (CoV), including SARS-CoV-2, modulate host proteostasis through activation of stress-responsive signaling pathways such as the Unfolded Protein Response (UPR), which remedies misfolded protein accumulation by attenuating translation and increasing protein folding capacity. While CoV nonstructural proteins (nsps) are essential for infection, little is known about the role of nsps in modulating the UPR. We characterized the impact of SARS-CoV-2 nsp4, a key driver of replication, on the UPR using quantitative proteomics to sensitively detect pathway-wide upregulation of effector proteins. We find nsp4 preferentially activates the ATF6 and PERK branches of the UPR. Previously, we found an N-terminal truncation of nsp3 (nsp3.1) can suppress pharmacological ATF6 activation. To determine how nsp3.1 and nsp4 tune the UPR, their co-expression demonstrated that nsp3.1 suppresses nsp4-mediated PERK, but not ATF6 activation. Re-analysis of SARS-CoV-2 infection proteomics data revealed time-dependent activation of PERK targets early in infection, which subsequently fades. This temporal regulation suggests a role for nsp3 and nsp4 in tuning the PERK pathway to attenuate host translation beneficial for viral replication while avoiding later apoptotic signaling caused by chronic activation. This work furthers our understanding of CoV-host proteostasis interactions and highlights the power of proteomic methods for systems-level analysis of the UPR.
Chaotic aging: Intrinsically disordered proteins in aging-related processes
Authors: Manyilov Vladimir D. , Ilyinsky Nikolay S. , Nesterov Semen V. , Saqr Baraa M.G.A. , Dayhoff Guy W. , Zinovev Egor V. , Matrenok Simon S. , Fonin Alexander V. , Kuznetsova Irina M. , Turoverov Konstantin K. , Ivanovich Valentin , Uversky Vladimir N.
Published: April 2023

1.

The development of aging is associated with the disruption of key cellular processes manifested as well-established hallmarks of aging. Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) have no stable tertiary structure that provide them a power to be configurable hubs in signaling cascades and regulate many processes, potentially including those related to aging. There is a need to clarify the roles of IDPs/IDRs in aging. The dataset of 1624 aging-related proteins was collected from established aging databases and experimental studies. There is a noticeable presence of IDPs/IDRs, accounting for about 36% of the aging-related dataset, which is comparable to the disorder content of the whole human proteome (about 40%). A Gene Ontology analysis of the our Aging proteome reveals an abundance of IDPs/IDRs in one-third of aging-associated processes, especially in genome regulation. Signaling pathways associated with aging also contain IDPs/IDRs on different hierarchical levels. Protein-protein interaction network analysis showed that IDPs present in different clusters associated with different aging hallmarks. Protein cluster with IDPs enrichment and high liquid-liquid phase separation (LLPS) probability has “nuclear” localization and DNA-associated functions, related to aging hallmarks: genomic instability, telomere attrition, epigenetic alterations, stem cells exhaustion. Some IDPs related to aging with high LLPS propensity were identified as “dangerous” based on the prediction of their propensity to aggregation. Overall, our analyses indicate that IDPs/IDRs play significant roles in aging-associated processes, particularly in the regulation of DNA functioning. IDP aggregation, which can lead to loss-of-function and toxicity, could be critically harmful to the cell. A structure-based analysis of aging and the identification of proteins that are particularly susceptible to disturbances can enhance our understanding of the molecular mechanisms of aging and open up new avenues for slowing it down.
A spatially resolved single cell genomic atlas of the adult human breast
Authors: Kumar Tapsi , Nee Kevin , Wei Runmin , He Siyuan , Nguyen Quy H. , Bai Shanshan , Blake Kerrigan , Gong Yanwen , Pein Maren , Sei Emi , Hu Min , Casasent Anna , Thennavan Aatish , Li Jianzhuo , Tran Tuan , Chen Ken , Nilges Benedikt , Kashikar Nachiket , Braubach Oliver , Cheikh Bassem Ben , Nikulina Nadya , Chen Hui , Teshome Mediget , Menegaz Brian , Javaid Huma , Nagi Chandandeep , Montalvan Jessica , Tifrea Delia F. , Edwards Robert , Lin Erin , Parajuli Ritesh , Winocour Sebastian , Thompson Alastair , Lim Bora , Lawson Devon A. , Kessenbrock Kai , Navin Nicholas
Published: April 2023

The adult human breast comprises an intricate network of epithelial ducts and lobules that are embedded in connective and adipose tissue. While previous studies have mainly focused on the breast epithelial system, many of the non-epithelial cell types remain understudied. Here, we constructed a comprehensive Human Breast Cell Atlas (HBCA) at single-cell and spatial resolution. Our single-cell transcriptomics data profiled 535,941 cells from 62 women, and 120,024 nuclei from 20 women, identifying 11 major cell types and 53 cell states. These data revealed abundant pericyte, endothelial and immune cell populations, and highly diverse luminal epithelial cell states. Our spatial mapping using three technologies revealed an unexpectedly rich ecosystem of tissue-resident immune cells in the ducts and lobules, as well as distinct molecular differences between ductal and lobular regions. Collectively, these data provide an unprecedented reference of adult normal breast tissue for studying mammary biology and disease states such as breast cancer.
Dynamics of cell-type transition mediated by epigenetic modifications
Authors: Huang Rongsheng , Situ Qiaojun , Lei Jinzhi
Published: April 2023

Maintaining tissue homeostasis requires appropriate regulation of stem cell differentiation. The Waddington landscape posits that gene circuits in a cell form a potential landscape of different cell types, wherein cells follow attractors of the probability landscape to develop into distinct cell types. However, how adult stem cells achieve a delicate balance between self-renewal and differentiation remains unclear. We propose that random inheritance of epigenetic states plays a pivotal role in stem cell differentiation and present a hybrid model of stem cell differentiation induced by epigenetic modifications. Our comprehensive model integrates gene regulation networks, epigenetic state inheritance, and cell regeneration, encompassing multi-scale dynamics ranging from transcription regulation to cell population. Through model simulations, we demonstrate that random inheritance of epigenetic states during cell divisions can spontaneously induce cell differentiation, dedifferentiation, and transdifferentiation. Further-more, we investigate the influences of interfering with epigenetic modifications and introducing additional transcription factors on the probabilities of dedifferentiation and transdifferentiation, revealing the underlying mechanism of cell reprogramming. Thisin silicomodel provides valuable insights into the intricate mechanism governing stem cell differentiation and cell reprogramming and offers a promising path to enhance the field of regenerative medicine.
Migration coupled with recombination explains disparate HIV-1 anatomical compartmentalization signals
Authors: Sarkar Sumantra , Romero-Severson Ethan , Leitner Thomas
Published: April 2023

The evolution of HIV-1 in a host is shaped by many evolutionary forces, including recombination of virus genomes and the potential isolation of viruses into different tissues with compartmentalized evolution. Recombination and compartmentalization have opposite effects on viral diversification, with the former causing global mixing and the latter countering it through spatial segregation of the virus population. Therefore, recombination and compartmentalization together give rise to complex evolutionary dynamics that convolutes their individual effects in standard, bifurcating phylogenetic trees. Although there are various theoretical methods available to infer the presence of recombination or compartmentalization individually, there is little knowledge of their combined effect. To study their interaction and whether that could explain the many disparate results that have been described in the HIV-1 literature, we developed an age-structured forward-time evolutionary model that includes compartments, migration, and recombination. By tracking the evolutionary history of individual virus variants in an Ancestral Recombination Graph (ARG) and resolving the ARG into standard bifurcating trees, we reexamined 771 anatomical tissue pairs infected with HIV-1. Remarkably, we found that recombination can make the resulting bifurcating tree appear more compartmentalized than the virus population actually is. However, we found migration between all 771 tissue pairs, typically at 2.8-4.9×10−3taxa-1day-1. Thus, while different point mutations may arise in different parts of the body, migration eventually brings these variants together and recombination merges them into a relatively homogeneous cloud of a universally evolving quasispecies. Modelling this process, we explain the many different results previous research found among distinct anatomical tissues. We also show that the popular Slatkin-Maddison test comes to different results about compartmentalization at the same migration rate depending on the sample size.

SIGNIFICANCE

Whether HIV-1 sampled in different anatomical tissues are compartmentalized or not has been a long-standing quest because it relates to both clinical and biological insight. Previous studies of this question have reported disparate results from the same as well as different tissue comparisons. Here, we consolidate and explain these contrasting results with a new evolutionary model that includes compartments, migration, and recombination. We show that no anatomical tissues are fully compartmentalized, and that the migration of HIV-1 between the tissues allows recombination to homogenize the diversity that may arise in separate tissues of an infected person.
Social network and household exposure explain the use of malaria prevention measures in rural communities of Meghalaya, India
Authors: Bellotti Elisa , Voros Andras , Passah Mattimi , Nongrum Quinnie Doreen , Nengnong Carinthia Balabet , Khongwir Charishma , van Eijk Annemieke , Kessler Anne , Sarkar Rajiv , Carlton Jane M. , Albert Sandra
Published: April 2023

Malaria remains a global concern despite substantial reduction in incidence over the past twenty years. Public health interventions to increase the uptake of preventive measures have contributed to this decline but their impact has not been uniform. To date, we know little about what determines the use of preventive measures in rural, hard-to-reach populations, which are crucial contexts for malaria eradication. We collected detailed interview data on the use of malaria preventive measures, health-related discussion networks, individual characteristics, and household composition in ten tribal, malaria-endemic villages in Meghalaya, India in 2020-2021 (n=1,530). Employing standard and network statistical models, we found that social network and household exposure were consistently positively associated with preventive measure use across villages. Network and household exposure were also the most important factors explaining behaviour, outweighing individual characteristics, opinion leaders, and network size. These results suggest that real-life data on social networks and household composition should be considered in studies of health-behaviour change.
Ranking Antibody Binding Epitopes and Proteins Across Samples from Whole Proteome Tiled Linear Peptides
Authors: McIlwain Sean J. , Hoefges Anna , Erbe Amy K. , Sondel Paul M. , Ong Irene M.
Published: April 2023

Ultradense peptide binding arrays that can probe millions of linear peptides comprising the entire proteomes or immunomes of human or mouse, or numerous microbes, are powerful tools for studying the abundance of different antibody repertoire in serum samples to understand adaptive immune responses. There are few statistical analysis tools for exploring high-dimensional, significant and reproducible antibody targets for ultradense peptide binding arrays at the linear peptide, epitope (grouping of adjacent peptides), and protein level across multiple samples/subjects (I.e. epitope spread or immunogenic regions within each protein) for understanding the heterogeneity of immune responses. We developed HERON (Hierarchical antibody bindingEpitopes and pROteins from liNear peptides), an R package, which allows users to identify immunogenic epitopes using meta-analyses and spatial clustering techniques to explore antibody targets at various resolution and confidence levels, that can be found consistently across a specified number of samples through the entire proteome to study antibody responses for diagnostics or treatment. Our approach estimates significance values at the linear peptide (probe), epitope, and protein level to identify top candidates for validation. We test the performance of predictions on all three levels using correlation between technical replicates and comparison of epitope calls on 2 datasets, which shows HERON’s competitiveness in estimating false discovery rates and finding general and sample-level regions of interest for antibody binding. The code is available as an R package downloadable fromhttp://github.com/Ong-Research/HERON.
BondGraphs.jl: Composable energy-based modelling in systems biology
Authors: Forrest Joshua , Rajagopal Vijay , Stumpf Michael PH , Pan Michael
Published: April 2023

BondGraphs.jl is a Julia implementation of bond graphs. Bond graphs provide a modelling framework that describes energy flow through a physical system and by construction enforce thermodynamic constraints. The framework is widely used in engineering and has recently been shown to be a powerful approach for modelling biology. Models are mutable, hierarchical, multi-scale, multi-physics, and BondGraphs.jl is compatible with the Julia modelling ecosystem.

Availability and Implementation

BondGraphs.jl is freely available under the MIT license. Source code and documentation can be found athttps://github.com/jedforrest/BondGraphs.jl.

Contact

pan.m@unimelb.edu.au,mstumpf@unimelb.edu.au

Supplementary information

Supplementary data are available atBioinformaticsonline.
Twitter and Mastodon presence of highly-cited scientists
Authors: Siebert Maximilian , Siena Leonardo Maria , Ioannidis John P.A.
Published: April 2023

Social media platforms have an increasing influence in biomedical and other disciplines of science and public health. While Twitter has been a popular platform for scientific communication, changes in ownership have led some users to consider migrating to other platforms such as Mastodon. We aimed to investigate how many top-cited scientists are active on these social media platforms, the magnitude of the migration to Mastodon, and correlates of Twitter presence. A random sample of 900 authors was examined among those who are at the top-2% of impact based on a previously validated composite citation indicator using Scopus data. Searches for their personal Twitter accounts were performed in early December 2022, and re-evaluations were performed at 2 weeks, 4 weeks, and 2 months (February 6, 2023). 262/900 (29.1%) of highly-cited scholars had Twitter accounts, and only 9/800 (1%) had Mastodon accounts. Female gender, North American and Australia locations, younger publication age, and clinical medicine or social science expertise correlated with higher percentages of Twitter use. The vast majority of highly-cited author users of Twitter had few followers and tweets. Only 6 had more than 10,000 followers and none had more than 100,000. One limitation of our study is that it is possible that some accounts, especially with Mastodon, could not be detected. However, the study suggests that Twitter remains the preferred social media platform for highly-cited authors, and Mastodon has not yet challenged Twitter’s dominance. Moreover, most highly-cited scientists with Twitter accounts have limited presence in this medium.
Emergence of resistance to succinate dehydrogenase inhibitor fungicides inPyrenophora teresf.teresandP. teresf.maculatain Australia
Authors: Mair W.J. , Wallwork H. , Garrard T.A. , Haywood J. , Sharma N. , Dodhia K.N. , Oliver R.P. , Lopez-Ruiz F.J.
Published: April 2023

The net blotches are among the most economically significant diseases of barley worldwide. There are two forms of the disease: net-form net-blotch (NFNB, causal agentPyrenophora teresf. sp.teres[Ptt]) and spot-form net blotch (SFNB, causal agentPyrenophora teresf. sp.maculata[Ptm]). Alongside varietal choice and cultural practices, fungicides form an important part of the regime for net blotch control. The succinate dehydrogenase inhibitors (SDHIs) are a key class of fungicides used in net blotch management. However, resistance to this group of compounds has emerged in the net blotches in recent years. Here, we describe the first cases of resistance to SDHIs in Australian populations of net blotches. This study was prompted by reports of field failures of SDHI fungicides in controlling NFNB in South Australia and SFNB in Western Australia. Target site mutations in theSdhcomplex genes, previously associated with reduced sensitivity in European net blotch populations, were found in Australian isolates, and two mutations which have not been previously observed inP. teres, are also described. The mutations found inPttincluded H134R and S135R inSdhC; and H134Y and D145G inSdhD; theSdhC-H134R mutation was the most frequently observed. InPtm, the mutations found included H277L inSdhB; S73P, N75S, H134R and S135R inSdhC; and D145G inSdhD; theSdhC-N75S mutation was the most common. These mutations were correlated with reducedin vitroSDHI fungicide sensitivity by microtiter assay. The highest resistance factors to fluxapyroxad and bixafen, the most important SDHI fungicides for net blotch control in Australia, were associated with theSdhC-H134R andSdhC-S135R mutations inPtt, and with theSdhB-H277L,SdhC-H134R, andSdhC-S135R mutations inPtm. Modelling of theP. teresSdh complex showed that the two novel mutations, H277L inSdhBand H134Y inSdhD, result in a highly altered binding mode and lower binding affinity of the SDHI compound compared to the wild-type.
Automatic quantification of disgust reactions in mice using machine learning
Authors: Inaba Shizuki , Uesaka Naofumi , Tanaka Daisuke H.
Published: April 2023

Disgust is a primary negative emotion that is crucial for avoiding intoxication and infection. Disgust in rodents has been quantified as the score of disgust reactions triggered by an unpleasant taste. Disgust reactions were video-recorded and manually quantified, requiring significant time and effort for analysis. Here we developed a method to automatically count disgust reactions in mice by using machine learning. The disgust reactions were automatically tracked using DeepLabCut as the coordinates of the nose and both front and rear paws. The automated tracking data were split into test and training data, and the latter were combined with manually labeled data on whether a disgust reaction was present and, if so, which type of disgust reaction was present. Then, a random forest classifier was constructed, and the performance of the classifier was evaluated in the test dataset. The total number of disgust reactions estimated by the classifier highly correlated with those counted manually (Pearson's r = 0.98). The present method will decrease the time and effort required to analyze disgust reactions, thus facilitating the implementation of the taste reactivity test in large-scale screening and long-term experiments that necessitate quantifying a substantial number of disgust reactions.
The cortical microtubules ofToxoplasma gondiiunderlie the helicity of parasite movement
Authors: Tengganu Isadonna F. , Padilla Luisa F. Arias , Lopez Jonathan Munera , Liu Jun , Brown Peter T. , Murray John M. , Hu Ke
Published: April 2023

Motility is essential for apicomplexan parasites to infect their hosts. In a three-dimensional (3-D) environment, the apicomplexan parasiteToxoplasma gondiimoves along a helical path. The cortical microtubules, which are ultra-stable and spirally arranged, have been considered to be a structure that guides the long-distance movement of the parasite. Here we address the role of the cortical microtubules in parasite motility, invasion, and egress by utilizing a previously generated mutant (dubbed “TKO”) in which these microtubules are destabilized in mature parasites. We found that the cortical microtubules in ~ 80% of the non-dividing (i.e. daughter-free) TKO parasites are much shorter than normal. The extent of depolymerization is further exacerbated upon commencement of daughter formation or cold treatment, but parasite replication is not affected. In a 3-D Matrigel matrix, the TKO mutant moves directionally over long distances, but along trajectories significantly more linear (i.e. less helical) than those of wild-type parasites. Interestingly, this change in trajectory does not impact either movement speed in the matrix or the speed and behavior of the parasite’s entry into and egress from the host cell.
Modelling drug resistance emergence and transmission in HIV-1 in the UK
Authors: Zhukova Anna , Dunn David , Gascuel Olivier ,   Anti-HIV Drug Resistance Network
Published: April 2023

A deeper understanding of HIV-1 transmission and drug resistance mechanisms can lead to improvement in current treatment policies. However, the rates at which HIV-1 drug resistance mutations (DRMs) are acquired and at which transmitted DRMs persist are multi-factorial and vary considerably between different mutations. We develop a method for estimation of drug resistance acquisition and transmission patterns, which refines the method we described in Mourad et al. AIDS 2015. The method uses maximum likelihood ancestral character reconstruction informed by treatment roll-out dates and allows for analysis of very large data sets. We apply our method to transmission trees reconstructed on the data obtained from the UK HIV drug resistance database to make predictions for known DRMs. Our results show important differences between DRMs, in particular between polymorphic and non-polymorphic DRMs, and between the B and C subtypes. Our estimates of reversion times, based on a very large number of sequences, are compatible but more accurate than those already available in the litterature, with narrower confidence intervals. We consistently find that large resistance clusters are associated with polymorphic DRMs and DRMs with long loss time, which require special surveillance. As in other high-income countries (e.g. Switzerland), the prevalence of sequences with DRMs is decreasing, but among these, the fraction of transmitted resistance is clearly increasing compared to the fraction of acquired resistance mutations. All this indicates that efforts to monitor these mutations and the emergence of resistance clusters in the population must be maintained in the long term.
What do people living with chronic pain want from a pain forecast? A research prioritisation study
Authors: Little Claire L , Druce Katie L , Dixon William G , Schultz David M , House Thomas , McBeth John
Published: April 2023

Background

People with chronic pain report feelings of uncertainty and unpredictability around their future pain. A pain-forecasting model could provide important information to support individuals to manage their daily pain and improve their quality of life. To be useful, the model should be developed with people living with chronic pain. We conducted Patient and Public Involvement (PPI) work, with the aim of this PPI to design the content of a pain-forecasting model by (1) learning participants’ priorities in the features of pain provided by a pain forecast and (2) understanding the benefits that participants perceive they would gain from such a forecast.

Methods

A focus group of 12 participants identified potential features, benefits and drawbacks of a pain forecast. In a survey, participants with chronic pain (n= 148) prioritised the identified pain features and perceived benefits.

Results

Focus group participants identified anticipatory anxiety and fears around data-sharing as potential drawbacks. Survey respondents prioritised forecasting of pain flares (68%) and fluctuations in pain severity (64%). Specific priorities about pain flares were the timing of the onset and the severity. Of those surveyed, 75% would use a future pain forecast and 80% perceived making plans (e.g. shopping, social) as a benefit.

Conclusions

For people with chronic pain, the timing of the onset of pain flares, the severity of pain flares and fluctuations in pain severity were prioritised as being key features of a pain forecast, and making plans was prioritised as being a key benefit.

Plain English Summary

Chronic pain is a symptom of many long-term health conditions. People with chronic pain have reported that the severity of their pain is both uncertain and unpredictable. To combat this, we want to build a pain forecast, to predict future pain severity. We hypothesise that a pain forecast would reduce pain-related uncertainty and improve quality of life. It is important that a pain forecast provides useful information to people living with chronic pain. Therefore, this work aimed to understand why participants might use a forecast, and what they would want to see in a pain forecast.

A focus group was conducted to identify features, benefits and drawbacks of a pain forecast. A survey was then conducted to prioritise the features and benefits. Participants of the focus group highlighted concerns around data-sharing and potential anxiety about knowing when pain might happen. Survey participants prioritised a forecast that provided information about pain flares (periods of increased pain severity) and fluctuations in pain severity. The key perceived benefit of a forecast was the ability to make plans (such as shopping and social plans).
Whole-Cerebrum distortion-free three-dimensional pseudo-Continuous Arterial Spin Labeling at 7T
Authors: Zhao Chenyang , Shao Xingfeng , Shou Qinyang , Ma Samantha J. , Gokyar Sayim , Graf Christina , Stollberger Rudolf , Wang Danny JJ
Published: April 2023

Fulfilling potentials of ultrahigh field for pseudo-Continuous Arterial Spin Labeling (pCASL) has been hampered by B1/B0 inhomogeneities that affect pCASL labeling, background suppression (BS), and the readout sequence. This study aimed to present a whole-cerebrum distortion-free three-dimensional (3D) pCASL sequence at 7T by optimizing pCASL labeling parameters, BS pulses, and an accelerated Turbo-FLASH (TFL) readout. A new set of pCASL labeling parameters (Gave=0.4mT/m, Gratio=14.67) was proposed to avoid interferences in bottom slices while achieving robust labeling efficiency (LE). An OPTIM BS pulse was designed based on the range of B1/B0 inhomogeneities at 7T. A 3D TFL readout with 2D-CAIPIRINHA undersampling (R=2×2) and centric ordering was developed, and the number of segments (Nseg) and flip angle (FA) were varied in simulation to achieve the optimal trade-off between SNR and spatial blurring. In-vivo experiments were performed on 19 subjects. The results showed that the new set of labeling parameters effectively achieved whole-cerebrum coverage by eliminating interferences in bottom slices while maintaining a high LE. The OPTIM BS pulse achieved 33.3% higher perfusion signal in gray matter (GM) than the original BS pulse with a cost of 4.8-fold SAR. Incorporating a moderate FA (8°) and Nseg (2), whole-cerebrum 3D TFL-pCASL imaging was achieved with a 2×2×4 mm3resolution without distortion and susceptibility artifacts compared to 3D GRASE-pCASL. In addition, 3D TFL-pCASL showed a good to excellent test-retest repeatability and potential of higher resolution (2 mm isotropic). The proposed technique also significantly improved SNR when compared to the same sequence at 3T and simultaneous multislice TFL-pCASL at 7T. By combining a new set of labeling parameters, OPTIM BS pulse, and accelerated 3D TFL readout, we achieved high resolution pCASL at 7T with whole-cerebrum coverage, detailed perfusion and anatomical information without distortion, and sufficient SNR.
Metabolite Signature of Life’s Essential 8 and Risk of Coronary Heart Disease among Low-Income Black and White Americans
Authors: Deng Kui , Gupta Deepak K. , Shu Xiao-Ou , Lipworth Loren , Zheng Wei , Thomas Victoria E. , Cai Hui , Cai Qiuyin , Wang Thomas J. , Yu Danxia
Published: April 2023

Background and Aims

Life’s Essential 8 (LE8) is a comprehensive construct of cardiovascular health. Yet, little is known about LE8 score, its metabolic correlates, and their predictive implications among Black Americans and low-income individuals.

Methods

In a nested case-control study of coronary heart disease (CHD) among 598 Black and 596 White low-income Americans, we estimated LE8 score, conducted untargeted plasma metabolites profiling, and used elastic net with leave-one-out cross-validation to identify metabolite signature (MetaSig) of LE8. Associations of LE8 score and MetaSig with incident CHD were examined using conditional logistic regression. Mediation effect of MetaSig on the LE8-CHD association was also examined. The external validity of MetaSig was evaluated in another nested CHD case-control study among 598 Chinese adults.

Results

Higher LE8 score was associated with lower CHD risk [standardized OR (95% CI)=0.61 (0.53-0.69)]. The identified MetaSig, consisting of 133 metabolites, showed strong correlation with LE8 score (r=0.61) and inverse association with CHD risk [OR (95% CI)=0.57 (0.49-0.65)], robust to adjustment for LE8 score and across participants with different sociodemographic and health status (ORs: 0.42-0.69; allP<0.05). MetaSig mediated a large portion of the LE8-CHD association: 53% (32%-80%) (P<0.001). Significant associations of MetaSig with LE8 score and CHD risk were found in validation cohort [r=0.49; OR (95% CI)=0.57 (0.46-0.69)].

Conclusions

Higher LE8 score and its MetaSig were associated with lower CHD risk among low-income Black and White Americans. Metabolomics may offer an objective and comprehensive measure of LE8 score and its metabolic phenotype relevant to CHD prevention among diverse populations.
Genome-wide Association Study of Postpartum Depression Identifies a Novel Susceptibility Locus at 18q12.1
Authors: Cordova-Palomera Aldo , Diogo Dorothée , Szalma Sándor
Published: April 2023

Postpartum depression (PPD) is among the most frequent and incapacitating conditions following childbirth, with significant consequences for mothers, newborns and families. Genetic factors have been proposed to influence disease risk and symptom heterogeneity, and can potentially inform drug target discovery and treatment strategies.

Here, we conducted a genetic association study to further our understanding of the genetic architecture of PPD. We identified PPD cases and controls in the UK Biobank using multiple sources of medical history and self-reported information. We performed genome-wide association studies of common and rare variants in in a harmonized set of up to 11,782 PPD cases and 167,480 controls among European-ancestry females.

Genetic association results displayed a significantly associated locus at chromosome 18q12.1 led by the common rs10502503 marker (minor allele frequency: 29.9%, effect allele: C, odds ratio: 0.92,p=6.4×10−9), within silicofunctional mapping suggesting Cadherin 2 (CDH2) as a candidate causal gene. This signal, if confirmed in independent replication cohorts with PPD diagnosis confirmed through psychometry, may contribute novel insights into the genetic basis of PPD.

The results illustrate the use of minimal phenotyping in large-scale general population cohorts to investigate the genetic etiology and heterogeneity of PPD, and to generate therapeutic hypotheses.