bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractCoronaviruses (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.AbstractThe 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

SUMMARYThe 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

AbstractMaintaining 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

ABSTRACTThe 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.SIGNIFICANCEWhether 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.
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

AbstractUltradense 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

AbstractSummaryBondGraphs.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 ImplementationBondGraphs.jl is freely available under the MIT license. Source code and documentation can be found athttps://github.com/jedforrest/BondGraphs.jl.Contactpan.m@unimelb.edu.au,mstumpf@unimelb.edu.auSupplementary informationSupplementary 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

AbstractSocial 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

AbstractThe 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.
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

ABSTRACTMotility 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

AbstractA 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

AbstractBackgroundPeople 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.MethodsA 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.ResultsFocus 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.ConclusionsFor 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 SummaryChronic 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).