bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recurrent innovation of protein-protein interactions in theDrosophilapiRNA pathway
Authors: Riedelbauch Sebastian , Masser Sarah , Fasching Sandra , Lin Sung-Ya , Salgania Harpreet Kaur , Aarup Mie , Ebert Anja , Jeske Mandy , Levine Mia , Stelzl Ulrich , Andersen Peter 
Published: October 2024

ABSTRACTDespite being essential for fertility, genome defence pathway genes often evolve rapidly. However, little is known about the molecular basis of this adaptation. Here, we characterize the evolution of a protein interaction network within the PIWI-interacting small RNA (piRNA) genome defence pathway inDrosophilaat unprecedented scale and evolutionary resolution. We uncover pervasive rapid evolution of a protein interaction network anchored at the Heterochromatin Protein 1 (HP1) paralog Rhino. Using complementary phylogenetic analysis, high-throughput yeast-two-hybrid matrix screening, andin vivointeraction analyses in cross-species transgenic flies, we characterized three distinct evolutionary protein interaction trajectories across ∼40 million years ofDrosophilaevolution. The data set covering 11 piRNA pathway proteins of fiveDrosophilaspecies revealed several protein interactions that are fully conserved, indicating functional conservation despite overall rapid amino acid sequence change. Other interactions are preserved through co-evolution and were detected only between proteins within or from closely related species. We also identified sets of species-restricted protein interactions which, through rewiring of a Rhino-anchored transcription factor network, may preserve critical roles in enabling and adapting piRNA production from heterochromatic loci. In sum, our analyses dissected principles of interaction evolution in an adaptively evolving protein-protein interaction network uncovering evolutionary and functional insight into germline piRNA production acrossDrosophilaspecies. Our work provides key experimental evidence in support of a model proposing that intermolecular interaction innovation is a major molecular mechanism of evolutionary adaptation in protein-coding genes.
A Fibronectin (FN)-Silk 3D Cell Culture Model as a Screening Tool for Repurposed Antifibrotic Drug Candidates for Endometriosis
Authors: Teworte Sarah , Behrens Mark C. , Widhe Mona , Gurzeler Lukas-Adrian , Hedhammar My , Luciani Paola 
Published: October 2024

AbstractThis study advances sustainable pharmaceutical research for endometriosis by aligning with the UN Sustainable Development Goals on health, gender equality, and responsible consumption in developingin vitro3D cell culture models of endometriotic pathophysiology. Fibrosis is a key aspect of endometriosis, yet current models to study it remain limited, especially in 3D. This work aims to bridge the translational gap betweenin vitrofibrosis research and preclinical testing of non-hormonal drug candidates. When grown in a 3D matrix of sustainably produced silk protein functionalized with a fibronectin-derived cell adhesion motif (FN-silk), endometrial stromal and epithelial cells respond to transforming growth factor beta-1 (TGF-β1) in a physiological manner as probed at the mRNA level. For stromal cells, this response to TGF-β1 is not observed in spheroids, while epithelial cell spheroids behave similarly to epithelial cell FN-silk networks. Pirfenidone, an antifibrotic drug approved for the treatment of idiopathic pulmonary fibrosis, reverses TGF-β1-induced upregulation of mRNA transcripts involved in fibroblast-to-myofibroblast transdifferentiation of endometrial stromal cells in FN-silk networks, supporting the drug’s potential as a repurposed non-hormonal therapy for endometriosis. This study demonstrates how a sustainable approach – from project conceptualization to material selection – can be integrated into pharmaceutical research for women’s health.Table of contentsThis paper presentsin vitro3D cell culture models of fibrosis in endometriosis. Endometrial stromal and epithelial cells cultured in networks of silk protein functionalized with a fibronectin-derived cell adhesion motif showed physiological-like fibrotic behavior. Pirfenidone was able to reverse fibrosis of endometrial stromal cellsin vitro, demonstrating this model’s suitability as a screening tool for antifibrotic drugs for endometriosis.
Splicing dysregulation in glioblastoma alters the function of cell migration-related genes
Authors: Seong Minu , Bak-Gordon Pedro , Liu Zhaoqi , Canoll Peter D. , Manley James L. 
Published: October 2024

SummaryGlioblastoma (GBM) has a poor prognosis with a high recurrence and low survival rate. Previous RNA-seq analyses have revealed that alternative splicing (AS) plays a role in GBM progression. Here, we present a novel AS analysis method (Semi-Q) and describe its use to identify GBM-specific AS events. We analyzed RNA-seq data from normal brain (NB), normal human astrocytes (NHAs) and GBM samples, and found that comparison between NHA and GBM was especially informative. Importantly, this analysis revealed that genes encoding cell migration-related proteins, including filamins (FLNs) and actinins (ACTNs), were among those most affected by differential AS. Functional assays revealed that dysregulated AS ofFLNA, BandCtranscripts produced protein isoforms that not only altered transcription of cell proliferation-related genes but also led to enhanced cell migration, resistance to cell death and/or mitochondrial respiratory function, while a dysregulated AS isoform ofACTN4enhanced cell migration. Together, our results indicate that cell migration and actin cytoskeleton-related genes are differentially regulated by AS in GBM, supporting a role for AS in facilitating tumor growth and invasiveness.
Validating the genusPocheina(Acrasidae, Heterolobosea, Excavata) leads to the recognition of three major lineages within Acrasidae
Authors: Tice Alexander K. , Regis Kevin , Shutt Timothy E. , Spiegel Frederick W. , Brown Matthew W. , Silberman Jeffery D. 
Published: October 2024

ABSTRACTPocheinaandAcrasisare two genera of heterolobosean sorocarpic amoebae within Acrasidae that have historically been considered close relatives. The two genera were differentiated based on their differing fruiting body morphologies. The validity of this taxonomic distinction was challenged when a SSU rRNA phylogenetic study placed an isolate morphologically identified as ‘Pocheina’roseawithin a clade ofAcrasis roseaisolates. The authors speculated that pocheinoid fruiting body morphology might be the result of aberrantA. roseafruiting body development, which if true, would nullify this taxonomic distinction between genera. To clarify Acrasidae systematics, we analyzed SSU rRNA and ITS region sequences from multiple isolates ofPocheina, Acrasis, andAllovahlkampfiagenerated by PCR and transcriptomics. We demonstrate that the initial SSU sequence attributed to ‘P. rosea’ originated from anA. roseaDNA contamination in its amplification reaction. Our analyses, based on morphology, SSU and 5.8S rRNA genes phylogenies, as well as comparative analyses of ITS1 and ITS2 sequences, resolve Acrasidae into three major lineages;Allovahlkampfiaand the strongly supported clades comprisingPocheinaandAcrasis. We confirm that the latter two genera can be identified by their fruiting body morphologies.
Something to sink your teeth into: the mechanics of tooth indentation in frugivorous fishes
Authors: Rosen Jack , Cohen Karly , Donatelli Cassandra M. , Summers Adam P. , Crofts Stephanie , Kolmann Matthew A. 
Published: October 2024

ABSTRACTFrugivorous vertebrates engage in a mutualism with fruiting plants: the former receive a nutrient subsidy and the latter benefit by having their seeds distributed far from parent plants. Vertebrate frugivores like primates and bats have particular morphologies, like wide jaws and blunt teeth, which are thought to aid in dismantling fruit and obtaining trapped sugars. However, variation among frugivores and fruits has made the identification of common frugivore phenotypes difficult. We measured the performance of frugivorous fish dentitions whether this performance was comparable to fruit-eating bats and primates. We also explored how fruit characteristics affect puncture performance, and how indentation of fruit differs mechanically from harder foods like nuts. Finally, we used photoelasticity and videography to visualize how serrasalmid dentitions propagate stresses in simple gel models. We expected that frugivore dentitions would exhibit low force and then high work when engaging fruit tissues. Aligning with our expectation, the most frugivorous serrasalmid we tested,Colossoma, had dental performance that matched the low force, high work model. Indentation behavior differed between food types, both between fruits and nuts, and among different fruits. We also documented considerable differences in the indentation performances of different serrasalmid dentitions, among frugivores, omnivores, and carnivores. We propose that some differences in the morphology of frugivore dentitions make them better for granivory (eating seeds) than the softer fruit tissues. Fishes exhibit convergent mechanical and morphological strategies with other vertebrates for obtaining nutrition from fruits and seeds.
No association betweenFMR1premutation and either ADHD or anxiety in 53,707 women undergoing genetic testing for family planning purposes
Authors: Klausner Liraz , Carmi Shai , Ben-Shachar Shay , Lev-El Halabi Noa , Basel-Salmon Lina , Goldstein Dana Brabbing 
Published: October 2024

AbstractBackgroundAnFMR1full mutation, which causes Fragile X Syndrome, is defined as >200 repeats of the CGG motif in the gene’s 5’ untranslated region. A repeat count in the range 55-200 is considered anFMR1premutation (PM) and was previously associated with neuropsychiatric phenotypes. However, these associations did not always replicate and may be due to ascertainment bias. Here, we studied the association between PM and attention deficit hyperactivity disorder (ADHD) and anxiety using large population-based screening data.MethodsWe used data on women who underwent genetic screening in Rabin Medical Center in Israel for family planning purposes between 2001-2020. PM carriers were defined as subjects with 58-200 CGG repeats. We linked the genetic testing results to longitudinal electronic medical records (EMR) from Clalit Health Services. We defined ADHD and anxiety based on either a formal diagnosis or the purchase of relevant medications. As a positive control, we considered premature ovarian insufficiency (POI) and high follicle-stimulating hormone (FSH) levels before the age of 40. Our primary analysis used Cox regression with socioeconomic status, immigration, and age at testing as covariates.ResultsOur sample included 53,707 women: 464 PM carriers and 53,243 non-carriers. PM was associated with POI (hazard ratio (HR): 4.08, 95% confidence interval (CI): 2.16-7.72) and high FSH (HR: 3.43, 95% CI: 2.65-4.43). However, PM was not associated with either ADHD (HR 0.95; 95% CI: 0.51-1.77; 1331 events) or anxiety (HR 0.81; 95% CI: 0.47-1.39; 1814 events). The results were similar when the phenotype was defined based on medications and with logistic regression. Our study was sufficiently powered to detect HR about 2 or higher.DiscussionWe found no association between PM and either ADHD or anxiety. Our study is less prone to ascertainment bias towards affected families; however, the ascertained subjects are likely healthier than the population average. While our sample size is the largest to date, given the low frequency of PM carriers, small effects cannot be excluded.
Stroke in adults with primary intracranial tumours
Authors: Innes Stuart C. , Yin Lucia , Finnerty Gerald T. 
Published: October 2024

ABSTRACTBACKGROUNDMalignant primary intracranial tumours are associated with stroke. Knowing how stroke differs in patients with either benign or malignant primary intracranial tumours would give insights into how intracranial tumours affect stroke and would help to improve the limited stroke guidelines for these patients.METHODSWe conducted a retrospective cohort study of patients with benign or malignant primary intracranial tumours admitted with stroke (2011 - 2022) to a single centre with regional stroke and neuro-oncology units. Data collected included: stroke aetiology, stroke timing relative to tumour diagnosis, pre-stroke disability, post-stroke disability, stroke recurrence and treatment.RESULTSWe identified 258 patients who had an index stroke (120 haemorrhagic, 135 ischaemic, three coincident haemorrhagic/ischaemic) at or after the diagnosis of their primary intracranial tumour (71% benign, 29% malignant). Symptomatic intracranial haemorrhage was more commonly associated with malignant primary intracranial tumours. Patients with a malignant primary intracranial tumour were 2.7 times more likely to have a stroke than patients with a benign intracranial tumour. We estimated that the risk of ischaemic stroke and symptomatic intracranial haemorrhage within six months of diagnosis of a benign primary intracranial were respectively 2.5 and 5.0 times that of the general population. In-hospital mortality and level of disability at hospital discharge (median modified Rankin scale score, 4) were similar for patients with benign or malignant primary intracranial tumours. Stroke recurrence was 22% at one year. Statins were associated with reduced stroke recurrence.Patients with malignant tumours and high post-stroke disability were less likely to receive chemotherapy after hospital discharge.CONCLUSIONSOur findings suggest that stroke is a wider issue for patients with primary intracranial tumours than commonly recognised. Our data indicated that statins may help to prevent stroke recurrence. Despite concerns about intracranial haemorrhage, antiplatelet agents should be considered after ischaemic stroke.
Identification and catalogue of viral transcriptional regulators in human diseases
Authors: Citu Citu , Chang Le , Manuel Astrid M. , Enduru Nitesh , Zhao Zhongming 
Published: October 2024

AbstractViral genomes encode viral transcriptional regulators (vTRs) that manipulate host gene expression to facilitate replication and evade immune detection. Nevertheless, their role in non-cancerous diseases remains largely underexplored. Here, we unveiled 268 new candidate vTRs from 14 viral families. We mapped vTRs’ genome-wide binding profiles and identified their potential human targets, which were enriched in immune-mediated pathways, neurodegenerative disorders, and cancers. Through vTR DNA-binding preference analysis, 283 virus-specific and human-like motifs were identified. Prioritized Epstein-Barr virus (EBV) vTR target genes were associated with multiple sclerosis (MS), rheumatoid arthritis, and systemic lupus erythematosus. The partitioned heritability study among 19 diseases indicated significant enrichment of these diseases in EBV vTR-binding sites, implicating EBV vTRs’ roles in immune-mediated disorders. Finally, drug repurposing analysis pinpointed candidate drugs for MS, asthma, and Alzheimer’s disease. This study enhances our understanding of vTRs in diverse human diseases and identifies potential therapeutic targets for future investigation.
Endogenous Huntingtin aggregates are a huge organized scaffold and mold for Golgi apparatus impaired by mutant Huntingtin protein
Authors: Ma Lixiang , Chen Xinyu , Liu Yang , Dai Lijun , Yang Weiqi , Buhe Hada , Ma Jixin , Song Chenyun , Li Li , Fan Dandan , Su Jianzhong , Saiyin Hexige 
Published: October 2024

AbstractHuntington’s disease (HD), an incurable neurodegenerative disease, is caused by polyglutamine (polyQ) expansion in Huntingtin (HTT) protein. Despite HTTs naturally aggregating, huge variations of HTTs in visualizing methods make it unpredictable. Using 64 nm resolution scanning in the fibroblasts, induced neurons, organoids from an HD family, and human brain tissues, we revealed massive/long polyQ aggregates of HTTs formed by paralleled and interfused spindles that preferentially include flat Golgi stacks/ribbons/vesicles and disassembled in the mitotic and stressed cells with fragmented Golgi, brefeldin A (BFA) treatment and postfixation, and fragmented Golgi in the mitotic and stressed cells but not in BFA-treated cells binds to small HTTs. The disassembling of HTTs aggregates degraded HTTs. PolyQ aggregates with mutant HTT (mHTT)include a flat Golgi stack with a deformed surface, fragment easier in starvation, attach fewer Golgi/clathrin+vesicles and ARF1 than polyQ assemblies without mHTT in fibroblasts or striatal/cortical neurons, and cause intranuclear inclusion bodies in striatal neurons. ScRNA data of striatal GABAergic neurons reveal impaired Golgi- or vesicle-related activities. Collectively, polyQ aggregates of HTTs are a stable form and highly organized scaffold and mold for flat Golgi stacks/ribbons/vesicles, and the existence of mHTT in polyQ assemblies reduced ARF-related activities and impaired Golgi in striatal/cortical neurons.
Decision analysis shows scientific and economic value of community-based monitoring in Madagascar
Authors: Soifer Lydia G. , Klinges David H. , Randriamiharisoa Lalatiana , Scheffers Brett R. 
Published: October 2024

AbstractCommunity-based monitoring (CBM) could enable long-term biodiversity monitoring in remote areas and benefit local communities, but its benefits have rarely been quantified. We use a multi-criteria decision analysis framework to systematically examine the scientific and socioeconomic values and financial costs associated with biodiversity monitoring for vertebrates by scientists and local community members in six protected areas (PAs) in Madagascar, encompassing diverse ecosystems spanning tropical rainforests to spiny deserts. We compare the number of species observed during scientist and community surveys, identify the ‘ideal’ number of scientist and community surveys that would be required to maximize the scientific and socioeconomic values of monitoring efforts while minimizing financial cost, and compare monitoring plans across several conservation philosophies representing “ecocentric” and “people-centered” perspectives. Scientists generally observed more species than community members. However, including a greater proportion of surveys conducted by community members improves wildlife monitoring across PAs, taxonomic groups, and diverse conservation philosophies due to the lower financial cost of travel and compensation relative to monitoring exclusively conducted by scientists. While the valuation schemes we use are simplistic representations of the complex costs and values associated with CBM, this study indicates the benefits of community monitoring regardless of the conservation philosophy used to anchor valuation and decision-making. Increasing integration of CBM into existing conservation management could therefore offer a financially viable method to consistently monitor biodiversity and benefit local communities in the face of limited funding and global challenges.
Regional deficits in endogenous regeneration of mouse olfactory sensory neuron axons
Authors: Kunkhyen Tenzin , Curtis Kendall A. , Deakin Thomas P. , Huang Jane S. , Gregory Jordan D. , Cheetham Claire E.J. 
Published: October 2024

AbstractPostnatal neurogenesis occurs in only a few regions of the mammalian nervous system. Hence, neurons that are lost due to neurodegenerative disease, stroke, traumatic brain injury or peripheral neuropathy cannot be replaced. Transplantation of stem cell-derived neurons provides a potential replacement strategy, but how these neurons can be encouraged to functionally integrate into circuits remains a significant challenge. In the mammalian olfactory epithelium (OE), olfactory sensory neurons (OSNs) continue to be generated throughout life from basal stem cells and can be repopulated even after complete ablation. However, the specialized population of navigator OSNs that ensures accurate odorant receptor-specific targeting of OSN axons to glomeruli in the olfactory bulb (OB) is only present perinatally. Despite this, some studies have reported complete regeneration of specific glomeruli, while others have found various degrees of recovery, following OSN cell death. Variability in the extent of both initial OSN ablation and subsequent repopulation of the OE, and the focus on anatomical recovery, leave the extent to which newly generated OSNs can reinnervate the OB unclear. Here, we employed the olfactotoxic drug methimazole to selectively ablate OSNs without damaging the basal stem cells that generate them, enabling us to assess the extent of functional recovery of OSN input to the OB in the context of complete OSN repopulation. We found profound deficits in the recovery of odor-evoked responses in OSN axons in the glomerular layer of the dorsal OB five weeks after OSN ablation, a time point at which OSNs are known to have repopulated the OE. Histological analysis of mature OSN axons in the OB at 10 and 20 weeks post-methimazole showed a persistent region-specific deficit in OSN axon reinnervation of the dorsal OB, with the dorsomedial region being particularly adversely affected. In contrast, reinnervation of the ventral, lateral and medial regions of the OB was almost complete by 10 weeks post-MMZ. Hence, we have identified a region-specific deficit in OSN reinnervation of the mouse OB, which sets the stage to identify the mechanisms that mediate successful vs. unsuccessful axonal regeneration in an endogenous population of stem cell-derived neurons.
Value Set Hub: Software for developing and curating high-quality value sets
Authors: Gold Sigfried , Flack Joseph E. , Lutters Wayne G. , Chute Christopher G. 
Published: October 2024

AbstractTerminology value sets are central to research studies using real-world patient data. We describe the considerable challenges that arise when researchers develop value sets for their studies or reuse those made by others. We present Value Set Hub (VS-Hub), software to overcome these challenges, describing its design, implementation, features, use in the field, lessons learned, and future directions. Over a five-month period, VS-Hub has been used by over 200 users and has been used in the development and curation of 95 recommended value sets for commonly studied conditions, treatments, and lab tests. Particular innovations include the presentation of multiple value sets on the same screen for easy comparison, the display of compared value sets in the context of vocabulary hierarchies, the integration of these analytic features and value set authoring, and value set browsing features that encourage users to review existing value sets that may be relevant to their needs.