bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using an agent based model to inform sampling design for animal social network analysis
Authors: Kaur Prabhleen , Ciuti Simone , Salter-Townshend Michael , Farine Damien 
Published: May 2024

AbstractProducing accurate and reliable inference from animal social network analysis depends on the sampling strategy during data collection. An increasing number of studies now use large-scale deployment of GPS tags to collect data on social behaviour. However, these can rarely capture whole populations or sample at very high frequencies. To date, little guidance exists when makingpriordecisions about how to maximise sampling effort to ensure that the data collected can be used to construct reliable social networks. We use a simulation-based approach to generate a functional understanding of how the accuracy of various network metrics is affected by decisions along three fundamental axes of sampling effort: coverage, frequency and duration. Researchers often face trade-offs between these three sampling axes, for example due to resource limitations, and thus we identify which axes need to be prioritised as well as the effectiveness of different deployment and analytical strategies. We found that the sampling level across the three axes has different consequences depending on the social network metrics that are estimated. For example, global metrics are more sensitive than local metrics to the proportion of the population tracked, and that among local metrics some are more sensitive to sampling duration than others. Our research demonstrates the importance of establishing an optimal sampling configuration for drawing relevant and robust inferences, and presents a range of practical advice for designing GPS based sampling strategies in accordance with the research objectives.
Mapping and Engineering Antibody-Antigen Interaction Landscapes for Systematic Affinity Enhancement
Authors: Chun Changju , Sohn Byeong-Kwon , Jo Ji Hye , Lee Jiyu , Yu Booyoung , Baek Minkyung , Yoon Tae-Young 
Published: May 2024

AbstractAntibodies, crucial in adaptive immunity, recognize antigens through specific interactions facilitated by Complementarity Determining Regions (CDRs), diversified via Variable-Diversity-Joining (VDJ) recombination. Traditional antibody development, limited by the scope of animal models and phage display libraries, captures a fraction of the potential antibody-antigen interactions. This underscores a gap in understanding antibody specificity and the relationship between antibody sequence and binding affinity. Here we introduce an approach using the Single-Protein Interaction Detection (SPID) platform, repurposed to systematically map local landscapes of antibody-antigen interactions with unprecedented depth and speed, aiming to rival the precision of methods like Surface Plasmon Resonance (SPR) and Bio-Layer Interferometry (BLI) while significantly boosting throughput. By editing CDR sequences and measuring effects on dissociation constants, we elucidated pathways for optimizing antibody affinity, enhancing predictive models for interactions. Our findings demonstrate the capability of the SPID platform to characterize thousands of variants weekly, offering a deeper insight into antibody-antigen interactions and advancing antibody development with finely-tuned affinities.
Association between mosaic loss of chromosome Y and pulmonary fibrosis susceptibility and severity
Authors: Wang Dapeng , Hadad Niran , Moss Samuel , Lopez-Jimenez Elena , Johnson Simon R. , Maher Toby M , Molyneaux Philip L , Zhao Yajie , Perry John R. B. , Wolters Paul J. , Kropski Jonathan A. , Jenkins R Gisli , Banovich Nicholas E. , Stewart Iain 
Published: May 2024

AbstractBackgroundPulmonary fibrosis (PF) is a rare lung disease with diverse pathogenesis and multiple interconnected underlying biological mechanisms. Mosaic loss of chromosome Y (mLOY) is one of the most common forms of acquired chromosome abnormality in men, which has been reported to be associated with increased risk of various chronic progressive diseases including fibrotic diseases. However, the exact role of mLOY in the development of PF remains elusive and to be elucidated.MethodsWe adopted three complementary approaches to explore the role of mLOY in the pathogenesis of PF. We used copy number on chromosome Y to estimate mLOY comparing patients in PROFILE and gnomAD cohorts and between cases and control patients from the GE100KGP cohort. Correlation of mLOY with demographic and clinical variables was tested using patients from PROFILE cohort. Lung single-cell transcriptomic data were analysed to assess the cell types implicated in mLOY. We performed Mendelian randomisation to examine the causal relationship between mLOY, IPF, and telomere length.ResultsThe genetic analysis suggests that mLOY is found in PF from both case cohorts but when compared with an age matched population the effect is minimal (P = 0.0032). mLOY is related to age (P = 0.00021) and shorter telomere length (P = 0.0081) rather than PF severity or progression. Single-cell analysis indicates that mLOY appears to be found primarily in immune cells and appears to be related to presence and severity of fibrosis. Mendelian randomisation demonstrates that mLOY is not on the causal pathway for IPF, but partial evidence supports that telomere shortening is on the causal pathway for mLOY.ConclusionOur study confirms the existence of mLOY in PF patients and suggests that mLOY is not a major driver of IPF. The combined evidence suggests a triangulation model where telomere shortening leads to both IPF and mLOY.
A discrete character evolution model for phylogenetic comparative biology with Γ-distributed rate heterogeneity among branches of the tree
Authors: Revell Liam J. , Harmon Luke J. 
Published: May 2024

ABSTRACTPhylogenetic comparative methods are now widely used to measure trait evolution on the tree of life. Often these methods involve fitting an explicit model of character evolution to trait data and then comparing the explanatory power of this model to alternative scenarios. In this article, we present a new model for discrete trait evolution in which the rate of character change in the tree varies from edge (i.e., “branch”) to edge of the phylogeny according to a discretized Γ distribution. When the edge-wise rates of evolution are, in fact, Γ-distributed, we show via simulation that this model can be used to reliably estimate the shape parameter (α) of the distribution of rate variation among edges. We also describe how our model can be employed in ancestral state reconstruction, and demonstrate via simulation how doing so will tend to increase the accuracy of our estimated states when the generating edge rates are Γ-distributed. We discuss how marginal edge rates are estimated under the model, and apply our method to a real dataset of digit number in squamate reptiles, modified from Brandley et al. (2008).
JUNB O-GlcNAcylation-mediated promoter accessibility of metabolic genes modulates distinct epithelial lineage in pulmonary fibrosis
Authors: Bammert Marie-Therese , Ansari Meshal , Haag Leoni , Ahmad Zuhdi , Schröder Victoria , Birch Joseph , Santacruz Diana , Rust Werner , Viollet Coralie , Strobel Benjamin , Dick Alec , Gantner Florian , Schlüter Holger , Ramirez Fidel , Lizé Muriel , Thomas Matthew J. , Le Huy Q. 
Published: May 2024

AbstractIdiopathic pulmonary fibrosis (IPF) is a lethal disease with substantial unmet medical needs. While aberrant epithelial remodelling is a key factor in IPF progression, the molecular mechanisms behind this process remain elusive. Using a patient-derived 3D distal airway epithelial organoid model, we successfully recapitulate important IPF features, including the emergence of aberrant KRT5+/COL1A1+ basal cells and a metabolic shift towards increased O-linked β-N-acetylglucosamine (O-GlcNAc) levels. Consistent with this, single-cell analysis of accessible chromatin reveals an increased chromatin accessibility in these aberrant basal cells, particularly at JUNB motif-enriched promoter regions of metabolic genes. O-GlcNAcylation shapes JUNB function and promotes a pro-fibrotic response to chronic injury, leading to aberrant epithelial remodelling. Site-specific deletion of O-GlcNAcylation on JUNB attenuates the metaplastic differentiation of basal cells, thereby aiding in the restoration of the alveolar lineage. Together, these data establish a novel link between metabolic dysregulation, mediated by the O-GlcNAc-JUNB axis, and bronchiolization in IPF, offering new therapeutic strategies to treat this fatal disease.
UsingCupriavidus necatorH16 to provide a roadmap for increasing electroporation efficiency in non-model bacteria
Authors: Vajente Matteo , Clerici Riccardo , Ballerstedt Hendrik , Blank Lars M. , Schmidt Sandy 
Published: May 2024

ABSTRACTBacteria are a treasure trove of metabolic reactions, but most industrial biotechnology applications rely on a limited set of established host organisms. In contrast, adopting non-model bacteria for the production of various chemicals of interest is often hampered by their limited genetic amenability coupled with their low transformation efficiency. In this study, we propose a series of steps that can be taken to increase electroporation efficiency in non-model bacteria. As a test strain, we useCupriavidus necatorH16, a lithoautotrophic bacterium that has been engineered to produce a wide range of products from CO2and hydrogen. However, its low electroporation efficiency hinders the high-throughput genetic modifications required to developC. necatorinto an industrially relevant host organism. First, we propose a species-independent technique based on natively methylated DNA and Golden Gate assembly to increase one-pot cloning and electroporation efficiency by 70-fold. Second, bioinformatic tools were used to predict defense systems and develop a restriction avoidance strategy that was used to introduce suicide plasmids by electroporation to obtain a domesticated strain. The results are discussed in the context of metabolic engineering of non-model bacteria.TABLE OF CONTENT
Protamine 2 Deficiency Results In Septin 12 Abnormalities
Authors: Sanovec Ondrej , Frolikova Michaela , Kraus Veronika , Vondrakova Jana , Qasemi Maryam , Spevakova Daniela , Simonik Ondrej , Moritz Lindsay , Caswell Drew Lewis , Liska Frantisek , Ded Lukas , Cerny Jiri , Avidor-Reiss Tomer , Hammoud Saher Sue , Schorle Hubert , Postlerova Pavla , Steger Klaus , Komrskova Katerina 
Published: May 2024

AbstractThere is a well-established link between abnormal sperm chromatin states and poor motility, however, how these two processes are interdependent is unknown. Here, we identified a possible mechanistic insight by showing that Protamine 2, a nuclear DNA packaging protein in sperm, directly interacts with cytoskeletal protein Septin 12, which is associated with sperm motility. Septin 12 has several isoforms, and we show, that in thePrm2-/-sperm, the short one (Mw 36 kDa) is mislocalized, while two long isoforms (Mw 40 and 41 kDa) are unexpectedly lost inPrm2-/-sperm chromatin-bound protein fractions. Septin 12 co-immunoprecipitated with Protamine 2 in the testicular cell lysate of WT mice and with Lamin B1/B2/B3 in co-transfected HEK cells despite we did not observe changes in Lamin B2/B3 protein or SUN4 expression inPrm2-/-testes. Furthermore, thePrm2-/-sperm have on average a smaller sperm nucleus and aberrant acrosome biogenesis. In humans, patients with low sperm motility (asthenozoospermia) have imbalanced histone– protamine 1/2 ratio and modified levels of cytoskeletal proteins. We detected retained Septin 12 isoforms (Mw 40 and 41 kDa) in the sperm membrane, chromatin-bound and tubulin/mitochondria protein fractions, which was not true for healthy normozoospermic men. In conclusion, our findings expand the current knowledge regarding the connection between Protamine 2 and Septin 12 expression and localization, resulting in low sperm motility and morphological abnormalities.
The Latent Aging of Cells
Authors: Niimi Peter , Gould Victoria , Thrush-Evensen Kyra , Levine Morgan E. 
Published: May 2024

AbstractAs epigenetic clocks have evolved from powerful estimators of chronological aging to predictors of mortality and disease risk, it begs the question of what role DNA methylation plays in the aging process. We hypothesize that while it has the potential to serve as an informative biomarker, DNA methylation could also be a key to understanding the biology entangled between aging, (de)differentiation, and epigenetic reprogramming. Here we use an unsupervised approach to analyze time associated DNA methylation from bothin vivoandin vitrosamples to measure an underlying signal that ties these phenomena together. We identify a methylation pattern shared across all three, as well as a signal that tracks aging in tissues but appears refractory to reprogramming, suggesting that aging and reprogramming may not be fully mirrored processes.
Branched chain α-ketoacids aerobically activate HIF1α signaling in vascular cells
Authors: Xiao Wusheng , Shrimali Nishith , Oldham William M. , Clish Clary B. , He Huamei , Wong Samantha J. , Wertheim Bradley M. , Arons Elena , Haigis Marcia C. , Leopold Jane A. , Loscalzo Joseph 
Published: May 2024

ABSTRACTHypoxia-inducible factor 1α (HIF1α) is a master regulator of numerous biological processes under low oxygen tensions. Yet, the mechanisms and biological consequences of aerobic HIF1α activation by intrinsic factors, particularly in primary cells remain elusive. Here, we show that HIF1α signaling is activated in several human primary vascular cells under ambient oxygen tensions, and in vascular smooth muscle cells (VSMCs) of normal human lung tissue, which contributed to a relative resistance to further enhancement of glycolytic activity in hypoxia. Mechanistically, aerobic HIFα activation is mediated by paracrine secretion of three branched chain α-ketoacids (BCKAs), which suppress prolyl hydroxylase domain-containing protein 2 (PHD2) activityviadirect inhibition andvialactate dehydrogenase A (LDHA)-mediated generation of L-2-hydroxyglutarate (L2HG). Metabolic dysfunction induced by BCKAs was observed in the lungs of rats with pulmonary arterial hypertension (PAH) and in pulmonary artery smooth muscle cells (PASMCs) from idiopathic PAH patients. BCKA supplementation stimulated glycolytic activity and promoted a phenotypic switch to the synthetic phenotype in PASMCs of normal and PAH subjects. In summary, we identify BCKAs as novel signaling metabolites that activate HIF1α signaling in normoxia and that the BCKA-HIF1α pathway modulates VSMC function and may be relevant to pulmonary vascular pathobiology.
CENP-C-Mis12 complex establishes a regulatory loop through Aurora B for chromosome segregation
Authors: Kong Weixia , Hara Masatoshi , Tokunaga Yurika , Okumura Kazuhiro , Hirano Yasuhiro , Miao Jiahang , Takenoshita Yusuke , Hashimoto Masakazu , Sasaki Hiroshi , Fujimori Toshihiko , Wakabayashi Yuichi , Fukagawa Tatsuo 
Published: May 2024

SummaryEstablishing the correct kinetochore-microtubule attachment is crucial for faithful chromosome segregation. The kinetochore has various regulatory mechanisms for establishing correct bipolar attachment. However, how the regulations are coupled is not fully understood. Here, we demonstrate a regulatory loop between the kinetochore protein CENP-C and Aurora B kinase, which is critical for the error correction of kinetochore-microtubule attachment. This regulatory loop is mediated through the binding of CENP-C to the outer kinetochore Mis12 complex (Mis12C). Although the Mis12C binding region of CENP-C is dispensable for mouse development and proliferation in human RPE-1 cells, those cells lacking this region display increased mitotic defects. The CENP-C-Mis12C interaction facilitates the centromeric recruitment of Aurora B and the mitotic error correction in human cells. Given that Aurora B reinforces the CENP-C-Mis12C interaction, our findings reveal a positive regulatory loop between Aurora B recruitment and the CENP-C-Mis12C interaction, which ensures chromosome bi-orientation for accurate chromosome segregation.
Fabrication, evolution, and mutual conversion of D-fucose-activatable and -repressible acetyltransferase upon mutations
Authors: Yanai Yuki , Tsukada Miyu , Kimura Yuki , Umeno Daisuke 
Published: May 2024

AbstractThe fusion of different proteins can result in the linkage-dependent emergence of molecular switches. In cases where allosteric regulation is designed between the input and output modules of fusion proteins, it is hard to predict whether on-switching or off-switching will occur. However, binding-induced folding, a non-allosteric molecular switch mechanism, has the potential to quickly establish a mutually regulatory relationship between the two fused proteins, in the way whether on-switching or off-switching will occur would be predictable. We inserted chloramphenicol acetyltransferase (CAT) fromE. coliinto a loop of a D-fucose-responsive mutant of transcription factor AraC, using linker libraries with various lengths. We found that on-switches tend to emerge when two proteins are fused with a small pitch gap at the junction, while fusion designs with a large pitch gap result in the frequent emergence of off-switches. Both types of switches rapidly evolved their switching efficiency upon mutations, establishing the D-fucose-on and -off regulation of CAT activity without disrupting the D-fucose-inducible logic of AraC function. To our surprise, both one-input/two-output split gates thus obtained could be easily inter-converted upon mutations. Through mutations, proteins not only frequently acquire properties as binding-induced folders, but also rapidly establish and evolve a mutual regulatory relationship with unrelated fusion partners, as well as transform their regulatory logic.
AAV Capsid Screening for Translational Pig Research Using a Mouse Xenograft Liver Model
Authors: Willimann Melanie , Tiyaboonchai Amita , Adachi Kei , Li Bin , Waldburger Lea , Nakai Hiroyuki , Grompe Markus , Thöny Beat 
Published: May 2024

AbstractIn gene therapy, delivery vectors are a key component for successful gene delivery and safety, based on which adeno-associated viruses (AAVs) gained popularity in particular for the liver, but also for other organs. Traditionally, rodents have been used as animal models to develop and optimize treatments, but species and organ specific tropism of AAV desire large animal models more closely related to humans for preclinical in-depth studies. Relevant AAV variants with the potential for clinical translation in liver gene therapy were previously evolvedin vivoin a xenogeneic mouse model transplanted with human hepatocytes. Here, we selected and evaluated efficient AAV capsids using chimeric mice with a >90% xenografted pig hepatocytes. The pig is a valuable preclinical model for therapy studies due to its anatomic and immunological similarities to humans. Using a DNA-barcoded recombinant AAV library containing 47 different capsids and subsequent Illumina sequencing of barcodes in the AAV vector genome DNA and transcripts in the porcine hepatocytes, we found the AAVLK03 and AAVrh20 capsid to be the most efficient delivery vectors regarding transgene expression in porcine hepatocytes. In attempting to validate these findings with primary porcine hepatocytes, we observed capsid-specific differences in cell entry and transgene expression efficiency where the AAV2, AAVAnc80, and AAVDJ capsids showed superior efficiency to AAVLK03 and AAVrh20. This work highlights intricacies ofin vitrotesting with primary hepatocytes and the requirements for suitable pre-clinical animal models but suggests the chimeric mouse to be a valuable model to predict AAV capsids to transduce porcine hepatocytes efficiently.
Bright New Resources for Syphilis Research: Genetically Encoded Fluorescent Tags forTreponema pallidumand Sf1Ep Cells
Authors: Grillová Linda , Romeis Emily , Lieberman Nicole A. P. , Tantalo Lauren C. , Xu Linda H. , Molini Barbara , Trejos Aldo T. , Lacey George , Goulding David , Thomson Nicholas R. , Greninger Alexander L. , Giacani Lorenzo 
Published: May 2024

SUMMARYThe recently discovered methodologies to cultivate and genetically manipulateTreponema pallidumsubsp.pallidum(T. pallidum) have significantly helped syphilis research, allowing thein vitroevaluation of antibiotic efficacy, performance of controlled studies to assess differential treponemal gene expression, and generation of loss-of-function mutants to evaluate the contribution of specific genetic loci toT. pallidumvirulence. Building on this progress, we engineered theT. pallidumSS14 strain to express a red-shifted Green Fluorescent Protein (GFP) and Sf1Ep cells to express mCherry and blue fluorescent protein (BFP) for enhanced visualization. These new resources improve microscopy- and cell sorting-based applications forT. pallidum, better capturing the physical interaction between the host and pathogen, among other possibilities. Continued efforts to develop and share new tools and resources are required to help our overall knowledge ofT. pallidumbiology and syphilis pathogenesis reach that of other bacterial pathogens, including spirochetes.Graphical abstractBy employing genetic engineering,T. pallidumwas modified to express GFP, and Sf1Ep cells to express mCherry on the cytoplasmic membrane and BFP in the nucleus. These new resources for syphilis research will facilitate experimental designs to better define the complex interplay betweenT. pallidumand the host during infection.
The role of Tyr34 in proton-coupled electron transfer of human manganese superoxide dismutase
Authors: Azadmanesh Jahaun , Slobodnik Katelyn , Struble Lucas R. , Cone Erika A. , Dasgupta Medhanjali , Lutz William E. , Kumar Siddhartha , Natarajan Amarnath , Coates Leighton , Weiss Kevin L. , Myles Dean A. A. , Kroll Thomas , Borgstahl Gloria E. O. 
Published: May 2024

ABSTRACTHuman manganese superoxide dismutase (MnSOD) plays a crucial role in controlling levels of reactive oxygen species (ROS) by converting superoxide (O2•−) to molecular oxygen (O2) and hydrogen peroxide (H2O2) with proton-coupled electron transfers (PCETs). The reactivity of human MnSOD is determined by the state of a key catalytic residue, Tyr34, that becomes post-translationally inactivated by nitration in various diseases associated with mitochondrial dysfunction. We previously reported that Tyr34 has an unusual pKadue to its proximity to the Mn metal and undergoes cyclic deprotonation and protonation events to promote the electron transfers of MnSOD. To shed light on the role of Tyr34 MnSOD catalysis, we performed neutron diffraction, X-ray spectroscopy, and quantum chemistry calculations of Tyr34Phe MnSOD in various enzymatic states. The data identifies the contributions of Tyr34 in MnSOD activity that support mitochondrial function and presents a thorough characterization of how a single tyrosine modulates PCET catalysis.