bluuebunny/crossref_metadata_2025_split huggingface dataset:
PRR14 organizes H3K9me3-modifed heterochromatin at the nuclear lamina
Authors: Kiseleva Anna A. , Cheng Yu-Chia , Smith Cheryl L. , Katz Richard A. , Poleshko Andrey 
Published: May 2022

ABSTRACTThe eukaryotic genome is organized in three dimensions within the nucleus. Transcriptionally active chromatin is spatially separated from silent heterochromatin, a large fraction of which is located at the nuclear periphery. However, the mechanisms by which chromatin is localized at the nuclear periphery remain poorly understood. Here we demonstrate that Proline Rich 14 (PRR14) protein specifically organizes H3K9me3-modified heterochromatin at the nuclear lamina. We show that PRR14 dynamically associates with both the nuclear lamina and heterochromatin, and is able to reorganize heterochromatin in the nucleus of interphase cells independent of mitosis. We demonstrate that PRR14 can bind all isoforms of heterochromatin protein 1 (HP1). We characterize two functional HP1-binding sites within PRR14 that contribute to its association with heterochromatin. Results of fluorescent recovery after photobleaching (FRAP) and super-resolution imaging indicate that PPR14 forms an anchoring surface for heterochromatin at the nuclear lamina where it interacts dynamically with HP1-associated, H3K9me3-modified chromatin. Our study reveals the mechanism through which PRR14 tethers heterochromatin to the nuclear lamina and we propose a model of dynamic heterochromatin organization at the nuclear periphery.
Maintaining a stable head direction representation in naturalistic visual environments
Authors: Haberkern Hannah , Chitnis Shivam S , Hubbard Philip M , Goulet Tobias , Hermundstad Ann M , Jayaraman Vivek 
Published: May 2022

ABSTRACTMany animals rely on a representation of head direction for flexible, goal-directed navigation. In insects, a compass-like head direction representation is maintained in a conserved brain region called the central complex. This head direction representation is updated by self-motion information and by tethering to sensory cues in the surroundings through a plasticity mechanism. However, under natural settings, some of these sensory cues may temporarily disappear—for example, when clouds hide the sun—and prominent landmarks at different distances from the insect may move across the animal’s field of view during translation, creating potential conflicts for a neural compass. We used two-photon calcium imaging in head-fixed Drosophila behaving in virtual reality to monitor the fly’s compass during navigation in immersive naturalistic environments with approachable local landmarks. We found that the fly’s compass remains stable even in these settings by tethering to available global cues, likely preserving the animal’s ability to perform compass-driven behaviors such as maintaining a constant heading.
Semi-supervised deep learning with graph neural network for cross-species regulatory sequence prediction
Authors: Mourad Raphaël 
Published: May 2022

AbstractGenome-wide association studies have systematically identified thousands of single nucleotide polymorphisms (SNPs) associated with complex genetic diseases. However, the majority of those SNPs were found in non-coding genomic regions, preventing the understanding of the underlying causal mechanism. Predicting molecular processes based on the DNA sequence represents a promising approach to understand the role of those non-coding SNPs. Over the past years, deep learning was successfully applied to regulatory sequence prediction. Such method required DNA sequences associated with functional data for training. However, the human genome has a finite size which strongly limits the amount of DNA sequence with functional data available for training. Conversely, the amount of mammalian DNA sequences is exponentially increasing due to ongoing large sequencing projects, but without functional data in most cases. Here, we propose a semi-supervised learning approach based on graph neural network which allows to borrow information from homologous mammal sequences during training. Our approach can be plugged into any existing deep learning model and showed improvements in many different situations, including classification and regression, and for different types of functional data.
Ultra-small bispecific fusion protein augments tumor penetration and treatment efficacy for pancreatic cancer
Authors: Wang Qian , Wang Jingyun , Yan Hao , Li Zheng , Wang Kun , Kang Feiyu , Tian Jie , Zhao Xinming 
Published: May 2022

AbstractPancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related deaths. Due to drugs’ low intrinsic anticancer activity and the unique physiological barrier of PDAC tumors, the once highly anticipated antibody-based pathway-targeted therapies have not achieved promising improvement in outcomes. Here, an ultra-small-sized bispecific fusion protein, termed Bi-fp50, that could largely enrich deep tumor tissue and effectively inhibit PDAC tumor growth was reported. The bispecific Bi-fp50 protein was constructed by a typical synthetic biology method that could efficiently target EGFR and VEGF of PDAC cells simultaneously in vitro and in vivo. For Bxpc3 and Aspc1 PDAC cells, the Bi-fp50 achieved a significant and synergistic therapeutic effect. Owing to the small size of only 50 kDa and the function of reducing the interstitial fluid pressure by vascular normalization, the Bi-fp50 showed enhanced penetration, considerable accumulation, and uniform distribution in tumor and subsequently led to effective inhibition of the growth of Bxpc3 cells-induced PDAC tumor in vivo. Furthermore, no noticeable side effect of Bi-fp50 was found in vitro and in vivo. This work demonstrates that the synthetic Bi-fp50 fusion protein could be used as a new effective pathway-specific targeted therapy for PDACs.
PPARγ/ETV2 Axis Regulates Endothelial-to-Mesenchymal Transition in Pulmonary Hypertension
Authors: Lee Dong Hun , Kim Minseong , Chang Sarah S. , Jang Andrew J. , Kim Juyoung , Ma Jing , Passineau Michael J. , Benza Raymond L. , Karmouty-Quintana Harry , Lam Wilbur A. , Sutliff Roy L. , Hart C. Michael , Park Changwon , Kang Bum-Yong 
Published: May 2022

ABSTRACTEndothelial-to-mesenchymal transition (EndoMT) plays an important role in pulmonary hypertension (PH). Also, the molecular mechanisms regulating EndoMT in PH remain to be defined. In this study, we first showed that reduced expression of the transcription factors ETV2 (ETS variant 2) and PPARγ (Peroxisome Proliferator-Activated Receptor gamma) along with reduced endothelial markers and increased EndoMT markers were consistently observed in lungs and pulmonary artery endothelial cells (PAECs) of idiopathic pulmonary arterial hypertension (IPAH) patients, in hypoxia-exposed mouse lungs, human PAECs, and in induced EndoMT cells. Base on this observation, we aimed to investigate the function of ETV2 and PPARγ in EndoMT. We have explored the function of ETV2 and PPARγ and its mechanism in PH using in Etv2+/- mice or PPARγ KO mice. Etv2+/- mice spontaneously developed PH and right ventricular hypertrophy, associated with increased EndoMT markers and decreased EC markers. PPARγ transcriptionally activated the ETV2 promoter. Endothelial PPARγ expression in mice is positively correlated with ETV2 expression, but inversely with EndoMT markers.Overexpression of ETV2 in hypoxia-exposed rat pulmonary artery led to vascular relaxation. We conclude that PPARγ-ETV2 signaling can function as a novel pathway in PH pathogenesis by attenuating EndoMT.
Endothelial neuropilin-1 and neuropilin-2 are essential for tumour angiogenesis
Authors: Benwell CJ , Johnson RT , Taylor JAGE , Price CA , Robinson SD 
Published: May 2022

AbstractNeuropilin (NRP) expression is highly correlated with poor outcome in multiple cancer subtypes. As known co-receptors for vascular endothelial growth factor receptors (VEGFRs), core drivers of angiogenesis, past investigations have alluded to their functional roles in facilitating tumorigenesis by promoting invasive vessel growth. Despite this, it remains unclear as to whether NRP1 and NRP2 act in a synergistic manner to enhance pathological angiogenesis. Here we demonstrate, using NRP1ECKO, NRP2ECKO and NRP1/NRP2ECKO mouse models, that maximum inhibition of primary tumour development and angiogenesis is only achieved when both endothelial NRP1 and NRP2 are targeted simultaneously. Metastasis and secondary site angiogenesis were also significantly inhibited in NRP1/NRP2ECKO animals. Mechanistic studies revealed that co-depleting NRP1 and NRP2 in mouse-microvascular endothelial cells (ECs) stimulates rapid shuttling of VEGFR-2 to Rab7+ endosomes for proteosomal degradation. Our results highlight the importance of targeting both NRP1 and NRP2 to modulate tumour angiogenesis.
Nitrogenase resurrection and the evolution of a singular enzymatic mechanism
Authors: Garcia Amanda K. , Harris Derek F. , Rivier Alex J. , Carruthers Brooke M. , Pinochet-Barros Azul , Seefeldt Lance C. , Kaçar Betül 
Published: May 2022

ABSTRACTThe planetary biosphere is powered by a suite of key metabolic innovations that emerged early in the history of life. However, it is unknown whether life has always followed the same set of strategies for performing these critical tasks. Today, microbes access atmospheric sources of bioessential nitrogen through the activities of just one family of enzymes, nitrogenases. Here, we show that the only dinitrogen reduction mechanism known to date is an ancient feature conserved from nitrogenase ancestors. We designed a paleomolecular engineering approach wherein ancestral nitrogenase genes were phylogenetically reconstructed and inserted into the genome of the diazotrophic bacterial model,Azotobacter vinelandii, enabling an integrated assessment of bothin vivofunctionality and purified nitrogenase biochemistry. Nitrogenase ancestors are active and robust to variable incorporation of one or more ancestral protein subunits. Further, we find that all ancestors exhibit the reversible enzymatic mechanism for dinitrogen reduction, specifically evidenced by hydrogen inhibition, that is also exhibited by extantA. vinelandiinitrogenase isozymes. Our results suggest that life may have been constrained in its sampling of protein sequence space to catalyze one of the most energetically challenging biochemical reactions in nature. The experimental framework established here is essential for probing how nitrogenase functionality has been shaped within a dynamic, cellular context to sustain a globally consequential metabolism.IMPACT STATEMENTThe enzymatic mechanism for dinitrogen reduction is an ancient feature of nitrogenases that persisted over hundreds of millions of years.
Short-term monocular deprivation boosts neural responsiveness to audio-visual events for the undeprived eye
Authors: Federici A. , Bernardi G. , Senna I. , Fantoni M. , Ernst M.O. , Ricciardi E. , Bottari D. 
Published: May 2022

AbstractA brief period of monocular deprivation (MD) induces short-term plasticity of the adult visual system. Whether MD elicits changes beyond visual processing is yet unclear. Here, we assessed the specific impact of MD on multisensory processes. Neural oscillations associated with visual and audio-visual processing were measured for both the deprived and the undeprived eye. Results revealed that MD changed neural activities associated with unimodal and multisensory processes in an eye-specific manner. Selectively for the deprived eye, alpha activity was reduced within the first 150 ms of visual processing. Conversely, gamma activity was enhanced in response to audio-visual events only for the undeprived eye within 100-300 ms after stimulus onset. The analysis of gamma responses to unimodal auditory events revealed that MD elicited a crossmodal upweighting for the undeprived eye. Distributed source modeling suggested that the right parietal cortex played a major role in all neural effects induced by MD. Finally, visual and audio-visual processing alterations emerged selectively for the induced (but not the evoked) component of the neural oscillations, indicating a major role of feedback connectivity. These findings support a model in which MD increases excitability to visual events for the deprived eye and to audio-visual and auditory events for the undeprived eye. On the one hand, these results reveal the causal impact of MD on both unisensory and multisensory processes but with distinct frequency-specific profiles. On the other hand, they highlight the feedback nature of short-term neural plasticity. Overall this study shed light on the high flexibility and interdependence of unimodal and multisensory functions.Highlights- We unveiled the impact of temporary MD on visual and audio-visual processing- MD enhanced visual excitability for the deprived eye- MD boosted neural responses to audio-visual events for the undeprived eye- Analyses of auditory processing revealed crossmodal effects following MD- Short-term MD primarily affects induced, non-phase-locked, oscillatory activity
scMoMaT: Mosaic integration of single cell multi-omics data using matrix tri-factorization
Authors: Zhang Ziqi , Sun Haoran , Mariappan Ragunathan , Chen Xi , Chen Xinyu , Jain Mika S , Efremova Mirjana , Teichmann Sarah A , Rajan Vaibhav , Zhang Xiuwei 
Published: May 2022

ABSTRACTSingle cell data integration methods aim to integrate cells across data batches and modalities, and obtain a comprehensive view of the cells. Single cell data integration tasks can be categorized into horizontal, vertical, diagonal, and mosaic integration, where mosaic integration is the most general and challenging case with few methods developed. We propose scMoMaT, a method that is able to integrate single cell multi-omics data under the mosaic integration scenario using matrix tri-factorization. During integration, scMoMaT is also able to uncover the cluster specific bio-markers across modalities. These multi-modal bio-markers are used to interpret and annotate the clusters to cell types. Moreover, scMoMaT can integrate cell batches with unequal cell type compositions. Applying scMoMaT to multiple real and simulated datasets demonstrated these features of scMoMaT and showed that scMoMaT has superior performance compared to existing methods. We also show that integrated cell embedding combined with learned bio-markers leads to cell type annotations of higher quality or resolution compared to their original annotations.
RNA sequence to structure analysis from comprehensive pairwise mutagenesis of multiple self-cleaving ribozymes
Authors: Roberts Jessica M. , Beck James D. , Pollock Tanner B. , Bendixsen Devin P. , Hayden Eric J. 
Published: May 2022

ABSTRACTSelf-cleaving ribozymes are RNA molecules that catalyze the cleavage of their own phosphodiester backbones. These ribozymes are found in all domains of life and are also a tool for biotechnical and synthetic biology applications. Self-cleaving ribozymes are also an important model of sequence to function relationships for RNA because their small size simplifies synthesis of genetic variants and self-cleaving activity is an accessible readout of the functional consequence of the mutation. Here we used a high-throughput experimental approach to determine the relative activity for every possible single and double mutant of five self-cleaving ribozymes. From this data, we comprehensively identified non-additive effects between pairs of mutations (epistasis) for all five ribozymes. We analyzed how changes in activity and trends in epistasis map to the ribozyme structures. The variety of structures studied provided opportunities to observe several examples of common structural elements, and the data was collected under identical experimental conditions to enable direct comparison. Heat-map based visualization of the data revealed patterns indicating structural features of the ribozymes including paired regions, unpaired loops, non-canonical structures and tertiary structural contacts. The data also revealed signatures of functionally critical nucleotides involved in catalysis. The results demonstrate that the data sets provide structural information similar to chemical or enzymatic probing experiments, but with additional quantitative functional information. The large-scale data sets can be used for models predicting structure and function and for efforts to engineer self-cleaving ribozymes.
Strain level centromere variation influences CENP-A association dynamics and centromere function
Authors: Arora Uma P. , Sullivan Beth A. , Dumont Beth L. 
Published: May 2022

ABSTRACTCentromeres are rapidly evolving chromatin domains that fulfill essential roles in chromosome segregation. Rapid centromere sequence evolution imposes strong selection for compensatory changes in centromere-associated kinetochore proteins, leading to striking co-evolutionary trends across species. However, it remains unknown whether within species centromere sequence diversity leads to functional differences in kinetochore protein association. House mice (Mus musculus) exhibit significant variation in centromere satellite array size and sequence heterogeneity, but the amino acid sequence of CENP-A, a centromere-specific histone variant that specifies centromere identity, is conserved. We hypothesize that centromere satellite sequence variation leads to differences in the localization of CENP-A among house mice, with potential consequences for meiotic drive and genome stability. Using CENP-A chromatin immunoprecipitation with a customized k-mer based, reference-blind bioinformatic analysis strategy, we compare the CENP-A sequence association landscape in four diverse inbred mouse strains (C57BL/6J, CAST/EiJ, LEWES/EiJ, and PWK/PhJ). We uncover significant strain-level diversity in CENP-A associated sequences, with more closely related strains exhibiting more similar CENP-A association profiles. LEWES/EiJ and CAST/EiJ show mild association of CENP-A with the pericentromeric satellite repeat, countering the prevailing notion that functional centromere size is solely determined by the size of the minor satellite array. Strain-specific CENP-A association profiles are enriched for unique suites of transcription factor motifs, hinting at strain differences in centromere transcription. Given the importance of centromere-CENP-A association and centromere transcription for both kinetochore assembly and chromosome segregation fidelity, our findings suggest a potential mechanism for centromere-mediated variation in genome stability among inbred mouse strains.
A computational proposal for tracking multiple molecules in a multi-focus confocal setup
Authors: Jazani Sina , Xu Lance W.Q. , Sgouralis Ioannis , Shepherd Douglas P. , Pressé Steve 
Published: May 2022

AbstractTracking single molecules continues to provide new insights into the fundamental rules governing biological function. Despite continued technical advances in fluorescent and non-fluorescent labeling as well as data analysis, direct observations of trajectories and interactions of multiple molecules in dense environments remain aspirational goals. While confocal methods provide a means to deduce dynamical parameters with high temporal resolution, such as diffusion coefficients, they do so at the expense of spatial resolution. Indeed, on account of a confocal volume’s symmetry, typically only distances from the center of the confocal spot can be deduced. Motivated by the need for true three dimensional high speed tracking in densely labeled environments, we propose a computational tool for tracking many fluorescent molecules traversing multiple, closely spaced, confocal measurement volumes providing independent observations. Various realizations of this multiple confocal volumes strategy have previously been used for long term, large area, tracking of one fluorescent molecule in three dimensions. What is more, we achieve tracking by directly using single photon arrival times to inform our likelihood and exploit Hamiltonian Monte Carlo to efficiently sample trajectories from our posterior within a Bayesian nonparametric paradigm. A nonparametric paradigm here is warranted as the number of molecules present are, themselves,a prioriunknown. Taken together, we provide a computational framework to infer trajectories of multiple molecules at once, below the diffraction limit (the width of a confocal spot), in three dimensions at sub-millisecond or faster time scales.
Liver humanized NSG-PiZ mice support the study of chronic hepatitis B virus infection and antiviral therapies
Authors: Colón-Thillet Rossana , Stone Daniel , Loprieno Michelle A. , Klouser Lindsay , Roychoudhury Pavitra , Santo Tracy K. , Xie Hong , Stensland Larry , Upham Sarah L. , Pepper Greg , Huang Meei-Li , Aubert Martine , Jerome Keith R. 
Published: May 2022

AbstractHepatitis B virus (HBV) is a pathogen of major public health importance that is largely incurable once a chronic hepatitis B (CHB) infection is established. Only humans and great apes are fully permissive to HBV replication, and this species restriction has impacted HBV research by limiting the utility of small animal models of HBV. To combat the species restriction of HBV and enable more HBV studies in vivo, liver-humanized mouse models have been developed that harbor primary human hepatocytes (PHH) and are fully permissive to HBV infection and replication. Unfortunately, these models can be difficult to establish and are expensive commercially, which has limited their academic use. As an alternative mouse model to study HBV, we evaluated liver-humanized NSG-PiZ mice and showed that they are fully permissive to HBV and can develop CHB. Mice were infected with a precore mutant clinical isolate that has now been serially passaged through 3 generations of mice without loss of fitness. HBV selectively replicates in hCK18+ human hepatocytes within chimeric livers, and HBV+ mice secrete infectious virions and HBsAg into blood, while also harboring covalently closed circular DNA (cccDNA). HBV+ mice remain viremic for at least 169 days, which should enable the study of new curative therapies targeting CHB and respond to antiviral entecavir therapy. The extended duration of viremia is sufficient to enable the study of established and new therapeutic approaches targeting CHB. Furthermore, HBV+ PHH in NSG-PiZ mice can be transduced by the hepatotropic AAV3b and AAV.LK03 vector capsids, which should enable the study of curative gene therapies that target CHB. In summary, our data demonstrates that liver humanized NSG-PiZ mice can be used as a robust and cost-effective alternative to existing CHB models and may enable more academic research labs to study HBV disease pathogenesis and antiviral therapy in a setting that is fully permissive to ongoing replication.