bluuebunny/crossref_metadata_2025_split huggingface dataset:
Silent transcription intervals and translational bursting lead to diverse phenotypic switching
Authors: Yang Xiyan , Luo Songhao , Zhang Zhenquan , Wang Zihao , Zhou Tianshou , Zhang Jiajun 
Published: August 2022

ABSTRACTBimodality of gene expression, as a mechanism generating phenotypic diversity, enhances the survival of cells in a fluctuating environment. Growing experimental evidence suggests that silent transcription intervals and translational bursting play important roles in regulating phenotypic switching. Characterizing these kinetics is challenging. Here, we develop an interpretable and tractable model, the generalized telegraph model (GTM), which considers silent transcription intervals described by a general waiting-time distribution and translational bursting characterized by an arbitrary distribution. Using methods of queuing theory, we derive analytical expressions of all moment statistics and distribution of protein counts. We show that non-exponential inactive times and translational bursting can lead to two nonzero bimodalities that cannot be captured in the classical telegraph model (CTM). In addition, we find that both silent-intervals noise and translational burst-size noise can amplify gene expression noise, as well as induce diverse dynamic expressions. Our results not only provide an alternative mechanism for phenotypic switching driven by silent transcription intervals and translational bursting, but also can be used to infer complex promoter structures based on experimental data.SIGNIFICANCEUnderstanding how phenotypic diversity arises among isogenic cell populations is a fundamental problem in biology. Previous studies have shown that the bimodality of gene expression contributing to phenotypic variations is mostly caused by the intrinsic or extrinsic regulations of underlying systems. It is unclear whether bimodality occurs in the absence of these regulations. The CTM has made great success in interpreting many experimental phenomena, but it cannot capture the bimodal distributions with two nonzero peaks that have been demonstrated in experiments. In particular, recent single-cell studies have shown non-exponential inactive periods and non-geometric translational bursting in gene expression. How to model these kinetics is challenging. We develop a stochastic gene model, namely the GTM, to model the silent transcription intervals by a general waiting-time distribution and translational bursting by an arbitrary distribution. By mapping the GTM into a queuing model, we derive the steady-state distribution of gene products that can be used for analyzing phenotypic switching. We find that non-exponential inactive times and translational bursting can lead to two nonzero bimodalities that cannot be captured in the CTM. These results indicate that both silent transcription intervals and translational bursting have important roles in controlling cell phenotypic variations in fluctuating environments.
Relaxed targeting rules allow PIWI-clade Argonaute proteins to silence ever-mutating transposons
Authors: Gainetdinov Ildar , Cecchini Katharine , Vega-Badillo Joel , Bagci Ayca , Colpan Cansu , Arif Amena , Wu Pei-Hsuan , Zamore Phillip D. 
Published: August 2022

AbstractIn animals, piRNAs direct PIWI-clade Argonaute proteins to slice complementary transposon transcripts. Transposons can evade silencing through target site mutations. We report that PIWIs efficiently cleave transcripts only partially paired to their piRNA guide. Measurements of mouse PIWI protein affinity and cleavage rates for thousands of RNAs in vitro and in vivo show that PIWI slicing tolerates mismatches to any target nucleotide, including those flanking the scissile phosphate. Although piRNA 5’ terminal nucleotides accelerate target finding, they are dispensable for binding or catalysis—unlike AGO-clade Argonautes, which require uninterrupted siRNA:target pairing from the seed to the nucleotides past the scissile bond. PIWIs are thus better equipped than AGOs to target newly acquired or rapidly diverging endogenous transposons without recourse to novel small RNA guides.
A cryptic transactivation domain of EZH2 binds AR and AR’s splice variant promoting oncogene activation and tumorous transformation
Authors: Wang Jun , Park Kwang-Su , Yu Xufen , Gong Weida , Earp H. Shelton , Wang Gang Greg , Jin Jian , Cai Ling 
Published: August 2022

AbstractEnhancer of Zeste Homolog 2 (EZH2) and androgen receptor (AR) are crucial chromatin regulators involved in the development and/or progression of prostate tumor, including advanced castration-resistant prostate cancer (CRPC). To sustain prostate tumorigenicity, EZH2 establishes noncanonical biochemical interaction with AR for mediating oncogene activation, in addition to its canonical role as a transcriptional repressor and enzymatic subunit of Polycomb Repressive Complex 2 (PRC2). However, the molecular basis underlying non-canonical activities of EZH2 in prostate cancer remains elusive and therapeutic strategies for targeting EZH2:AR-mediated oncogene activation activities are also lacking. Here, we report that a cryptic transactivation domain of EZH2 (EZH2TAD) binds both AR and AR spliced variant 7 (AR-V7, an AR variant enriched in CRPC), mediating assembly and/or recruitment of transactivation-related machineries at genomic sites that lack PRC2 binding. Such noncanonical targets of EZH2:AR/AR-V7:(co)activators are enriched for the clinically-relevant oncogenes. We also show that EZH2TADis required for the chromatin recruitment of EZH2, for EZH2-mediated oncogene activation, and for CRPC growth in vitro and in vivo. To completely block EZH2’s multifaceted oncogenic activities in prostate cancer, we employed MS177, a recently developed proteolysis targeting chimera (PROTAC) of EZH2. Strikingly, MS177 achieved on-target depletion of both EZH2’s canonical (EZH2:PRC2) and noncanonical (EZH2TAD:AR/AR-V7:coactivators) complexes in prostate tumor, eliciting much more potent antitumor effects than the catalytic inhibitors of EZH2. Overall, this study reports previously unappreciated requirements of EZH2TADfor mediating EZH2’s noncanonical (co)activator recruitment and gene-activation functions in prostate tumor and suggests EZH2-targeting PROTACs as potentially attractive therapeutics for the treatment of aggressive prostate tumors that rely on the circuits wired by EZH2 and AR.
An investigation of the sex-specific genetic architecture of fitness inDrosophila melanogaster
Authors: Singh Amardeep , Hasan Asad , Agrawal Aneil F. 
Published: August 2022

AbstractIn dioecious populations, the sexes employ divergent reproductive strategies to maximize fitness and, as a result, genetic variants can affect fitness differently in males and females. Moreover, recent studies have highlighted an important role of the mating environment in shaping the strength and direction of sex-specific selection. Here, we measure adult fitness for each sex of 357 lines from theDrosophilaSynthetic Population Resource (DSPR) in two different mating environments. We analyze the data using three different approaches to gain insight into the sex-specific genetic architecture for fitness: classical quantitative genetics, genomic associations, and a mutational burden approach. The quantitative genetics analysis finds that, on average segregating genetic variation in this population has concordant fitness effects both across the sexes and across mating environments. We do not find specific genomic regions with strong associations with either sexually antagonistic (SA) or sexually concordant (SC) fitness effects, yet there is modest evidence of an excess of genomic regions with weak associations, both with SA and SC fitness effects. Our examination of mutational burden indicates stronger selection against indels and loss-of-function variants in females than males.
Parallel evolution of reduced cancer risk and tumor suppressor duplications in Xenarthra
Authors: Vazquez Juan Manuel , Pena Maria T. , Muhammad Baaqeyah , Kraft Morgan , Adams Linda B. , Lynch Vincent J. 
Published: August 2022

AbstractThe risk of developing cancer is correlated with body size and lifespan within species, but there is no correlation between cancer and either body size or lifespan between species indicating that large, long-lived species have evolved enhanced cancer protection mechanisms. Previously we showed that several large bodied Afrotherian lineages evolved reduced intrinsic cancer risk, particularly elephants and their extinct relatives (Proboscideans), coincident with pervasive duplication of tumor suppressor genes (Vazquez and Lynch 2021). Unexpectedly, we also found that Xenarthrans (sloths, armadillos, and anteaters) evolved very low intrinsic cancer risk. Here, we show that: 1) several Xenarthran lineages that independently evolved large bodies, long lifespans, and reduced intrinsic cancer risk; 2) reduced cancer risk in the stem lineages of Xenarthra and Pilosa occurred coincident with bursts of tumor suppressor gene duplications; 3) cells from sloths proliferate extremely slowly while Xenarthran cells induce apoptosis are very low levels of DNA damage; and 4) the prevalence of cancer is extremely low Xenarthrans, and cancer is nearly absent from armadillos. These data implicate the duplication of tumor suppressor genes in the evolution of remarkably large body sizes and decreased cancer risk in Xenarthrans and suggest they are a remarkably cancer resistant group of mammals.Abstract Figure
mRNA vaccines and hybrid immunity use different B cell germlines to neutralize Omicron BA.4 and BA.5
Authors: Andreano Emanuele , Paciello Ida , Pierleoni Giulio , Maccari Giuseppe , Antonelli Giada , Abbiento Valentina , Pileri Piero , Benincasa Linda , Giglioli Ginevra , Piccini Giulia , De Santi Concetta , Sala Claudia , Medini Duccio , Montomoli Emanuele , Maes Piet , Rappuoli Rino 
Published: August 2022

ABSTRACTSARS-CoV-2 omicron BA.4 and BA.5, characterized by high transmissibility and ability to escape natural and vaccine induced immunity, are rampaging worldwide. To understand the escape mechanisms, we tested the neutralizing activity against omicron BA.4 and BA.5 of a panel of 482 human monoclonal antibodies that had been isolated from people who received two or three mRNA vaccine doses or from people that had been vaccinated after infection. None of the antibodies isolated after two vaccine doses neutralized omicron BA.4 and BA.5, while these variants were neutralized by approximately 15% of antibodies obtained from people that received three doses or had been vaccinated after infection. Remarkably, the antibodies isolated after three vaccine doses targeted mainly the receptor binding domain (RBD) Class 1/2 epitope region and were encoded by the IGHV1-69 and IGHV3-66 B cell germlines, while the antibodies isolated after infection recognized mostly the RBD Class 3 epitope region and the NTD, and were encoded by the IGHV2-5;IGHJ4-1 and IGHV1-24;IGHJ4-1 germlines. The observation that mRNA vaccination and hybrid immunity elicit a different immunity against the same antigen is intriguing and its understanding may help to design the next generation of therapeutics and vaccines against COVID-19.
Oncogenic IDH mutations increase heterochromatin-related replication stress without impacting tumor mutation burden
Authors: Schvartzman Juan-Manuel , Forsyth Grace , Walch Henry , Chatila Walid , Santella Anthony , Menghrajani Kamal , Sánchez-Vega Francisco , Koche Richard , Thompson Craig B. 
Published: August 2022

SummaryOncogenic mutations in the metabolic enzyme isocitrate dehydrogenase 1 and 2 (IDH1/2) have been found in a number of liquid and solid tumors. Their pathogenic mechanism of action involves production of 2-hydroxyglutarate (2HG), an oncometabolite that acts in part by inhibiting members of a family of dioxygenases that modulate chromatin dynamics. Recent work has suggested that mutant IDH (mIDH) and 2HG also impact sensitivity to inhibitors of poly-ADP ribose polymerases (PARP) but the molecular basis for this sensitivity is unclear. Unlike PARP inhibitor-sensitive BRCA1/2 tumors which exhibit impaired homologous recombination, IDH-mutant tumors have a silent mutational profile and lack mutational signatures associated with impaired homologous recombination. Instead, 2HG-producing IDH mutations lead to heterochromatin-dependent slowing of DNA replication and increased replication stress, resulting in DNA double strand breaks. This replicative stress manifests as replication fork slowing but the breaks are repaired without a significant increase in the cellular mutation burden. Faithful resolution of replicative stress in IDH-mutant cells is dependent on poly-ADP ribosylation. Treatment with PARP inhibitors restores replication fork speed but results in incomplete repair of DNA breaks. These findings provide evidence of a requirement for PARP in the replication of heterochromatin and further validate PARP as a potential therapeutic target in IDH-mutant tumors.
Dynamic remodeling of fiber networks with stiff inclusions under compressive loading
Authors: Carroll Bobby , Thanh Minh-Tri Ho , Patteson Alison 
Published: August 2022

AbstractThe ability of tissues to sustain and withstand mechanical stress is critical to tissue development and healthy tissue maintenance. The mechanical properties of tissues are typically considered to be dominated by the fibrous extracellular matrix (ECM) component of tissues. Fiber network mechanics can capture certain mechanical features of tissues, such as shear strain stiffening, but is insufficient in describing the compressive response of certain tissues and blood clots that are rich in extracellular matrix. To understand the mechanical response of tissues, we employ a contemporary mechanical model, a fibrous network of fibrin embedded with inert bead inclusions that preserve the volume-conserving constraints of cells in tissues. Combining bulk mechanical rheology and a custom imaging device, we show that the presence of inclusions alters the local dynamic remodeling of the networks undergoing uniaxial compressive strains and demonstrate non-affine correlated motion within a fiber-bead network, predicted to stretch fibers in the network and lead to the ability of the network to stiffen under compression, a key feature of real tissues. These findings have important implications for understanding how local structural properties of cells and ECM fibers impact the bulk mechanical response of real tissues.
Intrinsically disordered regions that drive phase separation form a robustly distinct protein class
Authors: Ibrahim Ayyam Y. , Khaodeuanepheng Nathan P. , Amarasekara Dhanush L. , Correia John J. , Lewis Karen A. , Fitzkee Nicholas C. , Hough Loren E. , Whitten Steven T. 
Published: August 2022

AbstractLiquid-liquid phase separation (LLPS) of proteins is thought to be a primary driving force for the formation of membraneless organelles, which control a wide range of biological functions from stress response to ribosome biogenesis. LLPS of proteins in cells is primarily, though not exclusively, driven by intrinsically disordered (ID) domains. Accurate identification of ID regions (IDRs) that drive phase separation is important for testing the underlying mechanisms of phase separation, identifying biological processes that rely on phase separation, and designing sequences that modulate phase separation. To identify IDRs that drive phase separation, we first curated datasets of folded, ID, and phase-separating (PS) ID sequences. We then used these sequence sets to examine how broadly existing amino acids scales can be used to distinguish between the three classes of protein regions. We found that there are robust property differences between the classes and, consequently, that numerous combinations of amino acid property scales can be used to make robust predictions of LLPS. This result indicates that multiple, redundant mechanisms contribute to the formation of phase-separated droplets from IDRs. The top-performing scales were used to further optimize our previously developed predictor of PS IDRs, ParSe. We then modified ParSe to account for interactions between amino acids and obtained reasonable predictive power for mutations that have been designed to test the role of amino acid interactions in driving LLPS.
Urinary proteome changes during pregnancy in rats
Authors: Tang Shuxuan , Gao Youhe 
Published: August 2022

AbstractPregnancy involves a significant amount of physiological changes. A normal pregnancy is essential to ensure healthy maternal and fetal development. We sought to explore whether the urinary proteome could reflect the pregnancy process. Urine samples were collected from pregnant rats on gestational day 1, 4, 7, 11, 14, 16, 18, 20 (GD 1 d, GD 4 d, GD 7 d, GD 11 d, GD 14 d, GD 16 d, GD 18 d, GD 20 d), and control rats on days 0, 4, 7, 11, 14, 16, 18 and 20. The urinary proteome was profiled by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), and differential proteins were obtained by comparing the 0 d (GD 1 d) of the same group at each time point within the two groups. Through the analysis of the enriched pathways of differentially expressed proteins in the pregnant group, during the period from fertilization to implantation, many pathways related to embryo implantation and trophoblast differentiation were enriched on GD 1 d, GD 4 d and GD 7 d. In addition, the developmental process of the fetal rat heart such as heart looping and endocardial cushion formation, are consistent with the timing of previous studies; the developmental process of the lung and the development of the rat embryo alveoli before birth are consistent with the reported timing; and the developmental time of the rat embryo pancreas is also during the period of pancreatic cell proliferation and differentiation. These processes were enriched only in the pregnancy group and not in the control group. Furthermore, coagulation-associated pathways were found to be increasingly prominent before labor, which is consistent with the previously reported trend of increasing coagulation function during pregnancy. Our results indicated urinary proteome can reflect some embryonic developmental and maternal changes in rat pregnancy.
ICAN: interpretable cross-attention network for identifying drug and target protein interactions
Authors: Kurata Hiroyuki , Tsukiyama Sho 
Published: August 2022

AbstractDrug–target protein interaction (DTI) identification is fundamental for drug discovery and drug repositioning, because therapeutic drugs act on disease-causing proteins. However, the DTI identification process often requires expensive and time-consuming tasks, including biological experiments involving large numbers of candidate compounds. Thus, a variety of computation approaches have been developed. Of the many approaches available, chemo-genomics feature-based methods have attracted considerable attention. These methods compute the feature descriptors of drugs and proteins as the input data to train machine and deep learning models to enable accurate prediction of unknown DTIs. In addition, attention-based learning methods have been proposed to identify and interpret DTI mechanisms. However, improvements are needed for enhancing prediction performance and DTI mechanism elucidation. To address these problems, we developed an attention-based method designated the interpretable cross-attention network (ICAN), which predicts DTIs using the Simplified Molecular Input Line Entry System of drugs and amino acid sequences of target proteins. We optimized the attention mechanism architecture by exploring the cross-attention or self-attention, attention layer depth, and selection of the context matrixes from the attention mechanism. We found that a plain attention mechanism that decodes drug-related protein context features without any protein-related drug context features effectively achieved high performance. The ICAN outperformed state-of-the-art methods in several respects and revealed with statistical significance that some weighted sites in the cross-attention weight represent experimental binding sites, thus demonstrating the high interpretability of the results.Key pointsWe created the interpretable cross-attention network (ICAN), which is composed of nn.Embedding of FCS label-encoding vectors of SMILES of drugs and AA sequences of target proteins, cross-attention mechanisms, and a CNN output layer.ICAN decoded drug-related protein context features without any protein-related drug context features, achieving high prediction performance despite the plain attention mechanism.In comparison with seven state-of-the-art methods, ICAN provided the highest PRAUC for the imbalanced datasets (DAVIS and BindingDB).Statistical analysis of attention-weight matrixes revealed that some weighted attention sites corresponded to experimental binding sites, demonstrating the high interpretability achievable with ICAN.
Single-cell Spatial Explorer: Easy exploration of spatial and multimodal transcriptomics
Authors: Pont Frédéric , Cerapio Juan Pablo , Gravelle Pauline , Ligat Laetitia , Valle Carine , Sarot Emeline , Perrier Marion , Lopez Frédéric , Laurent Camille , Fournié Jean Jacques , Tosolini Marie 
Published: August 2022

AbstractThe development of single cell technologies yields large datasets of informations as diverse and multimodal as transcriptomes, immunophenotypes, and spatial position from tissue sections in the so-called ‘spatial transcriptomics’. Currently however, user-friendly, powerful, and free algorithmic tools for straightforward analysis of spatial transcriptomic datasets are scarce. Here, we introduce Single-Cell Spatial Explorer, an open-source software for multimodal exploration of spatial transcriptomics, examplified with 6 human and murine tissues datasets.
Application of the fluorescence-activating and absorption-shifting tag (FAST) for flow cytometry in methanogenic archaea
Authors: Adlung Norman , Scheller Silvan 
Published: August 2022

AbstractMethane-producing archaea play a crucial role in the global carbon cycle and are used for biotechnological fuel production. Methanogenic model organisms such as Methanococcus maripaludis and Methanosarcina acetivorans are biochemically characterized and can be genetically engineered using a variety of molecular tools. Methanogens’ anaerobic lifestyle and autofluorescence, however, restrict the use of common fluorescent reporter proteins (e.g., GFP and derivatives) which require oxygen for chromophore maturation. Here, we employ the tandem activation and absorption-shifting tag protein 2 (tdFAST2) which is fluorescent when the cell-permeable fluorescent ligand (fluorogen) 4-hydroxy-3,5-dimethoxybenzylidene rhodanine (HBR-3,5DOM) is present. tdFAST2 expression in M. acetivorans and M. maripaludis is not cytotoxic and tdFAST2:HBR-3,5DOM fluorescence can be clearly distinguished from the autofluorescence. In flow cytometry experiments, mixed methanogen cultures can be clearly distinguished which allows high-throughput investigations of dynamics within single and mixed cultures.ImportanceMethane-producing archaea play an essential role in the global carbon cycle and have a high potential for biotechnological applications such as biofuel production, carbon dioxide capture, and in electrochemical systems. The oxygen sensitivity and high autofluorescence hinder the use of common fluorescent proteins to study methanogens. By using the tdFAST2:HBR-3,5DOM fluorescence, which is functional also under anaerobic conditions and distinguishable from the autofluorescence, real-time reporter studies and high-throughput investigation of dynamics within (mixed) cultures via flow cytometry are possible. This will accelerate the exploitation of the methanogens’ biotechnological potential.