bluuebunny/crossref_metadata_2025_split huggingface dataset:
LncRNA HOXA11-AS promotes glioma malignant phenotypes and reduces its sensitivity to ROS via Tpl2-MEK1/2-ERK1/2 pathway
Authors: Wei Cheng , Zhang Xiaoyang , Peng Dazhao , Zhang Xu , Guo Haizhen , Lu Yalin , Luo Lin , Wang Bo , Li Zesheng , He Yingjie , Du Xuezhi , Zhang Shu , Liang Hao , Li Shenghui , Wang Sheng , Han Lei , Zhang Jianning 
Published: November 2022

AbstractOur previous studies showed that dysregulation of the long noncoding RNA (lncRNA) HOXA11-AS plays an important role in the development of glioma. However, the molecular mechanism of HOXA11-AS in glioma remains largely unknown. In this study, we explore the molecular mechanisms underlying abnormal expression and biological function of HOXA11-AS for identifying novel therapeutic targets in glioma. The expression of HOXA11-AS, and the relationship between HOXA11-AS and the prognosis of glioma patients were analyzed using databases and glioma samples. Transcriptomics, proteomics, RIP, ChIRP, luciferase, and ChIP assays were used to explore its upstream and downstream targets in glioma. The role of HOXA11-AS in regulating the sensitivity of glioma cells to reactive oxygen species (ROS) was also investigated in vitro and in vivo. We found that HOXA11-AS was significantly upregulated in glioma, and was correlated with the poor prognosis of glioma patients. Ectopic expression of HOXA11-AS promoted the proliferation, migration, and invasion of glioma cells in vitro and in vivo. Mechanistically, HOXA11-AS acted as a molecular sponge for let-7b-5p in the cytoplasm, antagonizing its ability to repress the expression of CTHRC1, which activates the β-catenin/c-Myc pathway. In addition, c-Myc was involved in HOXA11-AS dysregulation via binding to its promoter region to form a self-activating loop. HOXA11-AS, functioned as a scaffold in the nucleus, also recruited transcription factor c-Jun to the Tpl2 promoter, which activates the Tpl2-MEK1/2-ERK1/2 pathway to promote ROS resistance in glioma. Importantly, HOXA11-AS knockdown could sensitize glioma cells to ROS. Above, oncogenic HOXA11-AS upregulates CTHRC1 expression as a ceRNA by adsorbing let-7b-5p, which activates c-Myc to regulate itself transcription. HOXA11-AS knockdown promotes ROS sensitivity in glioma cells by regulating the Tpl2-MEK1/2-ERK1/2 axis, demonstrating that HOXA11-AS may be translated to increase ROS sensitivity therapeutically.
Identification of TFPI as a receptor reveals recombination-driven receptor switching in Clostridioides difficile toxin B variants
Authors: Tian Songhai , Xiong Xiaozhe , Zeng Ji , Wang Siyu , Tremblay Benjamin Jean-Marie , Chen Peng , Chen Baohua , Liu Min , Chen Pengsheng , Sheng Kuanwei , Zeve Daniel , Qi Wanshu , Breault David T. , Rodríguez César , Gerhard Ralf , Jin Rongsheng , Doxey Andrew C. , Dong Min 
Published: November 2022

AbstractToxin B (TcdB) is a major exotoxin responsible for diseases associated with Clostridioides difficile infection. Its sequence variations among clinical isolates may contribute to the difficulty in developing effective therapeutics. Here, we investigate receptor-binding specificity of major TcdB subtypes (TcdB1 to TcdB12). We find that representative members of subtypes 2, 4, 7, 10, 11, and 12 do not recognize the established host receptor, frizzled proteins (FZDs). Using a genome-wide CRISPR-Cas9-mediated screen, we identify tissue factor pathway inhibitor (TFPI) as a host receptor for TcdB4. TFPI is recognized by a region in TcdB4 that is homologous to the FZD-binding site in TcdB1. Analysis of 206 TcdB variant sequences reveals a set of six residues within this receptor-binding site that defines a TFPI binding-associated haplotype (designated B4/B7) that is present in all TcdB4 members, a subset of TcdB7, and one member of TcdB2. Intragenic micro-recombination (IR) events have occurred around this receptor-binding region in TcdB7 and TcdB2 members, resulting in either TFPI- or FZD-binding capabilities. Introduction of B4/B7-haplotype residues into TcdB1 enables dual recognition of TFPI and FZDs. Finally, TcdB10 also recognizes TFPI, although it does not belong to the B4/B7 haplotype, and shows species selectivity: it recognizes TFPI of chicken and to a lesser degree mouse, but not human, dog, or cattle versions. These findings identify TFPI as a TcdB receptor and reveal IR-driven changes on receptor-specificity among TcdB variants.
The influence of recent and future climate change on spring Arctic cyclones
Authors: Parker Chelsea L. , Mooney Priscilla A. , Webster Melinda A. , Boisvert Linette N. 
Published: November 2022

AbstractIn recent decades, the Arctic has experienced rapid atmospheric warming and sea ice loss, with an ice-free Arctic projected by the end of this century. Cyclones are synoptic weather events that transport heat and moisture into the Arctic, and have complex impacts on sea ice, and the local and global climate. However, the effect of a changing climate on Arctic cyclone behavior remains poorly understood. This study uses high resolution (4 km), regional modeling techniques and downscaled global climate reconstructions and projections to examine how recent and future climatic changes alter cyclone behavior. Results suggest that recent climate change has not yet had an appreciable effect on Arctic cyclone characteristics. However, future sea ice loss and increasing surface temperatures drive large increases in the near-surface temperature gradient, sensible and latent heat fluxes, and convection during cyclones. The future climate can alter cyclone trajectories and increase and prolong intensity with greatly augmented wind speeds, temperatures, and precipitation. Such changes in cyclone characteristics could exacerbate sea ice loss and Arctic warming through positive feedbacks. The increasing extreme nature of these weather events has implications for local ecosystems, communities, and socio-economic activities.
Design of synthetic collagens that assemble into supramolecular banded fibers as a functional biomaterial testbed
Authors: Hu Jinyuan , Li Junhui , Jiang Jennifer , Wang Lingling , Roth Jonathan , McGuinness Kenneth N. , Baum Jean , Dai Wei , Sun Yao , Nanda Vikas , Xu Fei 
Published: November 2022

AbstractCollagens are the most abundant proteins of the extracellular matrix, and the hierarchical folding and supramolecular assembly of collagens into banded fibers is essential for mediating cell-matrix interactions and tissue mechanics. Collagen extracted from animal tissues is a valuable commodity, but suffers from safety and purity issues, limiting its biomaterials applications. Synthetic collagen biomaterials could address these issues, but their construction requires molecular-level control of folding and supramolecular assembly into ordered banded fibers, comparable to those of natural collagens. Here, we show an innovative class of banded fiber-forming synthetic collagens that recapitulate the morphology and some biological properties of natural collagens. The synthetic collagens comprise a functional-driver module that is flanked by adhesive modules that effectively promote their supramolecular assembly. Multiscale simulations support a plausible molecular-level mechanism of supramolecular assembly, allowing precise design of banded fiber morphology. We also experimentally demonstrate that synthetic fibers stimulate osteoblast differentiation at levels comparable to natural collagen. This work thus deepens understanding of collagen biology and disease by providing a ready source of safe, functional biomaterials that bridge the current gap between the simplicity of peptide biophysical models and the complexity of in vivo animal systems.
Regiospecific α-methylene functionalisation of tertiary amines with alkynes via Au-catalysed concerted one-proton/two-electron transfer to O2
Authors: Yatabe Takafumi , Yamaguchi Kazuya 
Published: November 2022

AbstractRegioselective transformations of tertiary amines, which are ubiquitously present in natural products and drugs, are important for the development of novel medicines. In particular, the oxidative α-C–H functionalisation of tertiary amines with nucleophiles via iminium cations is a promising approach because, theoretically, there is almost no limit to the type of amine and functionalisation. However, most of the reports on oxidative α-C–H functionalisations are limited to α-methyl-selective or non-selective reactions, despite the frequent appearance of α-methylene-substituted amines in pharmaceutical fields. Herein, we develop an unusual oxidative regiospecific α-methylene functionalisation of structurally diverse tertiary amines with alkynes to synthesise various propargylic amines using a catalyst comprising Zn salts and hydroxyapatite-supported Au nanoparticles. Thorough experimental investigations suggest that the unusual α-methylene regiospecificity is probably due to a concerted one-proton/two-electron transfer from amines to O2 on the Au nanoparticle catalyst, which paves the way to other α-methylene-specific functionalisations.
Symmetry-breaking in patch formation on triangular gold nanoparticles by asymmetric polymer grafting
Authors: Kim Ahyoung , Vo Thi , An Hyosung , Banerjee Progna , Yao Lehan , Zhou Shan , Kim Chansong , Milliron Delia J. , Glotzer Sharon C. , Chen Qian 
Published: November 2022

AbstractSynthesizing patchy particles with predictive control over patch size, shape, placement and number has been highly sought-after for nanoparticle assembly research, but is fraught with challenges. Here we show that polymers can be designed to selectively adsorb onto nanoparticle surfaces already partially coated by other chains to drive the formation of patchy nanoparticles with broken symmetry. In our model system of triangular gold nanoparticles and polystyrene-b-polyacrylic acid patch, single- and double-patch nanoparticles are produced at high yield. These asymmetric single-patch nanoparticles are shown to assemble into self-limited patch‒patch connected bowties exhibiting intriguing plasmonic properties. To unveil the mechanism of symmetry-breaking patch formation, we develop a theory that accurately predicts our experimental observations at all scales—from patch patterning on nanoparticles, to the size/shape of the patches, to the particle assemblies driven by patch‒patch interactions. Both the experimental strategy and theoretical prediction extend to nanoparticles of other shapes such as octahedra and bipyramids. Our work provides an approach to leverage polymer interactions with nanoscale curved surfaces for asymmetric grafting in nanomaterials engineering.
A biomimetic ocular prosthesis system: emulating autonomic pupil and corneal reflections
Authors: Kim Seongchan , Choi Yoon Young , Kim Taewan , Kim Yong Min , Ho Dong Hae , Choi Young Jin , Roe Dong Gue , Lee Ju-Hee , Park Joongpill , Choi Ji-Woong , Kim Jeong Won , Park Jin-Hong , Jo Sae Byeok , Moon Hong Chul , Jeong Sohee , Cho Jeong Ho 
Published: November 2022

AbstractThe human light modulation response allows humans to perceive objects clearly by receiving the appropriate amount of light from the environment. This paper proposes a biomimetic ocular prosthesis system that mimics the human light modulation response capable of pupil and corneal reflections. First, photoinduced synaptic properties of the quantum dot embedded photonic synapse and its biosimilar signal transmission is confirmed. Subsequently, the pupillary light reflex is emulated by incorporating the quantum dot embedded photonic synapse, electrochromic device, and CMOS components. Moreover, a solenoid-based eyelid is connected to the pupillary light reflex system to emulate the corneal reflex. The proposed ocular prosthesis system represents a platform for biomimetic prosthesis that can accommodate an appropriate amount of stimulus by self-regulating the intensity of external stimuli.
Bidirectional and parallel relationships in macaque face circuit revealed by fMRI and causal pharmacological inactivation
Authors: Liu Ning , Behrmann Marlene , Turchi Janita N. , Avidan Galia , Hadj-Bouziane Fadila , Ungerleider Leslie G. 
Published: November 2022

AbstractAlthough the presence of face patches in primate inferotemporal (IT) cortex is well established, the functional and causal relationships among these patches remain elusive. In two monkeys, muscimol was infused sequentially into each patch or pair of patches to assess their respective influence on the remaining IT face network and the amygdala, as determined using fMRI. The results revealed that anterior face patches required input from middle face patches for their responses to both faces and objects, while the face selectivity in middle face patches arose, in part, from top-down input from anterior face patches. Moreover, we uncovered a parallel fundal-lateral functional organization in the IT face network, supporting dual routes (dorsal-ventral) in face processing within IT cortex as well as between IT cortex and the amygdala. Our findings of the causal relationship among the face patches demonstrate that the IT face circuit is organized into multiple functional compartments.
Costimulation blockade in combination with IL-2 permits regulatory T cell sparing immunomodulation that inhibits autoimmunity
Authors: Wang Chun Jing , Petersone Lina , Edner Natalie M. , Heuts Frank , Ovcinnikovs Vitalijs , Ntavli Elisavet , Kogimtzis Alexandros , Fabri Astrid , Elfaki Yassin , Houghton Luke P. , Hosse Ralf J. , Schubert David A. , Frei Andreas P. , Ross Ellen M. , Walker Lucy S. K. 
Published: November 2022

AbstractBlockade of CD28 costimulation with CTLA-4-Ig/Abatacept is used to dampen effector T cell responses in autoimmune and transplantation settings. However, a significant drawback of this approach is impaired regulatory T cell homeostasis that requires CD28 signaling. Therefore, strategies that restrict the effects of costimulation blockade to effector T cells would be advantageous. Here we probe the relative roles of CD28 and IL-2 in maintaining Treg. We find provision of IL-2 counteracts the regulatory T cell loss induced by costimulation blockade while minimally affecting the conventional T cell compartment. These data suggest that combining costimulation blockade with IL-2 treatment may selectively impair effector T cell responses while maintaining regulatory T cells. Using a mouse model of autoimmune diabetes, we show combined therapy supports regulatory T cell homeostasis and protects from disease. These findings are recapitulated in humanised mice using clinically relevant reagents and provide an exemplar for rational use of a second immunotherapy to offset known limitations of the first.
Structural dynamics of AAA + ATPase Drg1 and mechanism of benzo-diazaborine inhibition
Authors: Ma Chengying , Wu Damu , Chen Qian , Gao Ning 
Published: November 2022

AbstractThe type II AAA + ATPase Drg1 is a ribosome assembly factor, functioning to release Rlp24 from the pre-60S particle just exported from nucleus, and its activity in can be inhibited by a drug molecule diazaborine. However, molecular mechanisms of Drg1-mediated Rlp24 removal and diazaborine-mediated inhibition are not fully understood. Here, we report Drg1 structures in different nucleotide-binding and benzo-diazaborine treated states. Drg1 hexamers transits between two extreme conformations (planar or helical arrangement of protomers). By forming covalent adducts with ATP molecules in both ATPase domain, benzo-diazaborine locks Drg1 hexamers in a symmetric and non-productive conformation to inhibits both inter-protomer and inter-ring communication of Drg1 hexamers. We also obtained a substrate-engaged mutant Drg1 structure, in which conserved pore-loops form a spiral staircase to interact with the polypeptide through a sequence-independent manner. Structure-based mutagenesis data highlight the functional importance of the pore-loop, the D1-D2 linker and the inter-subunit signaling motif of Drg1, which share similar regulatory mechanisms with p97. Our results suggest that Drg1 may function as an unfoldase that threads a substrate protein within the pre-60S particle.
Cryo-EM reveals the architecture of the PELP1-WDR18 molecular scaffold
Authors: Gordon Jacob , Chapus Fleur L. , Viverette Elizabeth G. , Williams Jason G. , Deterding Leesa J. , Krahn Juno M. , Borgnia Mario J. , Rodriguez Joseph , Warren Alan J. , Stanley Robin E. 
Published: November 2022

AbstractPELP1 (Proline-, Glutamic acid-, Leucine-rich protein 1) is a large scaffolding protein that functions in many cellular pathways including steroid receptor (SR) coactivation, heterochromatin maintenance, and ribosome biogenesis. PELP1 is a proto-oncogene whose expression is upregulated in many human cancers, but how the PELP1 scaffold coordinates its diverse cellular functions is poorly understood. Here we show that PELP1 serves as the central scaffold for the human Rix1 complex whose members include WDR18, TEX10, and SENP3. We reconstitute the mammalian Rix1 complex and identified a stable sub-complex comprised of the conserved PELP1 Rix1 domain and WDR18. We determine a 2.7 Å cryo-EM structure of the subcomplex revealing an interconnected tetrameric assembly and the architecture of PELP1’s signaling motifs, including eleven LxxLL motifs previously implicated in SR signaling and coactivation of Estrogen Receptor alpha (ERα) mediated transcription. However, the structure shows that none of these motifs is in a conformation that would support SR binding. Together this work establishes that PELP1 scaffolds the Rix1 complex, and association with WDR18 may direct PELP1’s activity away from SR coactivation.
Spatial genomics maps the structure, nature and evolution of cancer clones
Authors: Lomakin Artem , Svedlund Jessica , Strell Carina , Gataric Milana , Shmatko Artem , Rukhovich Gleb , Park Jun Sung , Ju Young Seok , Dentro Stefan , Kleshchevnikov Vitalii , Vaskivskyi Vasyl , Li Tong , Bayraktar Omer Ali , Pinder Sarah , Richardson Andrea L. , Santagata Sandro , Campbell Peter J. , Russnes Hege , Gerstung Moritz , Nilsson Mats , Yates Lucy R. 
Published: November 2022

AbstractGenome sequencing of cancers often reveals mosaics of different subclones present in the same tumour1–3. Although these are believed to arise according to the principles of somatic evolution, the exact spatial growth patterns and underlying mechanisms remain elusive4,5. Here, to address this need, we developed a workflow that generates detailed quantitative maps of genetic subclone composition across whole-tumour sections. These provide the basis for studying clonal growth patterns, and the histological characteristics, microanatomy and microenvironmental composition of each clone. The approach rests on whole-genome sequencing, followed by highly multiplexed base-specific in situ sequencing, single-cell resolved transcriptomics and dedicated algorithms to link these layers. Applying the base-specific in situ sequencing workflow to eight tissue sections from two multifocal primary breast cancers revealed intricate subclonal growth patterns that were validated by microdissection. In a case of ductal carcinoma in situ, polyclonal neoplastic expansions occurred at the macroscopic scale but segregated within microanatomical structures. Across the stages of ductal carcinoma in situ, invasive cancer and lymph node metastasis, subclone territories are shown to exhibit distinct transcriptional and histological features and cellular microenvironments. These results provide examples of the benefits afforded by spatial genomics for deciphering the mechanisms underlying cancer evolution and microenvironmental ecology.
Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir
Authors: Iketani Sho , Mohri Hiroshi , Culbertson Bruce , Hong Seo Jung , Duan Yinkai , Luck Maria I. , Annavajhala Medini K. , Guo Yicheng , Sheng Zizhang , Uhlemann Anne-Catrin , Goff Stephen P. , Sabo Yosef , Yang Haitao , Chavez Alejandro , Ho David D. 
Published: November 2022

AbstractNirmatrelvir, an oral antiviral targeting the 3CL protease of SARS-CoV-2, has been demonstrated to be clinically useful against COVID-19 (refs. 1,2). However, because SARS-CoV-2 has evolved to become resistant to other therapeutic modalities3–9, there is a concern that the same could occur for nirmatrelvir. Here we examined this possibility by in vitro passaging of SARS-CoV-2 in nirmatrelvir using two independent approaches, including one on a large scale. Indeed, highly resistant viruses emerged from both and their sequences showed a multitude of 3CL protease mutations. In the experiment peformed with many replicates, 53 independent viral lineages were selected with mutations observed at 23 different residues of the enzyme. Nevertheless, several common mutational pathways to nirmatrelvir resistance were preferred, with a majority of the viruses descending from T21I, P252L or T304I as precursor mutations. Construction and analysis of 13 recombinant SARS-CoV-2 clones showed that these mutations mediated only low-level resistance, whereas greater resistance required accumulation of additional mutations. E166V mutation conferred the strongest resistance (around 100-fold), but this mutation resulted in a loss of viral replicative fitness that was restored by compensatory changes such as L50F and T21I. Our findings indicate that SARS-CoV-2 resistance to nirmatrelvir does readily arise via multiple pathways in vitro, and the specific mutations observed herein form a strong foundation from which to study the mechanism of resistance in detail and to inform the design of next-generation protease inhibitors.
Moving beyond response times with accessible measures of manual dynamics
Authors: Smith Katie Ann , Morrison Samara , Henderson Annette M. E. , Erb Christopher D. 
Published: November 2022

AbstractButton-press measures of response time (RT) and accuracy have long served a central role in psychological research. However, RT and accuracy provide limited insight into how cognitive processes unfold over time. To address this limitation, researchers have used hand-tracking techniques to investigate how cognitive processes unfold over the course of a response, are modulated by recent experience, and function across the lifespan. Despite the efficacy of these techniques for investigating a wide range of psychological phenomena, widespread adoption of hand-tracking techniques within the field is hindered by a range of factors, including equipment costs and the use of specialized software. Here, we demonstrate that the behavioral dynamics previously observed with specialized motion-tracking equipment in an Eriksen flanker task can be captured with an affordable, portable, and easy-to-assemble response box. Six-to-eight-year-olds and adults (N = 90) completed a computerized version of the flanker task by pressing and holding a central button until a stimulus array appeared. Participants then responded by releasing the central button and reaching to press one of two response buttons. This method allowed RT to be separated into initiation time (when the central button was released) and movement time (time elapsed between initiation and completion of the response). Consistent with previous research using motion-tracking techniques, initiation times and movement times revealed distinct patterns of effects across trials and between age groups, indicating that the method used in the current study presents a simple solution for researchers from across the psychological and brain sciences looking to move beyond RTs.