bluuebunny/crossref_metadata_2025_split huggingface dataset:
All Songs Considered: The Persuasive Listening of Music Podcasts
Authors: MCDANIEL BYRD 
Published: November 2022

AbstractMusic podcasts have proliferated as public discourse about popular music. A significant part of the expanding podcast industry, music podcasts include titles such as All Songs Considered, Switched on Pop, Song Exploder, Sound Opinions, New York Times Popcast, and Lost Notes. These podcasts often feature a combination of conversation and musical selections, which highlight aspects of the music for podcast listeners. In this article, I argue that we should think of music podcasts as persuasive demonstrations of music consumption. Music podcasts present music as a subject for discussion and also implicitly model listening techniques, convincing podcast listeners to adopt specific approaches to music recordings. I explore three podcasts: All Songs Considered, Switched on Pop, and Disability Visibility. I examine how these podcasts present music as their subject, while advancing particular theories of listening that can serve or subvert privileged modes of music reception.
Longitudinal effects of a common UMOD variant on kidney function, blood pressure, cognitive and physical function in older women and men
Authors: Algharably Engi Abdel–Hady , Villagomez Fuentes Linda Elizabeth , Toepfer Sarah , König Maximilian , Regitz-Zagrosek Vera , Bertram Lars , Bolbrinker Juliane , Demuth Ilja , Kreutz Reinhold 
Published: November 2022

AbstractGenetic variants in UMOD associate with kidney function and hypertension. These phenotypes are also linked to sex-related differences and impairment in cognitive and physical function in older age. Here we evaluate longitudinal associations between a common UMOD rs4293393-A>G variant and changes in estimated glomerular filtration rate (eGFR), blood pressure (BP), cognitive and physical function parameters in older participants in the BASE-II after long-term follow-up as part of the GendAge study. Overall, 1010 older participants (mean age 75.7 ± 3.7 years, 51.6% women) were analyzed after follow-up (mean 7.4 years) both in cross-sectional analysis and in longitudinal analysis as compared to baseline. In cross-sectional analysis, heterozygous G–allele carriers exhibited significantly higher eGFR values (AA, 71.3 ml/min/1.73 m2, 95% CI, 70.3–72.3 vs. AG, 73.5 ml/min/1.73 m2, 95% CI, 72.1–74.9, P = 0.033). Male heterozygous G-allele carriers had lower odds of eGFR < 60 mL/min/1.73 m2 (OR 0.51, 95% CI, 0.28–0.95, P = 0.032) and in Timed Up and Go-Test ≥ 10 s (OR 0.50, 95% CI, 0.29–0.85, P = 0.011) whereas women were less likely to have hypertension (OR 0.58, CI, 0.37–0.91, P = 0.018). UMOD genotypes were not significantly associated with longitudinal changes in any investigated phenotype. Thus, while the impact of UMOD rs4293393 on kidney function is maintained in aging individuals, this variant has overall no impact on longitudinal changes in BP, kidney, cognitive or functional phenotypes. However, our results suggest a possible sex-specific modifying effect of UMOD on eGFR and physical function in men and hypertension prevalence in women.
Teloxantron inhibits the processivity of telomerase with preferential DNA damage on telomeres
Authors: Maciejewska Natalia , Olszewski Mateusz , Jurasz Jakub , Baginski Maciej , Stasevych Maryna , Zvarych Viktor , Folini Marco , Zaffaroni Nadia 
Published: November 2022

AbstractTelomerase reactivation is one of the hallmarks of cancer, which plays an important role in cellular immortalization and the development and progression of the tumor. Chemical telomerase inhibitors have been shown to trigger replicative senescence and apoptotic cell death both in vitro and in vivo. Due to its upregulation in various cancers, telomerase is considered a potential target in cancer therapy. In this study, we identified potent, small-molecule telomerase inhibitors using a telomerase repeat amplification protocol assay. The results of the assay are the first evidence of telomerase inhibition by anthraquinone derivatives that do not exhibit G-quadruplex-stabilizing properties. The stability of telomerase in the presence of its inhibitor was evaluated under nearly physiological conditions using a cellular thermal shift assay. Our data showed that the compound induced aggregation of the catalytic subunit (hTERT) of human telomerase, and molecular studies confirmed the binding of the hit compound with the active site of the enzyme. The ability of new derivatives to activate DNA double-strand breaks (DSBs) was determined by high-resolution microscopy and flow cytometry in tumor cell lines differing in telomere elongation mechanism. The compounds triggered DSBs in TERT-positive A549 and H460 lung cancer cell lines, but not in TERT-negative NHBE normal human bronchial epithelial and ALT-positive U2OS osteosarcoma cell lines, which indicates that the induction of DSBs was dependent on telomerase inhibition. The observed DNA damage activated DNA damage response pathways involving ATM/Chk2 and ATR/Chk1 cascades. Additionally, the compounds induced apoptotic cell death through extrinsic and intrinsic pathways in lung cancer cells. Taken together, our study demonstrated that anthraquinone derivatives can be further developed into novel telomerase-related anticancer agents.
Ciclopirox drives growth arrest and autophagic cell death through STAT3 in gastric cancer cells
Authors: Chen Lingyan , Chen Dejian , Li Jiwei , He Lipeng , Chen Ting , Song Dandan , Shan Shuang , Wang Jiaxin , Lu Xiaoang , Lu Bin 
Published: November 2022

AbstractCiclopirox (CPX), an antifungal drug, has recently been identified as a promising agent for cancer treatment. However, the effects and underlying mechanism of CPX as an antitumor agent of gastric cancer (GC) remain largely unknown. Here, we found that CPX dramatically suppresses GC xenograft growth in vitro via inhibiting proliferation and stimulating autophagic cell death rather than apoptosis. Moreover, CPX (20 mg/kg, intraperitoneally) substantially inhibits GC xenograft tumor growth in vivo. Mechanistically, CPX promotes growth arrest and autophagic cell death through suppressing the phosphorylation of signal transducers and activators of transcription 3 (STAT3) at tyrosine 705 (Tyr705) and serine 727 (Ser727) sites, respectively. Additionally, CPX induces STAT3 ubiquitination, which subsequently leads to a decrease in the p-STAT3 (Ser727) level. On the other hand, CPX represses the p-STAT3 (Tyr705) level via p-Src (Tyr416) inhibition. Collectively, our findings unmask a novel mechanism by which CPX regulates growth and autophagic cell death in GC cells via regulating the phosphorylation of STAT3 both at Tyr705 and Ser727 residues, and suggest that CPX may be a potential treatment for GC.
Low-dose IL-2 reduces IL-21+ T cell frequency and induces anti-inflammatory gene expression in type 1 diabetes
Authors: Zhang Jia-Yuan , Hamey Fiona , Trzupek Dominik , Mickunas Marius , Lee Mercede , Godfrey Leila , Yang Jennie H. M. , Pekalski Marcin L. , Kennet Jane , Waldron-Lynch Frank , Evans Mark L. , Tree Timothy I. M. , Wicker Linda S. , Todd John A. , Ferreira Ricardo C. 
Published: November 2022

AbstractDespite early clinical successes, the mechanisms of action of low-dose interleukin-2 (LD-IL-2) immunotherapy remain only partly understood. Here we examine the effects of interval administration of low-dose recombinant IL-2 (iLD-IL-2) in type 1 diabetes using high-resolution single-cell multiomics and flow cytometry on longitudinally-collected peripheral blood samples. Our results confirm that iLD-IL-2 selectively expands thymic-derived FOXP3+HELIOS+regulatory T cells and CD56brightNK cells, and show that the treatment reduces the frequency of IL-21-producing CD4+T cells and of two innate-like mucosal-associated invariant T and Vγ9Vδ2CD8+T cell subsets. The cellular changes induced by iLD-IL-2 associate with an anti-inflammatory gene expression signature, which remains detectable in all T and NK cell subsets analysed one month after treatment. These findings warrant investigations into the potential longer-term clinical benefits of iLD-IL-2 in immunotherapy.
Secreted EMC10 is upregulated in human obesity and its neutralizing antibody prevents diet-induced obesity in mice
Authors: Wang Xuanchun , Li Yanliang , Qiang Guifen , Wang Kaihua , Dai Jiarong , McCann Maximilian , Munoz Marcos D. , Gil Victoria , Yu Yifei , Li Shengxian , Yang Zhihong , Xu Shanshan , Cordoba-Chacon Jose , De Jesus Dario F. , Sun Bei , Chen Kuangyang , Wang Yahao , Liu Xiaoxia , Miao Qing , Zhou Linuo , Hu Renming , Ding Qiang , Kulkarni Rohit N. , Gao Daming , Blüher Matthias , Liew Chong Wee 
Published: November 2022

AbstractSecreted isoform of endoplasmic reticulum membrane complex subunit 10 (scEMC10) is a poorly characterized secreted protein of largely unknown physiological function. Here we demonstrate that scEMC10 is upregulated in people with obesity and is positively associated with insulin resistance. Consistent with a causal role for scEMC10 in obesity, Emc10-/- mice are resistant to diet-induced obesity due to an increase in energy expenditure, while scEMC10 overexpression decreases energy expenditure, thus promoting obesity in mouse. Furthermore, neutralization of circulating scEMC10 using a monoclonal antibody reduces body weight and enhances insulin sensitivity in obese mice. Mechanistically, we provide evidence that scEMC10 can be transported into cells where it binds to the catalytic subunit of PKA and inhibits its stimulatory action on CREB while ablation of EMC10 promotes thermogenesis in adipocytes via activation of the PKA signalling pathway and its downstream targets. Taken together, our data identify scEMC10 as a circulating inhibitor of thermogenesis and a potential therapeutic target for obesity and its cardiometabolic complications.
Active DNA damage response signaling initiates and maintains meiotic sex chromosome inactivation
Authors: Abe Hironori , Yeh Yu-Han , Munakata Yasuhisa , Ishiguro Kei-Ichiro , Andreassen Paul R. , Namekawa Satoshi H. 
Published: November 2022

AbstractMeiotic sex chromosome inactivation (MSCI) is an essential process in the male germline. While genetic experiments have established that the DNA damage response (DDR) pathway directs MSCI, due to limitations to the experimental systems available, mechanisms underlying MSCI remain largely unknown. Here we establish a system to study MSCI ex vivo, based on a short-term culture method, and demonstrate that active DDR signaling is required both to initiate and maintain MSCI via a dynamic and reversible process. DDR-directed MSCI follows two layers of modifications: active DDR-dependent reversible processes and irreversible histone post-translational modifications. Further, the DDR initiates MSCI independent of the downstream repressive histone mark H3K9 trimethylation (H3K9me3), thereby demonstrating that active DDR signaling is the primary mechanism of silencing in MSCI. By unveiling the dynamic nature of MSCI, and its governance by active DDR signals, our study highlights the sex chromosomes as an active signaling hub in meiosis.
mTORC1 links pathology in experimental models of Still’s disease and macrophage activation syndrome
Authors: Huang Zhengping , You Xiaomeng , Chen Liang , Du Yan , Brodeur Kailey , Jee Hyuk , Wang Qiang , Linder Grace , Darbousset Roxane , Cunin Pierre , Chang Margaret H. , Wactor Alexandra , Wauford Brian M. , Todd Marc J. C. , Wei Kevin , Li Ying , Levescot Anais , Iwakura Yoichiro , Pascual Virginia , Baldwin Nicole E. , Quartier Pierre , Li Tianwang , Gianatasio Maria T. , Hasserjian Robert P. , Henderson Lauren A. , Sykes David B. , Mellins Elizabeth D. , Canna Scott W. , Charles Julia F. , Nigrovic Peter A. , Lee Pui Y. 
Published: November 2022

AbstractStill’s disease is a severe inflammatory syndrome characterized by fever, skin rash and arthritis affecting children and adults. Patients with Still’s disease may also develop macrophage activation syndrome, a potentially fatal complication of immune dysregulation resulting in cytokine storm. Here we show that mTORC1 (mechanistic target of rapamycin complex 1) underpins the pathology of Still’s disease and macrophage activation syndrome. Single-cell RNA sequencing in a murine model of Still’s disease shows preferential activation of mTORC1 in monocytes; both mTOR inhibition and monocyte depletion attenuate disease severity. Transcriptomic data from patients with Still’s disease suggest decreased expression of the mTORC1 inhibitors TSC1/TSC2 and an mTORC1 gene signature that strongly correlates with disease activity and treatment response. Unrestricted activation of mTORC1 by Tsc2 deletion in mice is sufficient to trigger a Still’s disease-like syndrome, including both inflammatory arthritis and macrophage activation syndrome with hemophagocytosis, a cellular manifestation that is reproduced in human monocytes by CRISPR/Cas-mediated deletion of TSC2. Consistent with this observation, hemophagocytic histiocytes from patients with macrophage activation syndrome display prominent mTORC1 activity. Our study suggests a mechanistic link of mTORC1 to inflammation that connects the pathogenesis of Still’s disease and macrophage activation syndrome.
Thiocarbazate building blocks enable the construction of azapeptides for rapid development of therapeutic candidates
Authors: Altiti Ahmad , He Mingzhu , VanPatten Sonya , Cheng Kai Fan , Ahmed Umair , Chiu Pui Yan , Mughrabi Ibrahim T. , Jabari Bayan Al , Burch Ronald M. , Manogue Kirk R. , Tracey Kevin J. , Diamond Betty , Metz Christine N. , Yang Huan , Hudson LaQueta K. , Zanos Stavros , Son Myoungsun , Sherry Barbara , Coleman Thomas R. , Al-Abed Yousef 
Published: November 2022

AbstractPeptides, polymers of amino acids, comprise a vital and expanding therapeutic approach. Their rapid degradation by proteases, however, represents a major limitation to their therapeutic utility and chemical modifications to native peptides have been employed to mitigate this weakness. Herein, we describe functionalized thiocarbazate scaffolds as precursors of aza-amino acids, that, upon activation, can be integrated in a peptide sequence to generate azapeptides using conventional peptide synthetic methods. This methodology facilitates peptide editing—replacing targeted amino acid(s) with aza-amino acid(s) within a peptide—to form azapeptides with preferred therapeutic characteristics (extending half-life/bioavailability, while at the same time typically preserving structural features and biological activities). We demonstrate the convenience of this azapeptide synthesis platform in two well-studied peptides with short half-lives: FSSE/P5779, a tetrapeptide inhibitor of HMGB1/MD-2/TLR4 complex formation, and bradykinin, a nine-residue vasoactive peptide. This bench-stable thiocarbazate platform offers a robust and universal approach to optimize peptide-based therapeutics.
The fate of early perichondrial cells in developing bones
Authors: Matsushita Yuki , Chu Angel Ka Yan , Tsutsumi-Arai Chiaki , Orikasa Shion , Nagata Mizuki , Wong Sunny Y. , Welch Joshua D. , Ono Wanida , Ono Noriaki 
Published: November 2022

AbstractIn endochondral bone development, bone-forming osteoblasts and bone marrow stromal cells have dual origins in the fetal cartilage and its surrounding perichondrium. However, how early perichondrial cells distinctively contribute to developing bones remain unidentified. Here we show using in vivo cell-lineage analyses that Dlx5+ fetal perichondrial cells marked by Dlx5-creER do not generate cartilage but sustainably contribute to cortical bone and marrow stromal compartments in a manner complementary to fetal chondrocyte derivatives under the regulation of Hedgehog signaling. Postnatally, Dlx5+ fetal perichondrial cell derivatives preferentially populate the diaphyseal marrow stroma with a dormant adipocyte-biased state and are refractory to parathyroid hormone-induced bone anabolism. Therefore, early perichondrial cells of the fetal cartilage are destined to become an adipogenic subset of stromal cells in postnatal diaphyseal bone marrow, supporting the theory that the adult bone marrow stromal compartments are developmentally prescribed within the two distinct cells-of-origins of the fetal bone anlage.
PCGF1-PRC1 links chromatin repression with DNA replication during hematopoietic cell lineage commitment
Authors: Takano Junichiro , Ito Shinsuke , Dong Yixing , Sharif Jafar , Nakajima-Takagi Yaeko , Umeyama Taichi , Han Yong-Woon , Isono Kyoichi , Kondo Takashi , Iizuka Yusuke , Miyai Tomohiro , Koseki Yoko , Ikegaya Mika , Sakihara Mizuki , Nakayama Manabu , Ohara Osamu , Hasegawa Yoshinori , Hashimoto Kosuke , Arner Erik , Klose Robert J. , Iwama Atsushi , Koseki Haruhiko , Ikawa Tomokatsu 
Published: November 2022

AbstractPolycomb group proteins (PcG), polycomb repressive complexes 1 and 2 (PRC1 and 2), repress lineage inappropriate genes during development to maintain proper cellular identities. It has been recognized that PRC1 localizes at the replication fork, however, the precise functions of PRC1 during DNA replication are elusive. Here, we reveal that a variant PRC1 containing PCGF1 (PCGF1-PRC1) prevents overloading of activators and chromatin remodeling factors on nascent DNA and thereby mediates proper deposition of nucleosomes and correct downstream chromatin configurations in hematopoietic stem and progenitor cells (HSPCs). This function of PCGF1-PRC1 in turn facilitates PRC2-mediated repression of target genes such asHmga2and restricts premature myeloid differentiation. PCGF1-PRC1, therefore, maintains the differentiation potential of HSPCs by linking proper nucleosome configuration at the replication fork with PcG-mediated gene silencing to ensure life-long hematopoiesis.
SOTIP is a versatile method for microenvironment modeling with spatial omics data
Authors: Yuan Zhiyuan , Li Yisi , Shi Minglei , Yang Fan , Gao Juntao , Yao Jianhua , Zhang Michael Q. 
Published: November 2022

AbstractThe rapidly developing spatial omics generated datasets with diverse scales and modalities. However, most existing methods focus on modeling dynamics of single cells while ignore microenvironments (MEs). Here we present SOTIP (Spatial Omics mulTIPle-task analysis), a versatile method incorporating MEs and their interrelationships into a unified graph. Based on this graph, spatial heterogeneity quantification, spatial domain identification, differential microenvironment analysis, and other downstream tasks can be performed. We validate each module’s accuracy, robustness, scalability and interpretability on various spatial omics datasets. In two independent mouse cerebral cortex spatial transcriptomics datasets, we reveal a gradient spatial heterogeneity pattern strongly correlated with the cortical depth. In human triple-negative breast cancer spatial proteomics datasets, we identify molecular polarizations and MEs associated with different patient survivals. Overall, by modeling biologically explainable MEs, SOTIP outperforms state-of-art methods and provides some perspectives for spatial omics data exploration and interpretation.
Correlation driven near-flat band Stoner excitations in a Kagome magnet
Authors: Nag Abhishek , Peng Yiran , Li Jiemin , Agrestini S. , Robarts H. C. , García-Fernández Mirian , Walters A. C. , Wang Qi , Yin Qiangwei , Lei Hechang , Yin Zhiping , Zhou Ke-Jin 
Published: November 2022

AbstractAmong condensed matter systems, Mott insulators exhibit diverse properties that emerge from electronic correlations. In itinerant metals, correlations are usually weak, but can also be enhanced via geometrical confinement of electrons, that manifest as ‘flat’ dispersionless electronic bands. In the fast developing field of topological materials, which includes Dirac and Weyl semimetals, flat bands are one of the important components that can result in unusual magnetic and transport behaviour. To date, characterisation of flat bands and their magnetism is scarce, hindering the design of novel materials. Here, we investigate the ferromagnetic Kagomé semimetal Co3Sn2S2 using resonant inelastic X-ray scattering. Remarkably, nearly non-dispersive Stoner spin excitation peaks are observed, sharply contrasting with the featureless Stoner continuum expected in conventional ferromagnetic metals. Our band structure and dynamic spin susceptibility calculations, and thermal evolution of the excitations, confirm the nearly non-dispersive Stoner excitations as unique signatures of correlations and spin-polarized electronic flat bands in Co3Sn2S2. These observations serve as a cornerstone for further exploration of band-induced symmetry-breaking orders in topological materials.
Extensive germline-somatic interplay contributes to prostate cancer progression through HNF1B co-option of TMPRSS2-ERG
Authors: Giannareas Nikolaos , Zhang Qin , Yang Xiayun , Na Rong , Tian Yijun , Yang Yuehong , Ruan Xiaohao , Huang Da , Yang Xiaoqun , Wang Chaofu , Zhang Peng , Manninen Aki , Wang Liang , Wei Gong-Hong 
Published: November 2022

AbstractGenome-wide association studies have identified 270 loci conferring risk for prostate cancer (PCa), yet the underlying biology and clinical impact remain to be investigated. Here we observe an enrichment of transcription factor genes including HNF1B within PCa risk-associated regions. While focused on the 17q12/HNF1B locus, we find a strong eQTL for HNF1B and multiple potential causal variants involved in the regulation of HNF1B expression in PCa. An unbiased genome-wide co-expression analysis reveals PCa-specific somatic TMPRSS2-ERG fusion as a transcriptional mediator of this locus and the HNF1B eQTL signal is ERG fusion status dependent. We investigate the role of HNF1B and find its involvement in several pathways related to cell cycle progression and PCa severity. Furthermore, HNF1B interacts with TMPRSS2-ERG to co-occupy large proportion of genomic regions with a remarkable enrichment of additional PCa risk alleles. We finally show that HNF1B co-opts ERG fusion to mediate mechanistic and biological effects of the PCa risk-associated locus 17p13.3/VPS53/FAM57A/GEMIN4. Taken together, we report an extensive germline-somatic interaction between TMPRSS2-ERG fusion and genetic variations underpinning PCa risk association and progression.
Hydrophobicity of arginine leads to reentrant liquid-liquid phase separation behaviors of arginine-rich proteins
Authors: Hong Yuri , Najafi Saeed , Casey Thomas , Shea Joan-Emma , Han Song-I , Hwang Dong Soo 
Published: November 2022

AbstractIntrinsically disordered proteins rich in cationic amino acid groups can undergo Liquid-Liquid Phase Separation (LLPS) in the presence of charge-balancing anionic counterparts. Arginine and Lysine are the two most prevalent cationic amino acids in proteins that undergo LLPS, with arginine-rich proteins observed to undergo LLPS more readily than lysine-rich proteins, a feature commonly attributed to arginine’s ability to form stronger cation-π interactions with aromatic groups. Here, we show that arginine’s ability to promote LLPS is independent of the presence of aromatic partners, and that arginine-rich peptides, but not lysine-rich peptides, display re-entrant phase behavior at high salt concentrations. We further demonstrate that the hydrophobicity of arginine is the determining factor giving rise to the reentrant phase behavior and tunable viscoelastic properties of the dense LLPS phase. Controlling arginine-induced reentrant LLPS behavior using temperature and salt concentration opens avenues for the bioengineering of stress-triggered biological phenomena and drug delivery systems.