bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting the MYC interaction network in B-cell lymphoma via histone deacetylase 6 inhibition
Authors: Winkler René , Mägdefrau Ann-Sophie , Piskor Eva-Maria , Kleemann Markus , Beyer Mandy , Linke Kevin , Hansen Lisa , Schaffer Anna-Maria , Hoffmann Marina E. , Poepsel Simon , Heyd Florian , Beli Petra , Möröy Tarik , Mahboobi Siavosh , Krämer Oliver H. , Kosan Christian 
Published: September 2022

AbstractOverexpression of MYC is a genuine cancer driver in lymphomas and related to poor prognosis. However, therapeutic targeting of the transcription factor MYC remains challenging. Here, we show that inhibition of the histone deacetylase 6 (HDAC6) using the HDAC6 inhibitor Marbostat-100 (M-100) reduces oncogenic MYC levels and prevents lymphomagenesis in a mouse model of MYC-induced aggressive B-cell lymphoma. M-100 specifically alters protein-protein interactions by switching the acetylation state of HDAC6 substrates, such as tubulin. Tubulin facilitates nuclear import of MYC, and MYC-dependent B-cell lymphoma cells rely on continuous import of MYC due to its high turn-over. Acetylation of tubulin impairs this mechanism and enables proteasomal degradation of MYC. M-100 targets almost exclusively B-cell lymphoma cells with high levels of MYC whereas non-tumor cells are not affected. M-100 induces massive apoptosis in human and murine MYC-overexpressing B-cell lymphoma cells. We identified the heat-shock protein DNAJA3 as an interactor of tubulin in an acetylation-dependent manner and overexpression of DNAJA3 resulted in a pronounced degradation of MYC. We propose a mechanism by which DNAJA3 associates with hyperacetylated tubulin in the cytoplasm to control MYC turnover. Taken together, our data demonstrate a beneficial role of HDAC6 inhibition in MYC-dependent B-cell lymphoma.
RNA G-quadruplex formed in SARS-CoV-2 used for COVID-19 treatment in animal models
Authors: Qin Geng , Zhao Chuanqi , Liu Yan , Zhang Cheng , Yang Guang , Yang Jie , Wang Zhao , Wang Chunyu , Tu Changchun , Guo Zhendong , Ren Jinsong , Qu Xiaogang 
Published: September 2022

AbstractThe ongoing COVID-19 pandemic has continued to affect millions of lives worldwide, leading to the urgent need for novel therapeutic strategies. G-quadruplexes (G4s) have been demonstrated to regulate life cycle of multiple viruses. Here, we identify several highly conservative and stable G4s in SARS-CoV-2 and clarify their dual-function of inhibition of the viral replication and translation processes. Furthermore, the cationic porphyrin compound 5,10,15,20-tetrakis-(N-methyl-4-pyridyl)porphine (TMPyP4) targeting SARS-CoV-2 G4s shows excellent antiviral activity, while its N-methyl-2-pyridyl positional isomer TMPyP2 with low affinity for G4 has no effects on SARS-CoV-2 infection, suggesting that the antiviral activity of TMPyP4 attributes to targeting SARS-CoV-2 G4s. In the Syrian hamster and transgenic mouse models of SARS-CoV-2 infection, administration of TMPyP4 at nontoxic doses significantly suppresses SARS-CoV-2 infection, resulting in reduced viral loads and lung lesions. Worth to note, the anti-COVID-19 activity of TMPyP4 is more potent than remdesivir evidenced by both in vitro and in vivo studies. Our findings highlight SARS-CoV-2 G4s as a novel druggable target and the compelling potential of TMPyP4 for COVID-19 therapy. Different from the existing anti-SARS-CoV-2 therapeutic strategies, our work provides another alternative therapeutic tactic for SARS-CoV-2 infection focusing on targeting the secondary structures within SARS-CoV-2 genome, and would open a new avenue for design and synthesis of drug candidates with high selectivity toward the new targets.
MVsim is a toolset for quantifying and designing multivalent interactions
Authors: Bruncsics Bence , Errington Wesley J. , Sarkar Casim A. 
Published: September 2022

AbstractArising through multiple binding elements, multivalency can specify the avidity, duration, cooperativity, and selectivity of biomolecular interactions, but quantitative prediction and design of these properties has remained challenging. Here we present MVsim, an application suite built around a configurational network model of multivalency to facilitate the quantification, design, and mechanistic evaluation of multivalent binding phenomena through a simple graphical user interface. To demonstrate the utility and versatility of MVsim, we first show that both monospecific and multispecific multivalent ligand-receptor interactions, with their noncanonical binding kinetics, can be accurately simulated. Further, to illustrate the conceptual insights into multivalent systems that MVsim can provide, we apply it to quantitatively predict the ultrasensitivity and performance of multivalent-encoded protein logic gates, evaluate the inherent programmability of multispecificity for selective receptor targeting, and extract rate constants of conformational switching for the SARS-CoV-2 spike protein and model its binding to ACE2 as well as multivalent inhibitors of this interaction. MVsim and instructional tutorials are freely available at https://sarkarlab.github.io/MVsim/.
Lactate increases stemness of CD8 + T cells to augment anti-tumor immunity
Authors: Feng Qiang , Liu Zhida , Yu Xuexin , Huang Tongyi , Chen Jiahui , Wang Jian , Wilhelm Jonathan , Li Suxin , Song Jiwon , Li Wei , Sun Zhichen , Sumer Baran D. , Li Bo , Fu Yang-Xin , Gao Jinming 
Published: September 2022

AbstractLactate is a key metabolite produced from glycolytic metabolism of glucose molecules, yet it also serves as a primary carbon fuel source for many cell types. In the tumor-immune microenvironment, effect of lactate on cancer and immune cells can be highly complex and hard to decipher, which is further confounded by acidic protons, a co-product of glycolysis. Here we show that lactate is able to increase stemness of CD8+ T cells and augments anti-tumor immunity. Subcutaneous administration of sodium lactate but not glucose to mice bearing transplanted MC38 tumors results in CD8+ T cell-dependent tumor growth inhibition. Single cell transcriptomics analysis reveals increased proportion of stem-like TCF-1-expressing CD8+ T cells among intra-tumoral CD3+ cells, a phenotype validated by in vitro lactate treatment of T cells. Mechanistically, lactate inhibits histone deacetylase activity, which results in increased acetylation at H3K27 of the Tcf7 super enhancer locus, leading to increased Tcf7 gene expression. CD8+ T cells in vitro pre-treated with lactate efficiently inhibit tumor growth upon adoptive transfer to tumor-bearing mice. Our results provide evidence for an intrinsic role of lactate in anti-tumor immunity independent of the pH-dependent effect of lactic acid, and might advance cancer immune therapy.
Changes in limiting factors for forager population dynamics in Europe across the last glacial-interglacial transition
Authors: Ordonez Alejandro , Riede Felix 
Published: September 2022

AbstractPopulation dynamics set the framework for human genetic and cultural evolution. For foragers, demographic and environmental changes correlate strongly, although the causal relations between different environmental variables and human responses through time and space likely varied. Building on the notion of limiting factors, namely that at any one time, the scarcest resource caps population size, we present a statistical approach to identify the dominant climatic constraints for hunter-gatherer population densities and then hindcast their changing dynamics in Europe for the period between 21,000 to 8000 years ago. Limiting factors shifted from temperature-related variables (effective temperature) during the Pleistocene to a regional mosaic of limiting factors in the Holocene dominated by temperature seasonality and annual precipitation. This spatiotemporal variation suggests that hunter-gatherers needed to overcome very different adaptive challenges in different parts of Europe and that these challenges varied over time. The signatures of these changing adaptations may be visible archaeologically. In addition, the spatial disaggregation of limiting factors from the Pleistocene to the Holocene coincided with and may partly explain the diversification of the cultural geography at this time.
Extensive gut virome variation and its associations with host and environmental factors in a population-level cohort
Authors: Nishijima Suguru , Nagata Naoyoshi , Kiguchi Yuya , Kojima Yasushi , Miyoshi-Akiyama Tohru , Kimura Moto , Ohsugi Mitsuru , Ueki Kohjiro , Oka Shinichi , Mizokami Masashi , Itoi Takao , Kawai Takashi , Uemura Naomi , Hattori Masahira 
Published: September 2022

AbstractIndigenous bacteriophage communities (virome) in the human gut have a huge impact on the structure and function of gut bacterial communities (bacteriome), but virome variation at a population scale is not fully investigated yet. Here, we analyse the gut dsDNA virome in the Japanese 4D cohort of 4198 deeply phenotyped individuals. By assembling metagenomic reads, we discover thousands of high-quality phage genomes including previously uncharacterised phage clades with different bacterial hosts than known major ones. The distribution of host bacteria is a strong determinant for the distribution of phages in the gut, and virome diversity is highly correlated with anti-viral defence mechanisms of the bacteriome, such as CRISPR-Cas and restriction-modification systems. We identify 97 various intrinsic/extrinsic factors that significantly affect the virome structure, including age, sex, lifestyle, and diet, most of which showed consistent associations with both phages and their predicted bacterial hosts. Among the metadata categories, disease and medication have the strongest effects on the virome structure. Overall, these results present a basis to understand the symbiotic communities of bacteria and their viruses in the human gut, which will facilitate the medical and industrial applications of indigenous viruses.
Msx1+ stem cells recruited by bioactive tissue engineering graft for bone regeneration
Authors: Zhang Xianzhu , Jiang Wei , Xie Chang , Wu Xinyu , Ren Qian , Wang Fei , Shen Xilin , Hong Yi , Wu Hongwei , Liao Youguo , Zhang Yi , Liang Renjie , Sun Wei , Gu Yuqing , Zhang Tao , Chen Yishan , Wei Wei , Zhang Shufang , Zou Weiguo , Ouyang Hongwei 
Published: September 2022

AbstractCritical-sized bone defects often lead to non-union and full-thickness defects of the calvarium specifically still present reconstructive challenges. In this study, we show that neurotrophic supplements induce robust in vitro expansion of mesenchymal stromal cells, and in situ transplantation of neurotrophic supplements-incorporated 3D-printed hydrogel grafts promote full-thickness regeneration of critical-sized bone defects. Single-cell RNA sequencing analysis reveals that a unique atlas of in situ stem/progenitor cells is generated during the calvarial bone healing in vivo. Notably, we find a local expansion of resident Msx1+ skeletal stem cells after transplantation of the in situ cell culture system. Moreover, the enhanced calvarial bone regeneration is accompanied by an increased endochondral ossification that closely correlates to the Msx1+ skeletal stem cells. Our findings illustrate the time-saving and regenerative efficacy of in situ cell culture systems targeting major cell subpopulations in vivo for rapid bone tissue regeneration.
Multimodal single cell sequencing implicates chromatin accessibility and genetic background in diabetic kidney disease progression
Authors: Wilson Parker C. , Muto Yoshiharu , Wu Haojia , Karihaloo Anil , Waikar Sushrut S. , Humphreys Benjamin D. 
Published: September 2022

AbstractThe proximal tubule is a key regulator of kidney function and glucose metabolism. Diabetic kidney disease leads to proximal tubule injury and changes in chromatin accessibility that modify the activity of transcription factors involved in glucose metabolism and inflammation. Here we use single nucleus RNA and ATAC sequencing to show that diabetic kidney disease leads to reduced accessibility of glucocorticoid receptor binding sites and an injury-associated expression signature in the proximal tubule. We hypothesize that chromatin accessibility is regulated by genetic background and closely-intertwined with metabolic memory, which pre-programs the proximal tubule to respond differently to external stimuli. Glucocorticoid excess has long been known to increase risk for type 2 diabetes, which raises the possibility that glucocorticoid receptor inhibition may mitigate the adverse metabolic effects of diabetic kidney disease.
Long-term memory CD8+ T cells specific for SARS-CoV-2 in individuals who received the BNT162b2 mRNA vaccine
Authors: Kuse Nozomi , Zhang Yu , Chikata Takayuki , Nguyen Hung The , Oka Shinichi , Gatanaga Hiroyuki , Takiguchi Masafumi 
Published: September 2022

AbstractLong-term memory T cells have not been well analyzed in individuals vaccinated with a COVID-19 vaccine although analysis of these T cells is necessary to evaluate vaccine efficacy. Here, investigate HLA-A*24:02-restricted CD8+ T cells specific for SARS-CoV-2-derived spike (S) epitopes in individuals immunized with the BNT162b2 mRNA vaccine. T cells specific for the S-QI9 and S-NF9 immunodominant epitopes have higher ability to recognize epitopes than other epitope-specific T cell populations. This higher recognition of S-QI9-specific T cells is due to the high stability of the S-QI9 peptide for HLA-A*24:02, whereas that of S-NF9-specific T cells results from the high affinity of T cell receptor. T cells specific for S-QI9 and S-NF9 are detectable >30 weeks after the second vaccination, indicating that the vaccine induces long-term memory T cells specific for these epitopes. Because the S-QI9 epitope is highly conserved among SARS-CoV-2 variants, S-QI9-specific T cells may help prevent infection with SARS-CoV-2 variants.
Ultrathin ferrite nanosheets for room-temperature two-dimensional magnetic semiconductors
Authors: Cheng Ruiqing , Yin Lei , Wen Yao , Zhai Baoxing , Guo Yuzheng , Zhang Zhaofu , Liao Weitu , Xiong Wenqi , Wang Hao , Yuan Shengjun , Jiang Jian , Liu Chuansheng , He Jun 
Published: September 2022

AbstractThe discovery of magnetism in ultrathin crystals opens up opportunities to explore new physics and to develop next-generation spintronic devices. Nevertheless, two-dimensional magnetic semiconductors with Curie temperatures higher than room temperature have rarely been reported. Ferrites with strongly correlated d-orbital electrons may be alternative candidates offering two-dimensional high-temperature magnetic ordering. This prospect is, however, hindered by their inherent three-dimensional bonded nature. Here, we develop a confined-van der Waals epitaxial approach to synthesizing air-stable semiconducting cobalt ferrite nanosheets with thickness down to one unit cell using a facile chemical vapor deposition process. The hard magnetic behavior and magnetic domain evolution are demonstrated by means of vibrating sample magnetometry, magnetic force microscopy and magneto-optical Kerr effect measurements, which shows high Curie temperature above 390 K and strong dimensionality effect. The addition of room-temperature magnetic semiconductors to two-dimensional material family provides possibilities for numerous novel applications in computing, sensing and information storage.
Cerebro-cerebellar motor networks in clinical subtypes of Parkinson’s disease
Authors: Basaia Silvia , Agosta Federica , Francia Alessandro , Cividini Camilla , Balestrino Roberta , Stojkovic Tanja , Stankovic Iva , Markovic Vladana , Sarasso Elisabetta , Gardoni Andrea , De Micco Rosita , Albano Luigi , Stefanova Elka , Kostic Vladimir S. , Filippi Massimo 
Published: September 2022

AbstractParkinson’s disease (PD) patients can be classified in tremor-dominant (TD) and postural-instability-and-gait-disorder (PIGD) motor subtypes. PIGD represents a more aggressive form of the disease that TD patients have a potentiality of converting into. This study investigated functional alterations within the cerebro-cerebellar system in PD-TD and PD-PIGD patients using stepwise functional connectivity (SFC) analysis and identified neuroimaging features that predict TD to PIGD conversion. Thirty-two PD-TD, 26 PD-PIGD patients and 60 healthy controls performed clinical/cognitive evaluations and resting-state functional MRI (fMRI). Four-year clinical follow-up data were available for 28 PD-TD patients, who were classified in 10 converters (cTD-PD) and 18 non-converters (ncTD-PD) to PIGD. The cerebellar seed-region was identified using a fMRI motor task. SFC analysis, characterizing regions that connect brain areas to the cerebellar seed at different levels of link-step distances, evaluated similar and divergent alterations in PD-TD and PD-PIGD. The discriminatory power of clinical data and/or SFC in distinguishing cPD-TD from ncPD-TD patients was assessed using ROC curve analysis. Compared to PD-TD, PD-PIGD patients showed decreased SFC in temporal lobe and occipital lobes and increased SFC in cerebellar cortex and ponto-medullary junction. Considering the subtype-conversion analysis, cPD-TD patients were characterized by increased SFC in temporal and occipital lobes and in cerebellum and ponto-medullary junction relative to ncPD-TD group. Combining clinical and SFC data, ROC curves provided the highest classification power to identify conversion to PIGD. These findings provide novel insights into the pathophysiology underlying different PD motor phenotypes and a potential tool for early characterization of PD-TD patients at risk of conversion to PIGD.
Identification of a broad lipid repertoire associated to the endothelial cell protein C receptor (EPCR)
Authors: Erausquin Elena , Morán-Garrido María , Sáiz Jorge , Barbas Coral , Dichiara-Rodríguez Gilda , Urdiciain Alejandro , López-Sagaseta Jacinto 
Published: September 2022

AbstractEvidence is mounting that the nature of the lipid bound to the endothelial cell protein C receptor (EPCR) has an impact on its biological roles, as observed in anticoagulation and more recently, in autoimmune disease. Phosphatidylethanolamine and phosphatidylcholine species dominate the EPCR lipid cargo, yet, the extent of diversity in the EPCR-associated lipid repertoire is still unknown and remains to be uncovered. We undertook mass spectrometry analyses to decipher the EPCR lipidome, and identified species not yet described as EPCR ligands, such as phosphatidylinositols and phosphatidylserines. Remarkably, we found further, more structurally divergent lipids classes, represented by ceramides and sphingomyelins, both in less abundant quantities. In support of our mass spectrometry results and previous studies, high-resolution crystal structures of EPCR in three different space groups point to a prevalent diacyl phospholipid moiety in EPCR’s pocket but a mobile and ambiguous lipid polar head group. In sum, these studies indicate that EPCR can associate with varied lipid classes, which might impact its properties in anticoagulation and the onset of autoimmune disease.
Sex-specific familial aggregation of cancers in Finland
Authors: Sipilä Lauri J. , Seppä Karri , Aavikko Mervi , Ravantti Janne , Heikkinen Sanna , Aaltonen Lauri A. , Pitkäniemi Janne 
Published: September 2022

AbstractDespite the fact that the effect of sex on the occurrence of cancers has been studied extensively, it remains unclear whether sex modifies familial aggregation of cancers. We explored sex-specific familial aggregation of cancers in a large population-based historical cohort study. We combined cancer and population registry data, inferring familial relationships from birth municipality-surname-sex (MNS) combinations. Our data consisted of 391,529 incident primary cancers in 377,210 individuals with 319,872 different MNS combinations. Cumulative sex-specific numbers of cancers were compared to expected cumulative incidence. Familial cancer risks were similar between the sexes in our population-wide analysis. Families with concordant cancer in both sexes exhibited similar sex-specific cancer risks. However, some families had exceptionally high sex-specific cumulative cancer incidence. We identified six families with exceptionally strong aggregation in males: three families with thyroid cancer (ratio between observed and expected incidence 184.6; 95% credible interval (95% CI) 33.1–1012.7, 173.4 (95% CI 65.4–374.3), and 161.4 (95% CI 29.6–785.7), one with stomach (ratio 14.4 (95% CI 6.9–37.2)), colon (ratio 15.5 (95% CI 5.7–56.3)) cancers and one with chronic lymphocytic leukaemia (ratio 33.5 (95% CI 17.2–207.6)). Our results imply that familial aggregation of cancers shows no sex-specific preference. However, the atypical sex-specific aggregation of stomach cancer, colon cancer, thyroid cancer and chronic lymphocytic leukaemia in certain families is difficult to fully explain with present knowledge of possible causes, and could yield useful knowledge if explored further.
Cultivating epizoic diatoms provides insights into the evolution and ecology of both epibionts and hosts
Authors: Ashworth Matt P. , Majewska Roksana , Frankovich Thomas A. , Sullivan Michael , Bosak Sunčica , Filek Klara , Van de Vijver Bart , Arendt Michael , Schwenter Jeffrey , Nel Ronel , Robinson Nathan J. , Gary Meagan P. , Theriot Edward C. , Stacy Nicole I. , Lam Daryl W. , Perrault Justin R. , Manire Charles A. , Manning Schonna R. 
Published: September 2022

AbstractOur understanding of the importance of microbiomes on large aquatic animals—such as whales, sea turtles and manatees—has advanced considerably in recent years. The latest observations indicate that epibiotic diatom communities constitute diverse, polyphyletic, and compositionally stable assemblages that include both putatively obligate epizoic and generalist species. Here, we outline a successful approach to culture putatively obligate epizoic diatoms without their hosts. That some taxa can be cultured independently from their epizoic habitat raises several questions about the nature of the interaction between these animals and their epibionts. This insight allows us to propose further applications and research avenues in this growing area of study. Analyzing the DNA sequences of these cultured strains, we found that several unique diatom taxa have evolved independently to occupy epibiotic habitats. We created a library of reference sequence data for use in metabarcoding surveys of sea turtle and manatee microbiomes that will further facilitate the use of environmental DNA for studying host specificity in epizoic diatoms and the utility of diatoms as indicators of host ecology and health. We encourage the interdisciplinary community working with marine megafauna to consider including diatom sampling and diatom analysis into their routine practices.
Electron temperature and density measurement by Thomson scattering with a high repetition rate laser of 20 kHz on LHD
Authors: Funaba H. , Yasuhara R. , Uehara H. , Yamada I. , Sakamoto R. , Osakabe M. , Den Hartog D. J. 
Published: September 2022

AbstractThomson scattering measurements with a high-repetition-rate laser have commenced in the Large Helical Device. As an example of the fast phenomena captured by this diagnostic system, measurements at a 20 kHz repetition-rate in hydrogen pellet-injected plasmas are presented. Signal processing methods for this measurement have been developed and electron temperature profiles with almost 70 spatial points were evaluated at time intervals of 50 $$\upmu$$
μ
s. After Raman scattering calibration, electron density profiles were derived. Fast changes in the electron temperature and density profiles within 1 ms were observed.