bluuebunny/crossref_metadata_2025_split huggingface dataset:
PPARγ lipodystrophy mutants reveal intermolecular interactions required for enhancer activation
Authors: Madsen Maria Stahl , Broekema Marjoleine F. , Madsen Martin Rønn , Koppen Arjen , Borgman Anouska , Gräwe Cathrin , Thomsen Elisabeth G. K. , Westland Denise , Kranendonk Mariette E. G. , Koerkamp Marian Groot , Hamers Nicole , Bonvin Alexandre M. J. J. , Pittol José M. Ramos , Natarajan Kedar Nath , Kersten Sander , Holstege Frank C. P. , Monajemi Houshang , van Mil Saskia W. C. , Vermeulen Michiel , Kragelund Birthe B. , Cassiman David , Mandrup Susanne , Kalkhoven Eric 
Published: November 2022

AbstractPeroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipocyte differentiation, and mutations that interfere with its function cause lipodystrophy. PPARγ is a highly modular protein, and structural studies indicate that PPARγ domains engage in several intra- and inter-molecular interactions. How these interactions modulate PPARγ’s ability to activate target genes in a cellular context is currently poorly understood. Here we take advantage of two previously uncharacterized lipodystrophy mutations, R212Q and E379K, that are predicted to interfere with the interaction of the hinge of PPARγ with DNA and with the interaction of PPARγ ligand binding domain (LBD) with the DNA-binding domain (DBD) of the retinoid X receptor, respectively. Using biochemical and genome-wide approaches we show that these mutations impair PPARγ function on an overlapping subset of target enhancers. The hinge region-DNA interaction appears mostly important for binding and remodelling of target enhancers in inaccessible chromatin, whereas the PPARγ-LBD:RXR-DBD interface stabilizes the PPARγ:RXR:DNA ternary complex. Our data demonstrate how in-depth analyses of lipodystrophy mutants can unravel molecular mechanisms of PPARγ function.
Model spread in tropical low cloud feedback tied to overturning circulation response to warming
Authors: Schiro Kathleen A. , Su Hui , Ahmed Fiaz , Dai Ni , Singer Clare E. , Gentine Pierre , Elsaesser Gregory S. , Jiang Jonathan H. , Choi Yong-Sang , David Neelin J. 
Published: November 2022

AbstractAmong models participating in the Coupled Model Intercomparison Project phase 6 (CMIP6), here we show that the magnitude of the tropical low cloud feedback, which contributes considerably to uncertainty in estimates of climate sensitivity, is intimately linked to tropical deep convection and its effects on the tropical atmospheric overturning circulation. First, a reduction in tropical ascent area and an increased frequency of heavy precipitation result in high cloud reduction and upper-tropospheric drying, which increases longwave cooling and reduces subsidence weakening, favoring low cloud reduction (Radiation-Subsidence Pathway). Second, increased longwave cooling decreases tropospheric stability, which also reduces subsidence weakening and low cloudiness (Stability-Subsidence Pathway). In summary, greater high cloud reduction and upper-tropospheric drying (negative longwave feedback) lead to a more positive cloud feedback among CMIP6 models by contributing to a greater reduction in low cloudiness (positive shortwave feedback). Varying strengths of the two pathways contribute considerably to the intermodel spread in climate sensitivity.
Phosphorylation disrupts long-distance electron transport in cytochrome c
Authors: Gomila Alexandre M. J. , Pérez-Mejías Gonzalo , Nin-Hill Alba , Guerra-Castellano Alejandra , Casas-Ferrer Laura , Ortiz-Tescari Sthefany , Díaz-Quintana Antonio , Samitier Josep , Rovira Carme , De la Rosa Miguel A. , Díaz-Moreno Irene , Gorostiza Pau , Giannotti Marina I. , Lagunas Anna 
Published: November 2022

AbstractIt has been recently shown that electron transfer between mitochondrial cytochrome c and the cytochrome c1 subunit of the cytochrome bc1 can proceed at long-distance through the aqueous solution. Cytochrome c is thought to adjust its activity by changing the affinity for its partners via Tyr48 phosphorylation, but it is unknown how it impacts the nanoscopic environment, interaction forces, and long-range electron transfer. Here, we constrain the orientation and separation between cytochrome c1 and cytochrome c or the phosphomimetic Y48pCMF cytochrome c, and deploy an array of single-molecule, bulk, and computational methods to investigate the molecular mechanism of electron transfer regulation by cytochrome c phosphorylation. We demonstrate that phosphorylation impairs long-range electron transfer, shortens the long-distance charge conduit between the partners, strengthens their interaction, and departs it from equilibrium. These results unveil a nanoscopic view of the interaction between redox protein partners in electron transport chains and its mechanisms of regulation.
Transposable element-mediated rearrangements are prevalent in human genomes
Authors: Balachandran Parithi , Walawalkar Isha A. , Flores Jacob I. , Dayton Jacob N. , Audano Peter A. , Beck Christine R. 
Published: November 2022

AbstractTransposable elements constitute about half of human genomes, and their role in generating human variation through retrotransposition is broadly studied and appreciated. Structural variants mediated by transposons, which we call transposable element-mediated rearrangements (TEMRs), are less well studied, and the mechanisms leading to their formation as well as their broader impact on human diversity are poorly understood. Here, we identify 493 unique TEMRs across the genomes of three individuals. While homology directed repair is the dominant driver of TEMRs, our sequence-resolved TEMR resource allows us to identify complex inversion breakpoints, triplications or other high copy number polymorphisms, and additional complexities. TEMRs are enriched in genic loci and can create potentially important risk alleles such as a deletion in TRIM65, a known cancer biomarker and therapeutic target. These findings expand our understanding of this important class of structural variation, the mechanisms responsible for their formation, and establish them as an important driver of human diversity.
Pharmacological inhibition of HDAC6 improves muscle phenotypes in dystrophin-deficient mice by downregulating TGF-β via Smad3 acetylation
Authors: Osseni Alexis , Ravel-Chapuis Aymeric , Belotti Edwige , Scionti Isabella , Gangloff Yann-Gaël , Moncollin Vincent , Mazelin Laetitia , Mounier Remi , Leblanc Pascal , Jasmin Bernard J. , Schaeffer Laurent 
Published: November 2022

AbstractThe absence of dystrophin in Duchenne muscular dystrophy disrupts the dystrophin-associated glycoprotein complex resulting in skeletal muscle fiber fragility and atrophy, associated with fibrosis as well as microtubule and neuromuscular junction disorganization. The specific, non-conventional cytoplasmic histone deacetylase 6 (HDAC6) was recently shown to regulate acetylcholine receptor distribution and muscle atrophy. Here, we report that administration of the HDAC6 selective inhibitor tubastatin A to the Duchenne muscular dystrophy,mdxmouse model increases muscle strength, improves microtubule, neuromuscular junction, and dystrophin-associated glycoprotein complex organization, and reduces muscle atrophy and fibrosis. Interestingly, we found that the beneficial effects of HDAC6 inhibition involve the downregulation of transforming growth factor beta signaling. By increasing Smad3 acetylation in the cytoplasm, HDAC6 inhibition reduces Smad2/3 phosphorylation, nuclear translocation, and transcriptional activity. These findings provide in vivo evidence that Smad3 is a new target of HDAC6 and implicate HDAC6 as a potential therapeutic target in Duchenne muscular dystrophy.
Photocatalytic direct borylation of carboxylic acids
Authors: Wei Qiang , Lee Yuhsuan , Liang Weiqiu , Chen Xiaolei , Mu Bo-shuai , Cui Xi-Yang , Wu Wangsuo , Bai Shuming , Liu Zhibo 
Published: November 2022

AbstractThe preparation of high value-added boronic acids from cheap and plentiful carboxylic acids is desirable. To date, the decarboxylative borylation of carboxylic acids is generally realized through the extra step synthesized redox-active ester intermediate or in situ generated carboxylic acid covalent derivatives above 150 °C reaction temperature. Here, we report a direct decarboxylative borylation method of carboxylic acids enabled by visible-light catalysis and that does not require any extra stoichiometric additives or synthesis steps. This operationally simple process produces CO2 and proceeds under mild reaction conditions, in terms of high step economy and good functional group compatibility. A guanidine-based biomimetic active decarboxylative mechanism is proposed and rationalized by mechanistic studies. The methodology reported herein should see broad application extending beyond borylation.
Covalent organic framework membranes for efficient separation of monovalent cations
Authors: Wang Hongjian , Zhai Yeming , Li Yang , Cao Yu , Shi Benbing , Li Runlai , Zhu Zingting , Jiang Haifei , Guo Zheyuan , Wang Meidi , Chen Long , Liu Yawei , Zhou Kai-Ge , Pan Fusheng , Jiang Zhongyi 
Published: November 2022

AbstractCovalent organic frameworks (COF), with rigid, highly ordered and tunable structures, can actively manipulate the synergy of entropic selectivity and enthalpic selectivity, holding great potential as next-generation membrane materials for ion separations. Here, we demonstrated the efficient separation of monovalent cations by COF membrane. The channels of COF membrane are decorated with three different kinds of acid groups. A concept of confined cascade separation was proposed to elucidate the separation process. The channels of COF membrane comprised two kinds of domains, acid-domains and acid-free-domains. The acid-domains serve as confined stages, rendering high selectivity, while the acid-free-domains preserve the pristine channel size, rendering high permeation flux. A set of descriptors of stage properties were designed to elucidate their effect on selective ion transport behavior. The resulting COF membrane acquired high ion separation performances, with an actual selectivity of 4.2–4.7 for K+/Li+ binary mixtures and an ideal selectivity of ~13.7 for K+/Li+.
DNA mechanical flexibility controls DNA potential to activate cGAS-mediated immune surveillance
Authors: Wang Lina , Li Siru , Wang Kai , Wang Na , Liu Qiaoling , Sun Zhen , Wang Li , Wang Lulu , Liu Quentin , Song Chengli , Liu Caigang , Yang Qingkai 
Published: November 2022

AbstractDNA is well-documented to stimulate immune response. However, the nature of the DNA to activate immune surveillance is less understood. Here, we show that the activation of cyclic GMP-AMP synthase (cGAS) depends on DNA mechanical flexibility, which is controlled by DNA-sequence, -damage and -length. Consistently, DNA-sequence was shown to control cGAS activation. Structural analyses revealed that a conserved cGAS residue (mouse R222 or human R236) contributed to the DNA-flexibility detection. And the residue substitution neutralised the flexibility-controlled DNA-potential to activate cGAS, and relaxed the DNA-length specificity of cGAS. Moreover, low dose radiation was shown to mount cGAS-mediated acute immune surveillance (AIS) via repairable (reusable) DNAs in hrs. Loss of cGAS-mediated AIS decreased the regression of local and abscopal tumours in the context of focal radiation and immune checkpoint blockade. Our results build a direct link between immunosurveillance and DNA mechanical feature.
Continuous resin refilling and hydrogen bond synergistically assisted 3D structural color printing
Authors: Zhang Yu , Zhang Lidian , Zhang Chengqi , Wang Jingxia , Liu Junchao , Ye Changqing , Dong Zhichao , Wu Lei , Song Yanlin 
Published: November 2022

Abstract3D photonic crystals (PCs) have attracted extensive attention due to their unique optical properties. However, fabricating 3D PCs structure by 3D printing colloidal particles is limited by control of assembly under a fast-printing speed. Here, we employ continuous digital light processing (DLP) 3D printing strategy with hydrogen bonds assisted colloidal inks for fabricating well-assembled 3D PCs structures. Stable dispersion of colloidal particles inside UV-curable system induced by hydrogen bonding and suction force induced by continuous curing manner cooperatively realize the simultaneous macroscopic printing and microscopic particle assembly, which endows volumetric color property. Structural color can be well regulated by controlling the particle diameter and printing speed, through which various complex 3D structures with desired structural color distribution and optical light-guide properties are acquired. This 3D color construction approach shows great potential in customized jewelry accessories, decoration and optical device preparation, and will innovate the development of structural color.
PEAR1 regulates expansion of activated fibroblasts and deposition of extracellular matrix in pulmonary fibrosis
Authors: Geng Yan , Li Lin , Yan Jie , Liu Kevin , Yang Aizhen , Zhang Lin , Shen Yingzhi , Gao Han , Wu Xuefeng , Noth Imre , Huang Yong , Liu Junling , Fan Xuemei 
Published: November 2022

AbstractPulmonary fibrosis is a chronic interstitial lung disease that causes irreversible and progressive lung scarring and respiratory failure. Activation of fibroblasts plays a central role in the progression of pulmonary fibrosis. Here we show that platelet endothelial aggregation receptor 1 (PEAR1) in fibroblasts may serve as a target for pulmonary fibrosis therapy. Pear1 deficiency in aged mice spontaneously causes alveolar collagens accumulation. Mesenchyme-specific Pear1 deficiency aggravates bleomycin-induced pulmonary fibrosis, confirming that PEAR1 potentially modulates pulmonary fibrosis progression via regulation of mesenchymal cell function. Moreover, single cell and bulk tissue RNA-seq analysis of pulmonary fibroblast reveals the expansion of Activated-fibroblast cluster and enrichment of marker genes in extracellular matrix development in Pear1−/− fibrotic lungs. We further show that PEAR1 associates with Protein Phosphatase 1 to suppress fibrotic factors-induced intracellular signalling and fibroblast activation. Intratracheal aerosolization of monoclonal antibodies activating PEAR1 greatly ameliorates pulmonary fibrosis in both WT and Pear1-humanized mice, significantly improving their survival rate.
Structure of the human heparan sulfate polymerase complex EXT1-EXT2
Authors: Leisico Francisco , Omeiri Juneina , Le Narvor Christine , Beaudouin Joël , Hons Michael , Fenel Daphna , Schoehn Guy , Couté Yohann , Bonnaffé David , Sadir Rabia , Lortat-Jacob Hugues , Wild Rebekka 
Published: November 2022

AbstractHeparan sulfates are complex polysaccharides that mediate the interaction with a broad range of protein ligands at the cell surface. A key step in heparan sulfate biosynthesis is catalyzed by the bi-functional glycosyltransferases EXT1 and EXT2, which generate the glycan backbone consisting of repeating N-acetylglucosamine and glucuronic acid units. The molecular mechanism of heparan sulfate chain polymerization remains, however, unknown. Here, we present the cryo-electron microscopy structure of human EXT1-EXT2, which reveals the formation of a tightly packed hetero-dimeric complex harboring four glycosyltransferase domains. A combination of in vitro and in cellulo mutational studies is used to dissect the functional role of the four catalytic sites. While EXT1 can catalyze both glycosyltransferase reactions, our results indicate that EXT2 might only have N-acetylglucosamine transferase activity. Our findings provide mechanistic insight into heparan sulfate chain elongation as a nonprocessive process and lay the foundation for future studies on EXT1-EXT2 function in health and disease.
Mutant RIG-I enhances cancer-related inflammation through activation of circRIG-I signaling
Authors: Song Jia , Zhao Wei , Zhang Xin , Tian Wenyu , Zhao Xuyang , Ma Liang , Cao Yongtong , Yin Yuxin , Zhang Xuehui , Deng Xuliang , Lu Dan 
Published: November 2022

AbstractRIG-I/DDX58 plays a key role in host innate immunity. However, its therapeutic potential for inflammation-related cancers remains to be explored. Here we identify frameshift germline mutations of RIG-I occurring in patients with colon cancer. Accordingly, Rig-ifs/fs mice bearing a frameshift mutant Rig-i exhibit increased susceptibility to colitis-related colon cancer as well as enhanced inflammatory response to chemical, virus or bacteria. In addition to interruption of Rig-i mRNA translation, the Rig-i mutation changes the secondary structure of Rig-i pre-mRNA and impairs its association with DHX9, consequently inducing a circular RNA generation from Rig-i transcript, thereby, designated as circRIG-I. CircRIG-I is frequently upregulated in colon cancers and its upregulation predicts poor outcome of colon cancer. Mechanistically, circRIG-I interacts with DDX3X, which in turn stimulates MAVS/TRAF5/TBK1 signaling cascade, eventually activating IRF3-mediated type I IFN transcription and aggravating inflammatory damage. Reciprocally, all-trans retinoic acid acts as a DHX9 agonist, ameliorates immunopathology through suppression of circRIG-I biogenesis. Collectively, our results provide insight into mutant RIG-I action and propose a potential strategy for the treatment of colon cancer.
Regioselective Ni-Catalyzed reductive alkylsilylation of acrylonitrile with unactivated alkyl bromides and chlorosilanes
Authors: Sun Jinwei , Zhou Yongze , Gu Rui , Li Xin , Liu Ao , Zhang Xuan 
Published: November 2022

AbstractTransition-metal catalyzed carbosilylation of alkenes using carbon electrophiles and silylmetal (-B, -Zn) reagents as the nucleophiles offers a powerful strategy for synthesizing organosilicones, by incorporating carbon and silyl groups across on C-C double bonds in one step. However, to the best of our knowledge, the study of silylative alkenes difunctionalization based on carbon and silyl electrophiles remains underdeveloped. Herein, we present an example of silylative alkylation of activated olefins with unactivated alkyl bromides and chlorosilanes as electrophiles under nickel catalysis. The main feature of this protocol is employing more easily accessible substrates including primary, secondary and tertiary alkyl bromides, as well as various chlorosilanes without using pre-generated organometallics. A wide range of alkylsilanes with diverse structures can be efficiently assembled in a single step, highlighting the good functionality tolerance of this approach. Furthermore, successful functionalization of bioactive molecules and synthetic applications using this method demonstrate its practicability.
BRAF activation by metabolic stress promotes glycolysis sensitizing NRASQ61-mutated melanomas to targeted therapy
Authors: McGrail Kimberley , Granado-Martínez Paula , Esteve-Puig Rosaura , García-Ortega Sara , Ding Yuxin , Sánchez-Redondo Sara , Ferrer Berta , Hernandez-Losa Javier , Canals Francesc , Manzano Anna , Navarro-Sabaté Aura , Bartrons Ramón , Yanes Oscar , Pérez-Alea Mileidys , Muñoz-Couselo Eva , Garcia-Patos Vicenç , Recio Juan A. 
Published: November 2022

AbstractNRAS-mutated melanoma lacks a specific line of treatment. Metabolic reprogramming is considered a novel target to control cancer; however,NRAS-oncogene contribution to this cancer hallmark is mostly unknown. Here, we show thatNRASQ61-mutated melanomas specific metabolic settings mediate cell sensitivity to sorafenib upon metabolic stress. Mechanistically, these cells are dependent on glucose metabolism, in which glucose deprivation promotes a switch from CRAF to BRAF signaling. This scenario contributes to cell survival and sustains glucose metabolism through BRAF-mediated phosphorylation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-2/3 (PFKFB2/PFKFB3). In turn, this favors the allosteric activation of phosphofructokinase-1 (PFK1), generating a feedback loop that couples glycolytic flux and the RAS signaling pathway. An in vivo treatment ofNRASQ61mutant melanomas, including patient-derived xenografts, with 2-deoxy-D-glucose (2-DG) and sorafenib effectively inhibits tumor growth. Thus, we provide evidence forNRAS-oncogene contributions to metabolic rewiring and a proof-of-principle for the treatment ofNRASQ61-mutated melanoma combining metabolic stress (glycolysis inhibitors) and previously approved drugs, such as sorafenib.
Back-illuminated photoelectrochemical flow cell for efficient CO2 reduction
Authors: Liu Bin , Wang Tuo , Wang Shujie , Zhang Gong , Zhong Dazhong , Yuan Tenghui , Dong Hao , Wu Bo , Gong Jinlong 
Published: November 2022

AbstractPhotoelectrochemical CO2 reduction reaction flow cells are promising devices to meet the requirements to produce solar fuels at the industrial scale. Photoelectrodes with wide bandgaps do not allow for efficient CO2 reduction at high current densities, while the integration of opaque photoelectrodes with narrow bandgaps in flow cell configurations still remains a challenge. This paper describes the design and fabrication of a back-illuminated Si photoanode promoted PEC flow cell for CO2 reduction reaction. The illumination area and catalytic sites of the Si photoelectrode are decoupled, owing to the effective passivation of defect states that allows for the long minority carrier diffusion length, that surpasses the thickness of the Si substrate. Hence, a solar-to-fuel conversion efficiency of CO of 2.42% and a Faradaic efficiency of 90% using Ag catalysts are achieved. For CO2 to C2+ products, the Faradaic efficiency of 53% and solar-to-fuel of 0.29% are achieved using Cu catalyst in flow cell.
Toxicity Index, patient-reported outcomes, and persistence of breast cancer chemotherapy-associated side effects in NRG Oncology/NSABP B-30
Authors: Henry N. Lynn , Kim Sungjin , Hays Ron D. , Diniz Marcio A. , Tighiouart Mourad , Gresham Gillian , Luu Michael , Cecchini Reena S. , Yothers Greg , Rogatko André , Ganz Patricia A. 
Published: November 2022

AbstractAdjuvant chemotherapy improves breast cancer survival but is associated with bothersome short- and long-term toxicity. Factors associated with toxicity, especially subacute toxicity up to 2 years following chemotherapy, have not been fully elucidated. The NRG Oncology/NSABP B-30 clinical trial compared 3 different doxorubicin-, cyclophosphamide-, and docetaxel-based chemotherapy regimens given over 3–6 months. Patients with hormone receptor-positive breast cancer received subsequent adjuvant endocrine therapy. From baseline through 24 months, 2156 patients completed questionnaires serially. We used multivariable probabilistic index models to identify factors associated with acute (>0–12 months) and subacute (>12–24 months) difficulties with pain, cognition, vasomotor symptoms, and vaginal symptoms. For all symptom domains, presence of symptoms prior to chemotherapy initiation were associated with symptoms in the subacute period (all p < 0.001). In addition, different combinations of patient factors and breast cancer treatments were associated with increased likelihood of pain, vasomotor, and vaginal symptoms in the subacute period. Consideration of pre-treatment symptoms and patient factors, as well as treatments for breast cancer, can facilitate identification of groups of patients that may experience symptoms following completion of chemotherapy. This information may be important for treatment-decision-making when alternative regimens are equivalent in benefit.