bluuebunny/crossref_metadata_2025_split huggingface dataset:
NLK is required for Ras/ERK/SRF/ELK signaling to tune skeletal muscle development by phosphorylating SRF and antagonizing the SRF/MKL pathway
Authors: Li Shang-Ze , Zhang Ze-Yan , Chen Jie , Dong Ming-You , Du Xue-Hua , Gao Jie , Shu Qi-Peng , Li Chao , Liang Xin-Yi , Ding Zhi-Hao , Du Run-Lei , Wang Junli , Zhang Xiao-Dong 
Published: January 2022

AbstractSerum response factor (SRF) regulates differentiation and proliferation by binding to RhoA-actin-activated MKL or Ras-MAPK-activated ELK transcriptional coactivators, but the molecular mechanisms responsible for SRF regulation remain unclear. Here, we show that Nemo-like kinase (NLK) is required for the promotion of SRF/ELK signaling in human and mouse cells. NLK was found to interact with and phosphorylate SRF at serine residues 101/103, which in turn enhanced the association between SRF and ELK. The enhanced affinity of SRF/ELK antagonized the SRF/MKL pathway and inhibited mouse myoblast differentiation in vitro. In a skeletal muscle-specific Nlk conditional knockout mouse model, forming muscle myofibers underwent hypertrophic growth, resulting in an increased muscle and body mass phenotype. We propose that both phosphorylation of SRF by NLK and phosphorylation of ELKs by MAPK are required for RAS/ELK signaling, confirming the importance of this ancient pathway and identifying an important role for NLK in modulating muscle development in vivo.
Tumor-derived extracellular vesicles inhibit HGF/c-Met and EGF/EGFR pathways to accelerate the radiosensitivity of nasopharyngeal carcinoma cells via microRNA-142-5p delivery
Authors: Zhu Changyu , Jiang Xiaolei , Xiao Hua , Guan Jianmei 
Published: January 2022

AbstractRadioresistance prevails as one of the largest obstacles in the clinical treatment of nasopharyngeal carcinoma (NPC). Meanwhile, tumor-derived extracellular vesicles (TEVs) possess the ability to manipulate radioresistance in NPC. However, its mechanism remains to be further explored. Therefore, the current study set out to explore the mechanism of microRNA (miR)-142-5p delivered by TEVs in regard to the radiosensitivity of NPC. Firstly, peripheral blood samples were collected from patients with radioresistance and radiosensitivity, followed by RT-qPCR detection of miR-142-5p expression. A dual-luciferase reporter assay was carried out to elucidate the targeting relationship of miR-142-5p with HGF and EGF. In addition, radiotherapy-resistant NPC cell models were established by screening NPC cells with gradient increasing radiation exposure, and co-incubated with EVs isolated from miR-142-5p mimic-transfected NPC cells, followed by overexpression of HGF and EGF. Moreover, cell viability was detected by means of MTS, cell proliferation with a colony formation assay, cell apoptosis with flow cytometry, and expression patterns of related genes with the help of Western blot analysis. NPC xenotransplantation models in nude mice were also established by subcutaneous injection of 5-8FR cells to determine apoptosis, tumorigenicity, and radiosensitivity in nude mice. It was found that miR-142-5p was poorly expressed in peripheral blood from NPC patients with radioresistance. Mechanistic experimentation illustrated that miR-142-5p inversely targeted HGF and EGF to inactivate the HGF/c-Met and EGF/EGFR pathways, respectively. NPC cell apoptosis was observed to be augmented, while their radioresistance and proliferation were restricted by EVs-miR-142-5p or HGF silencing, or EGF silencing. Furthermore, EVs-miR-142-5p inhibited growth and radioresistance and accelerated the apoptosis of radiotherapy-resistant NPC cells in nude mice by inhibiting the HGF/c-Met and EGF/EGFR pathways. Collectively, our findings indicated that TEVs might inhibit the HGF/c-Met and EGF/EGFR pathways by delivering miR-142-5p into radiotherapy-resistant NPC cells to enhance radiosensitivity in NPC.
METTL14 promotes apoptosis of spinal cord neurons by inducing EEF1A2 m6A methylation in spinal cord injury
Authors: Gao Gang , Duan Yufen , Chang Feng , Zhang Ting , Huang Xinhu , Yu Chen 
Published: January 2022

AbstractSpinal cord injury (SCI) is a devastating traumatic condition. METTL14-mediated m6A modification is associated with SCI. This study was intended to investigate the functional mechanism of RNA methyltransferase METTL14 in spinal cord neuron apoptosis during SCI. The SCI rat model was established, followed by evaluation of pathological conditions, apoptosis, and viability of spinal cord neurons. The neuronal function of primary cultured spinal motoneurons of rats was assessed after hypoxia/reoxygenation treatment. Expressions of EEF1A2, Akt/mTOR pathway-related proteins, inflammatory cytokines, and apoptosis-related proteins were detected. EEF1A2 was weakly expressed and Akt/mTOR pathway was inhibited in SCI rat models. Hypoxia/Reoxygenation decreased the viability of spinal cord neurons, promoted LDH release and neuronal apoptosis. EEF1A2 overexpression promoted the viability of spinal cord neurons, inhibited neuronal apoptosis, and decreased inflammatory cytokine levels. Silencing METTL14 inhibited m6A modification of EEF1A2 and increased EEF1A2 expression while METTL14 overexpression showed reverse results. EEF1A2 overexpression promoted viability and inhibited apoptosis of spinal cord neurons and inflammation by activating the Akt/mTOR pathway. In conclusion, silencing METTL14 repressed apoptosis of spinal cord neurons and attenuated SCI by inhibiting m6A modification of EEF1A2 and activating the Akt/mTOR pathway.
A de novo paradigm for male infertility
Authors: Oud M. S. , Smits R. M. , Smith H. E. , Mastrorosa F. K. , Holt G. S. , Houston B. J. , de Vries P. F. , Alobaidi B. K. S. , Batty L. E. , Ismail H. , Greenwood J. , Sheth H. , Mikulasova A. , Astuti G. D. N. , Gilissen C. , McEleny K. , Turner H. , Coxhead J. , Cockell S. , Braat D. D. M. , Fleischer K. , D’Hauwers K. W. M. , Schaafsma E. ,   Genetics of Male Infertility Initiative (GEMINI) consortium, Conrad Donald F. , Nagirnaja Liina , Aston Kenneth I. , Carrell Douglas T. , Hotaling James M. , Jenkins Timothy G. , McLachlan Rob , O’Bryan Moira K. , Schlegel Peter N. , Eisenberg Michael L. , Sandlow Jay I. , Jungheim Emily S. , Omurtag Kenan R. , Lopes Alexandra M. , Seixas Susana , Carvalho Filipa , Fernandes Susana , Barros Alberto , Gonçalves João , Caetano Iris , Pinto Graça , Correia Sónia , Laan Maris , Punab Margus , Meyts Ewa Rajpert-De , Jørgensen Niels , Almstrup Kristian , Krausz Csilla G. , Jarvi Keith A. , Nagirnaja L. , Conrad D. F. , Friedrich C. , Kliesch S. , Aston K. I. , Riera-Escamilla A. , Krausz C. , Gonzaga-Jauregui C. , Santibanez-Koref M. , Elliott D. J. , Vissers L. E. L. M. , Tüttelmann F. , O’Bryan M. K. , Ramos L. , Xavier M. J. , van der Heijden G. W. , Veltman J. A. 
Published: January 2022

AbstractDe novo mutations are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that de novo mutations play an important role in severe male infertility and explain a portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome sequencing in a cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare (MAF < 0.1%) protein-altering de novo mutations are classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of loss-of-function de novo mutations in loss-of-function-intolerant genes (p-value = 1.00 × 10−5) in infertile men compared to controls. Additionally, we detected a significant increase in predicted pathogenic de novo missense mutations affecting missense-intolerant genes (p-value = 5.01 × 10−4) in contrast to predicted benign de novo mutations. One gene we identify, RBM5, is an essential regulator of male germ cell pre-mRNA splicing and has been previously implicated in male infertility in mice. In a follow-up study, 6 rare pathogenic missense mutations affecting this gene are observed in a cohort of 2,506 infertile patients, whilst we find no such mutations in a cohort of 5,784 fertile men (p-value = 0.03). Our results provide evidence for the role of de novo mutations in severe male infertility and point to new candidate genes affecting fertility.
Aminoacyl chain translocation catalysed by a type II thioesterase domain in an unusual non-ribosomal peptide synthetase
Authors: Wang Shan , Brittain William D. G. , Zhang Qian , Lu Zhou , Tong Ming Him , Wu Kewen , Kyeremeh Kwaku , Jenner Matthew , Yu Yi , Cobb Steven L. , Deng Hai 
Published: January 2022

AbstractNon-Ribosomal Peptide Synthetases (NRPSs) assemble a diverse range of natural products with important applications in both medicine and agriculture. They consist of several multienzyme subunits that must interact with each other in a highly controlled manner to facilitate efficient chain transfer, thus ensuring biosynthetic fidelity. Several mechanisms for chain transfer are known for NRPSs, promoting structural diversity. Herein, we report the first biochemically characterized example of a type II thioesterase (TEII) domain capable of catalysing aminoacyl chain transfer between thiolation (T) domains on two separate NRPS subunits responsible for installation of a dehydrobutyrine moiety. Biochemical dissection of this process reveals the central role of the TEII-catalysed chain translocation event and expands the enzymatic scope of TEII domains beyond canonical (amino)acyl chain hydrolysis. The apparent co-evolution of the TEII domain with the NRPS subunits highlights a unique feature of this enzymatic cassette, which will undoubtedly find utility in biosynthetic engineering efforts.
Clenbuterol exerts antidiabetic activity through metabolic reprogramming of skeletal muscle cells
Authors: Meister Jaroslawna , Bone Derek B. J. , Knudsen Jonas R. , Barella Luiz F. , Velenosi Thomas J. , Akhmedov Dmitry , Lee Regina J. , Cohen Amanda H. , Gavrilova Oksana , Cui Yinghong , Karsenty Gerard , Chen Min , Weinstein Lee S. , Kleinert Maximilian , Berdeaux Rebecca , Jensen Thomas E. , Richter Erik A. , Wess Jürgen 
Published: January 2022

AbstractActivation of the sympathetic nervous system causes pronounced metabolic changes that are mediated by multiple adrenergic receptor subtypes. Systemic treatment with β2-adrenergic receptor agonists results in multiple beneficial metabolic effects, including improved glucose homeostasis. To elucidate the underlying cellular and molecular mechanisms, we chronically treated wild-type mice and several newly developed mutant mouse strains with clenbuterol, a selective β2-adrenergic receptor agonist. Clenbuterol administration caused pronounced improvements in glucose homeostasis and prevented the metabolic deficits in mouse models of β-cell dysfunction and insulin resistance. Studies with skeletal muscle-specific mutant mice demonstrated that these metabolic improvements required activation of skeletal muscle β2-adrenergic receptors and the stimulatory G protein, Gs. Unbiased transcriptomic and metabolomic analyses showed that chronic β2-adrenergic receptor stimulation caused metabolic reprogramming of skeletal muscle characterized by enhanced glucose utilization. These findings strongly suggest that agents targeting skeletal muscle metabolism by modulating β2-adrenergic receptor-dependent signaling pathways may prove beneficial as antidiabetic drugs.
Time-periodic corner states from Floquet higher-order topology
Authors: Zhu Weiwei , Xue Haoran , Gong Jiangbin , Chong Yidong , Zhang Baile 
Published: January 2022

AbstractThe recent discoveries of higher-order topological insulators (HOTIs) have shifted the paradigm of topological materials, previously limited to topological states at boundaries of materials, to include topological states at boundaries of boundaries, such as corners. So far, all HOTI realisations have been based on static systems described by time-invariant Hamiltonians, without considering the time-variant situation. There is growing interest in Floquet systems, in which time-periodic driving can induce unconventional phenomena such as Floquet topological phases and time crystals. Recent theories have attempted to combine Floquet engineering and HOTIs, but there has been no experimental realisation so far. Here we report on the experimental demonstration of a two-dimensional (2D) Floquet HOTI in a three-dimensional (3D) acoustic lattice, with modulation along a spatial axis serving as an effective time-dependent drive. Acoustic measurements reveal Floquet corner states with double the period of the underlying drive; these oscillations are robust, like time crystal modes, except that the robustness arises from topological protection. This shows that space-time dynamics can induce anomalous higher-order topological phases unique to Floquet systems.
The 2018 European heatwave led to stem dehydration but not to consistent growth reductions in forests
Authors: Salomón Roberto L. , Peters Richard L. , Zweifel Roman , Sass-Klaassen Ute G. W. , Stegehuis Annemiek I. , Smiljanic Marko , Poyatos Rafael , Babst Flurin , Cienciala Emil , Fonti Patrick , Lerink Bas J. W. , Lindner Marcus , Martinez-Vilalta Jordi , Mencuccini Maurizio , Nabuurs Gert-Jan , van der Maaten Ernst , von Arx Georg , Bär Andreas , Akhmetzyanov Linar , Balanzategui Daniel , Bellan Michal , Bendix Jörg , Berveiller Daniel , Blaženec Miroslav , Čada Vojtěch , Carraro Vinicio , Cecchini Sébastien , Chan Tommy , Conedera Marco , Delpierre Nicolas , Delzon Sylvain , Ditmarová Ľubica , Dolezal Jiri , Dufrêne Eric , Edvardsson Johannes , Ehekircher Stefan , Forner Alicia , Frouz Jan , Ganthaler Andrea , Gryc Vladimír , Güney Aylin , Heinrich Ingo , Hentschel Rainer , Janda Pavel , Ježík Marek , Kahle Hans-Peter , Knüsel Simon , Krejza Jan , Kuberski Łukasz , Kučera Jiří , Lebourgeois François , Mikoláš Martin , Matula Radim , Mayr Stefan , Oberhuber Walter , Obojes Nikolaus , Osborne Bruce , Paljakka Teemu , Plichta Roman , Rabbel Inken , Rathgeber Cyrille B. K. , Salmon Yann , Saunders Matthew , Scharnweber Tobias , Sitková Zuzana , Stangler Dominik Florian , Stereńczak Krzysztof , Stojanović Marko , Střelcová Katarína , Světlík Jan , Svoboda Miroslav , Tobin Brian , Trotsiuk Volodymyr , Urban Josef , Valladares Fernando , Vavrčík Hanuš , Vejpustková Monika , Walthert Lorenz , Wilmking Martin , Zin Ewa , Zou Junliang , Steppe Kathy 
Published: January 2022

AbstractHeatwaves exert disproportionately strong and sometimes irreversible impacts on forest ecosystems. These impacts remain poorly understood at the tree and species level and across large spatial scales. Here, we investigate the effects of the record-breaking 2018 European heatwave on tree growth and tree water status using a collection of high-temporal resolution dendrometer data from 21 species across 53 sites. Relative to the two preceding years, annual stem growth was not consistently reduced by the 2018 heatwave but stems experienced twice the temporary shrinkage due to depletion of water reserves. Conifer species were less capable of rehydrating overnight than broadleaves across gradients of soil and atmospheric drought, suggesting less resilience toward transient stress. In particular, Norway spruce and Scots pine experienced extensive stem dehydration. Our high-resolution dendrometer network was suitable to disentangle the effects of a severe heatwave on tree growth and desiccation at large-spatial scales in situ, and provided insights on which species may be more vulnerable to climate extremes.
Polygenic contribution to the relationship of loneliness and social isolation with schizophrenia
Authors: Andreu-Bernabeu Álvaro , Díaz-Caneja Covadonga M. , Costas Javier , De Hoyos Lucía , Stella Carol , Gurriarán Xaquín , Alloza Clara , Fañanás Lourdes , Bobes Julio , González-Pinto Ana , Crespo-Facorro Benedicto , Martorell Lourdes , Vilella Elisabet , Muntané Gerard , Nacher Juan , Molto María Dolores , Aguilar Eduardo Jesús , Parellada Mara , Arango Celso , González-Peñas Javier 
Published: January 2022

AbstractPrevious research suggests an association of loneliness and social isolation (LNL-ISO) with schizophrenia. Here, we demonstrate a LNL-ISO polygenic score contribution to schizophrenia risk in an independent case-control sample (N = 3,488). We then subset schizophrenia predisposing variation based on its effect on LNL-ISO. We find that genetic variation with concordant effects in both phenotypes shows significant SNP-based heritability enrichment, higher polygenic contribution in females, and positive covariance with mental disorders such as depression, anxiety, attention-deficit hyperactivity disorder, alcohol dependence, and autism. Conversely, genetic variation with discordant effects only contributes to schizophrenia risk in males and is negatively correlated with those disorders. Mendelian randomization analyses demonstrate a plausible bi-directional causal relationship between LNL-ISO and schizophrenia, with a greater effect of LNL-ISO liability on schizophrenia than vice versa. These results illustrate the genetic footprint of LNL-ISO on schizophrenia.
EZH2 depletion potentiates MYC degradation inhibiting neuroblastoma and small cell carcinoma tumor formation
Authors: Wang Liyuan , Chen Chan , Song Zemin , Wang Honghong , Ye Minghui , Wang Donghai , Kang Wenqian , Liu Hudan , Qing Guoliang 
Published: January 2022

AbstractEfforts to therapeutically target EZH2 have generally focused on inhibition of its methyltransferase activity, although it remains less clear whether this is the central mechanism whereby EZH2 promotes cancer. In the current study, we show that EZH2 directly interacts with both MYC family oncoproteins, MYC and MYCN, and promotes their stabilization in a methyltransferase-independent manner. By competing against the SCFFBW7 ubiquitin ligase to bind MYC and MYCN, EZH2 counteracts FBW7-mediated MYC(N) polyubiquitination and proteasomal degradation. Depletion, but not enzymatic inhibition, of EZH2 induces robust MYC(N) degradation and inhibits tumor cell growth in MYC(N) driven neuroblastoma and small cell lung carcinoma. Here, we demonstrate the MYC family proteins as global EZH2 oncogenic effectors and EZH2 pharmacologic degraders as potential MYC(N) targeted cancer therapeutics, pointing out that MYC(N) driven cancers may develop inherent resistance to the canonical EZH2 enzymatic inhibitors currently in clinical development.
Potential for future reductions of global GHG and air pollutants from circular waste management systems
Authors: Gómez-Sanabria Adriana , Kiesewetter Gregor , Klimont Zbigniew , Schoepp Wolfgang , Haberl Helmut 
Published: January 2022

AbstractThe rapidly rising generation of municipal solid waste jeopardizes the environment and contributes to climate heating. Based on the Shared Socioeconomic Pathways, we here develop a global systematic approach for evaluating the potentials to reduce emissions of greenhouse gases and air pollutants from the implementation of circular municipal waste management systems. We contrast two sets of global scenarios until 2050, namely baseline and mitigation scenarios, and show that mitigation strategies in the sustainability-oriented scenario yields earlier, and major, co-benefits compared to scenarios in which inequalities are reduced but that are focused solely on technical solutions. The sustainability-oriented scenario leaves 386 Tg CO2eq/yr of GHG (CH4 and CO2) to be released while air pollutants from open burning can be eliminated, indicating that this source of ambient air pollution can be entirely eradicated before 2050.
An assembly of nuclear bodies associates with the active VSG expression site in African trypanosomes
Authors: Budzak James , Jones Robert , Tschudi Christian , Kolev Nikolay G. , Rudenko Gloria 
Published: January 2022

AbstractA Variant Surface Glycoprotein (VSG) coat protects bloodstream form Trypanosoma brucei. Prodigious amounts of VSG mRNA (~7-10% total) are generated from a single RNA polymerase I (Pol I) transcribed VSG expression site (ES), necessitating extremely high levels of localised splicing. We show that splicing is required for processive ES transcription, and describe novel ES-associated T. brucei nuclear bodies. In bloodstream form trypanosomes, the expression site body (ESB), spliced leader array body (SLAB), NUFIP body and Cajal bodies all frequently associate with the active ES. This assembly of nuclear bodies appears to facilitate the extraordinarily high levels of transcription and splicing at the active ES. In procyclic form trypanosomes, the NUFIP body and SLAB do not appear to interact with the Pol I transcribed procyclin locus. The congregation of a restricted number of nuclear bodies at a single active ES, provides an attractive mechanism for how monoallelic ES transcription is mediated.
Skeletal muscle derived Musclin protects the heart during pathological overload
Authors: Szaroszyk Malgorzata , Kattih Badder , Martin-Garrido Abel , Trogisch Felix A. , Dittrich Gesine M. , Grund Andrea , Abouissa Aya , Derlin Katja , Meier Martin , Holler Tim , Korf-Klingebiel Mortimer , Völker Katharina , Garfias Macedo Tania , Pablo Tortola Cristina , Boschmann Michael , Huang Nora , Froese Natali , Zwadlo Carolin , Malek Mohammadi Mona , Luo Xiaojing , Wagner Michael , Cordero Julio , Geffers Robert , Batkai Sandor , Thum Thomas , Bork Nadja , Nikolaev Viacheslav O. , Müller Oliver J. , Katus Hugo A. , El-Armouche Ali , Kraft Theresia , Springer Jochen , Dobreva Gergana , Wollert Kai C. , Fielitz Jens , von Haehling Stephan , Kuhn Michaela , Bauersachs Johann , Heineke Joerg 
Published: January 2022

AbstractCachexia is associated with poor prognosis in chronic heart failure patients, but the underlying mechanisms of cachexia triggered disease progression remain poorly understood. Here, we investigate whether the dysregulation of myokine expression from wasting skeletal muscle exaggerates heart failure. RNA sequencing from wasting skeletal muscles of mice with heart failure reveals a reduced expression ofOstn, which encodes the secreted myokine Musclin, previously implicated in the enhancement of natriuretic peptide signaling. By generating skeletal muscle specificOstnknock-out and overexpressing mice, we demonstrate that reduced skeletal muscle Musclin levels exaggerate, while its overexpression in muscle attenuates cardiac dysfunction and myocardial fibrosis during pressure overload. Mechanistically, Musclin enhances the abundance of C-type natriuretic peptide (CNP), thereby promoting cardiomyocyte contractility through protein kinase A and inhibiting fibroblast activation through protein kinase G signaling. Because we also find reducedOSTNexpression in skeletal muscle of heart failure patients, augmentation of Musclin might serve as therapeutic strategy.