bluuebunny/crossref_metadata_2025 huggingface dataset:
MiRNA-124-3p.1 sensitizes hepatocellular carcinoma cells to sorafenib by regulating FOXO3a by targeting AKT2 and SIRT1
Authors: Dong Zhe-bin , Wu Heng-miao , He Yi-cheng , Huang Zhong-ting , Weng Yi-hui , Li Hong , Liang Chao , Yu Wei-ming , Chen Wei
Published: January 2022

As a multikinase inhibitor, sorafenib is commonly used to treat patients with advanced hepatocellular carcinoma (HCC), however, acquired resistance to sorafenib is a major obstacle to the effectiveness of this treatment. Thus, in this study, we investigated the mechanisms underlying sorafenib resistance as well as approaches devised to increase the sensitivity of HCC to sorafenib. We demonstrated that miR-124-3p.1 downregulation is associated with early recurrence in HCC patients who underwent curative surgery and sorafenib resistance in HCC cell lines. Regarding the mechanism of this phenomenon, we identified FOXO3a, an important cellular stress transcriptional factor, as the key factor in the function of miR-124-3p.1 in HCC. We showed that miR-124-3p.1 binds directly to AKT2 and SIRT1 to reduce the levels of these proteins. Furthermore, we showed that AKT2 and SIRT1 phosphorylate and deacetylate FOXO3a. We also found that miR-124-3p.1 maintains the dephosphorylation and acetylation of FOXO3a, leading to the nuclear location of FOXO3a and enhanced sorafenib-induced apoptosis. Moreover, the combination of miR-124-3p.1 mimics and sorafenib significantly enhanced the curative efficacy of sorafenib in a nude mouse HCC xenograft model. Collectively, our data reveal that miR-124-3p.1 represents a predictive indicator of early recurrence and sorafenib sensitivity in HCC. Furthermore, we demonstrate that miR-124-3p.1 enhances the curative efficacy of sorafenib through dual effects on FOXO3a. Thus, the miR-124-3p.1-FOXO3a axis is implicated as a potential target for the diagnosis and treatment of HCC.
ATF4/CEMIP/PKCα promotes anoikis resistance by enhancing protective autophagy in prostate cancer cells
Authors: Yu Ying , Liu Bing , Li Xuexiang , Lu Dingheng , Yang Likun , Chen Liang , Li Yunxue , Cheng Lulin , Lv Fang , Zhang Pu , Song Yarong , Xing Yifei
Published: January 2022

The survival of cancer cells after detaching from the extracellular matrix (ECM) is essential for the metastatic cascade. The programmed cell death after detachment is known as anoikis, acting as a metastasis barrier. However, the most aggressive cancer cells escape anoikis and other cell death patterns to initiate the metastatic cascade. This study revealed the role of cell migration-inducing protein (CEMIP) in autophagy modulation and anoikis resistance during ECM detachment. CEMIP amplification during ECM detachment resulted in protective autophagy induction via a mechanism dependent on the dissociation of the B-cell lymphoma-2 (Bcl-2)/Beclin1 complex. Additional investigation revealed that acting transcription factor 4 (ATF4) triggered CEMIP transcription and enhanced protein kinase C alpha (PKCα) membrane translocation, which regulated the serine70 phosphorylation of Bcl-2, while the subsequent dissociation of the Bcl-2/Beclin1 complex led to autophagy. Therefore, CEMIP antagonization attenuated metastasis formation in vivo. In conclusion, inhibiting CEMIP-mediated protective autophagy may provide a therapeutic strategy for metastatic prostate cancer (PCa). This study delineates a novel role of CEMIP in anoikis resistance and provides new insight into seeking therapeutic strategies for metastatic PCa.
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

Serum 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

Radioresistance 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

Spinal 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

De 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

Non-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

Activation 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

The 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

Heatwaves 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

Previous 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

Efforts 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

The 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

A 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

Cachexia 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.
Synthetic recovery of impulse propagation in myocardial infarction via silicon carbide semiconductive nanowires
Authors: Lagonegro Paola , Rossi Stefano , Salvarani Nicolò , Lo Muzio Francesco Paolo , Rozzi Giacomo , Modica Jessica , Bigi Franca , Quaretti Martina , Salviati Giancarlo , Pinelli Silvana , Alinovi Rossella , Catalucci Daniele , D’Autilia Francesca , Gazza Ferdinando , Condorelli Gianluigi , Rossi Francesca , Miragoli Michele
Published: January 2022

Myocardial infarction causes 7.3 million deaths worldwide, mostly for fibrillation that electrically originates from the damaged areas of the left ventricle. Conventional cardiac bypass graft and percutaneous coronary interventions allow reperfusion of the downstream tissue but do not counteract the bioelectrical alteration originated from the infarct area. Genetic, cellular, and tissue engineering therapies are promising avenues but require days/months for permitting proper functional tissue regeneration. Here we engineered biocompatible silicon carbide semiconductive nanowires that synthetically couple, via membrane nanobridge formations, isolated beating cardiomyocytes over distance, restoring physiological cell-cell conductance, thereby permitting the synchronization of bioelectrical activity in otherwise uncoupled cells. Local in-situ multiple injections of nanowires in the left ventricular infarcted regions allow rapid reinstatement of impulse propagation across damaged areas and recover electrogram parameters and conduction velocity. Here we propose this nanomedical intervention as a strategy for reducing ventricular arrhythmia after acute myocardial infarction.
Hyphal compartmentalization and sporulation in Streptomyces require the conserved cell division protein SepX
Authors: Bush Matthew J. , Gallagher Kelley A. , Chandra Govind , Findlay Kim C. , Schlimpert Susan
Published: January 2022

Filamentous actinobacteria such as Streptomyces undergo two distinct modes of cell division, leading to partitioning of growing hyphae into multicellular compartments via cross-walls, and to septation and release of unicellular spores. Specific determinants for cross-wall formation and the importance of hyphal compartmentalization for Streptomyces development are largely unknown. Here we show that SepX, an actinobacterial-specific protein, is crucial for both cell division modes in Streptomyces venezuelae. Importantly, we find that sepX-deficient mutants grow without cross-walls and that this substantially impairs the fitness of colonies and the coordinated progression through the developmental life cycle. Protein interaction studies and live-cell imaging suggest that SepX contributes to the stabilization of the divisome, a mechanism that also requires the dynamin-like protein DynB. Thus, our work identifies an important determinant for cell division in Streptomyces that is required for cellular development and sporulation.
TASOR epigenetic repressor cooperates with a CNOT1 RNA degradation pathway to repress HIV
Authors: Matkovic Roy , Morel Marina , Lanciano Sophie , Larrous Pauline , Martin Benjamin , Bejjani Fabienne , Vauthier Virginie , Hansen Maike M. K. , Emiliani Stéphane , Cristofari Gael , Gallois-Montbrun Sarah , Margottin-Goguet Florence
Published: January 2022

The Human Silencing Hub (HUSH) complex constituted of TASOR, MPP8 and Periphilin recruits the histone methyl-transferase SETDB1 to spread H3K9me3 repressive marks across genes and transgenes in an integration site-dependent manner. The deposition of these repressive marks leads to heterochromatin formation and inhibits gene expression, but the underlying mechanism is not fully understood. Here, we show that TASOR silencing or HIV-2 Vpx expression, which induces TASOR degradation, increases the accumulation of transcripts derived from the HIV-1 LTR promoter at a post-transcriptional level. Furthermore, using a yeast 2-hybrid screen, we identify new TASOR partners involved in RNA metabolism including the RNA deadenylase CCR4-NOT complex scaffold CNOT1. TASOR and CNOT1 synergistically repress HIV expression from its LTR. Similar to the RNA-induced transcriptional silencing complex found in fission yeast, we show that TASOR interacts with the RNA exosome and RNA Polymerase II, predominantly under its elongating state. Finally, we show that TASOR facilitates the association of RNA degradation proteins with RNA polymerase II and is detected at transcriptional centers. Altogether, we propose that HUSH operates at the transcriptional and post-transcriptional levels to repress HIV proviral expression.
Metal oxide charge transfer complex for effective energy band tailoring in multilayer optoelectronics
Authors: Kim Moohyun , Kwon Byoung-Hwa , Joo Chul Woong , Cho Myeong Seon , Jang Hanhwi , Kim Ye ji , Cho Hyunjin , Jeon Duk Young , Cho Eugene N. , Jung Yeon Sik
Published: January 2022

Metal oxides are intensively used for multilayered optoelectronic devices such as organic light-emitting diodes (OLEDs). Many approaches have been explored to improve device performance by engineering electrical properties. However, conventional methods cannot enable both energy level manipulation and conductivity enhancement for achieving optimum energy band configurations. Here, we introduce a metal oxide charge transfer complex (NiO:MoO3-complex), which is composed of few-nm-size MoO3 domains embedded in NiO matrices, as a highly tunable carrier injection material. Charge transfer at the finely dispersed interfaces of NiO and MoO3 throughout the entire film enables effective energy level modulation over a wide work function range of 4.47 – 6.34 eV along with enhanced electrical conductivity. The high performance of NiO:MoO3-complex is confirmed by achieving 189% improved current efficiency compared to that of MoO3-based green OLEDs and also an external quantum efficiency of 17% when applied to blue OLEDs, which is superior to 1,4,5,8,9,11-hexaazatriphenylene-hexacarbonitrile-based conventional devices.
Integrated near-infrared spectral sensing
Authors: Hakkel Kaylee D. , Petruzzella Maurangelo , Ou Fang , van Klinken Anne , Pagliano Francesco , Liu Tianran , van Veldhoven Rene P. J. , Fiore Andrea
Published: January 2022

Spectral sensing is increasingly used in applications ranging from industrial process monitoring to agriculture. Sensing is usually performed by measuring reflected or transmitted light with a spectrometer and processing the resulting spectra. However, realizing compact and mass-manufacturable spectrometers is a major challenge, particularly in the infrared spectral region where chemical information is most prominent. Here we propose a different approach to spectral sensing which dramatically simplifies the requirements on the hardware and allows the monolithic integration of the sensors. We use an array of resonant-cavity-enhanced photodetectors, each featuring a distinct spectral response in the 850-1700 nm wavelength range. We show that prediction models can be built directly using the responses of the photodetectors, despite the presence of multiple broad peaks, releasing the need for spectral reconstruction. The large etendue and responsivity allow us to demonstrate the application of an integrated near-infrared spectral sensor in relevant problems, namely milk and plastic sensing. Our results open the way to spectral sensors with minimal size, cost and complexity for industrial and consumer applications.
Topographic mapping of the glioblastoma proteome reveals a triple-axis model of intra-tumoral heterogeneity
Authors: Lam K. H. Brian , Leon Alberto J. , Hui Weili , Lee Sandy Che-Eun , Batruch Ihor , Faust Kevin , Klekner Almos , Hutóczki Gábor , Koritzinsky Marianne , Richer Maxime , Djuric Ugljesa , Diamandis Phedias
Published: January 2022

Glioblastoma is an aggressive form of brain cancer with well-established patterns of intra-tumoral heterogeneity implicated in treatment resistance and progression. While regional and single cell transcriptomic variations of glioblastoma have been recently resolved, downstream phenotype-level proteomic programs have yet to be assigned across glioblastoma’s hallmark histomorphologic niches. Here, we leverage mass spectrometry to spatially align abundance levels of 4,794 proteins to distinct histologic patterns across 20 patients and propose diverse molecular programs operational within these regional tumor compartments. Using machine learning, we overlay concordant transcriptional information, and define two distinct proteogenomic programs, MYC- and KRAS-axis hereon, that cooperate with hypoxia to produce a tri-dimensional model of intra-tumoral heterogeneity. Moreover, we highlight differential drug sensitivities and relative chemoresistance in glioblastoma cell lines with enhanced KRAS programs. Importantly, these pharmacological differences are less pronounced in transcriptional glioblastoma subgroups suggesting that this model may provide insights for targeting heterogeneity and overcoming therapy resistance.
Structural assessment of HLA-A2-restricted SARS-CoV-2 spike epitopes recognized by public and private T-cell receptors
Authors: Wu Daichao , Kolesnikov Alexander , Yin Rui , Guest Johnathan D. , Gowthaman Ragul , Shmelev Anton , Serdyuk Yana , Dianov Dmitry V. , Efimov Grigory A. , Pierce Brian G. , Mariuzza Roy A.
Published: January 2022

T cells play a vital role in combatting SARS-CoV-2 and forming long-term memory responses. Whereas extensive structural information is available on neutralizing antibodies against SARS-CoV-2, such information on SARS-CoV-2-specific T-cell receptors (TCRs) bound to their peptide–MHC targets is lacking. Here we determine the structures of a public and a private TCR from COVID-19 convalescent patients in complex with HLA-A2 and two SARS-CoV-2 spike protein epitopes (YLQ and RLQ). The structures reveal the basis for selection of particular TRAV and TRBV germline genes by the public but not the private TCR, and for the ability of the TCRs to recognize natural variants of RLQ but not YLQ. Neither TCR recognizes homologous epitopes from human seasonal coronaviruses. By elucidating the mechanism for TCR recognition of an immunodominant yet variable epitope (YLQ) and a conserved but less commonly targeted epitope (RLQ), this study can inform prospective efforts to design vaccines to elicit pan-coronavirus immunity.
A star-nose-like tactile-olfactory bionic sensing array for robust object recognition in non-visual environments
Authors: Liu Mengwei , Zhang Yujia , Wang Jiachuang , Qin Nan , Yang Heng , Sun Ke , Hao Jie , Shu Lin , Liu Jiarui , Chen Qiang , Zhang Pingping , Tao Tiger H.
Published: January 2022

Object recognition is among the basic survival skills of human beings and other animals. To date, artificial intelligence (AI) assisted high-performance object recognition is primarily visual-based, empowered by the rapid development of sensing and computational capabilities. Here, we report a tactile-olfactory sensing array, which was inspired by the natural sense-fusion system of star-nose mole, and can permit real-time acquisition of the local topography, stiffness, and odor of a variety of objects without visual input. The tactile-olfactory information is processed by a bioinspired olfactory-tactile associated machine-learning algorithm, essentially mimicking the biological fusion procedures in the neural system of the star-nose mole. Aiming to achieve human identification during rescue missions in challenging environments such as dark or buried scenarios, our tactile-olfactory intelligent sensing system could classify 11 typical objects with an accuracy of 96.9% in a simulated rescue scenario at a fire department test site. The tactile-olfactory bionic sensing system required no visual input and showed superior tolerance to environmental interference, highlighting its great potential for robust object recognition in difficult environments where other methods fall short.
Topoisomerase I (TOP1) dynamics: conformational transition from open to closed states
Authors: Takahashi Diane T. , Gadelle Danièle , Agama Keli , Kiselev Evgeny , Zhang Hongliang , Yab Emilie , Petrella Stephanie , Forterre Patrick , Pommier Yves , Mayer Claudine
Published: January 2022

Eukaryotic topoisomerases I (TOP1) are ubiquitous enzymes removing DNA torsional stress. However, there is little data concerning the three-dimensional structure of TOP1 in the absence of DNA, nor how the DNA molecule can enter/exit its closed conformation. Here, we solved the structure of thermostable archaeal Caldiarchaeum subterraneum CsTOP1 in an apo-form. The enzyme displays an open conformation resulting from one substantial rotation between the capping (CAP) and the catalytic (CAT) modules. The junction between these two modules is a five-residue loop, the hinge, whose flexibility permits the opening/closing of the enzyme and the entry of DNA. We identified a highly conserved tyrosine near the hinge as mediating the transition from the open to closed conformation upon DNA binding. Directed mutagenesis confirmed the importance of the hinge flexibility, and linked the enzyme dynamics with sensitivity to camptothecin, a TOP1 inhibitor targeting the TOP1 enzyme catalytic site in the closed conformation.
Cryo-EM demonstrates the in vitro proliferation of an ex vivo amyloid fibril morphology by seeding
Authors: Heerde Thomas , Rennegarbe Matthies , Biedermann Alexander , Savran Dilan , Pfeiffer Peter B. , Hitzenberger Manuel , Baur Julian , Puscalau-Girtu Ioana , Zacharias Martin , Schwierz Nadine , Haupt Christian , Schmidt Matthias , Fändrich Marcus
Published: January 2022

Several studies showed that seeding of solutions of monomeric fibril proteins with ex vivo amyloid fibrils accelerated the kinetics of fibril formation in vitro but did not necessarily replicate the seed structure. In this research we use cryo-electron microscopy and other methods to analyze the ability of serum amyloid A (SAA)1.1-derived amyloid fibrils, purified from systemic AA amyloidosis tissue, to seed solutions of recombinant SAA1.1 protein. We show that 98% of the seeded fibrils remodel the full fibril structure of the main ex vivo fibril morphology, which we used for seeding, while they are notably different from unseeded in vitro fibrils. The seeded fibrils show a similar proteinase K resistance as ex vivo fibrils and are substantially more stable to proteolytic digestion than unseeded in vitro fibrils. Our data support the view that the fibril morphology contributes to determining proteolytic stability and that pathogenic amyloid fibrils arise from proteolytic selection.
Maternal regulation of biliary disease in neonates via gut microbial metabolites
Authors: Jee Jai Junbae , Yang Li , Shivakumar Pranavkumar , Xu Pei-pei , Mourya Reena , Thanekar Unmesha , Yu Pu , Zhu Yu , Pan Yongkang , Wang Haibin , Duan Xufei , Ye Yongqin , Wang Bin , Jin Zhu , Liu Yuanmei , Cao Zhiqing , Watanabe-Chailland Miki , Romick-Rosendale Lindsey E. , Wagner Michael , Fei Lin , Luo Zhenhua , Ollberding Nicholas J. , Tang Shao-tao , Bezerra Jorge A.
Published: January 2022

Maternal seeding of the microbiome in neonates promotes a long-lasting biological footprint, but how it impacts disease susceptibility in early life remains unknown. We hypothesized that feeding butyrate to pregnant mice influences the newborn’s susceptibility to biliary atresia, a severe cholangiopathy of neonates. Here, we show that butyrate administration to mothers renders newborn mice resistant to inflammation and injury of bile ducts and improves survival. The prevention of hepatic immune cell activation and survival trait is linked to fecal signatures of Bacteroidetes and Clostridia and increases glutamate/glutamine and hypoxanthine in stool metabolites of newborn mice. In human neonates with biliary atresia, the fecal microbiome signature of these bacteria is under-represented, with suppression of glutamate/glutamine and increased hypoxanthine pathways. The direct administration of butyrate or glutamine to newborn mice attenuates the disease phenotype, but only glutamine renders bile duct epithelial cells resistant to cytotoxicity by natural killer cells. Thus, maternal intake of butyrate influences the fecal microbial population and metabolites in newborn mice and the phenotypic expression of experimental biliary atresia, with glutamine promoting survival of bile duct epithelial cells.
Cryo-EM structure of native human thyroglobulin
Authors: Adaixo Ricardo , Steiner Eva M. , Righetto Ricardo D. , Schmidt Alexander , Stahlberg Henning , Taylor Nicholas M. I.
Published: January 2022

The thyroglobulin (TG) protein is essential to thyroid hormone synthesis, plays a vital role in the regulation of metabolism, development and growth and serves as intraglandular iodine storage. Its architecture is conserved among vertebrates. Synthesis of triiodothyronine (T3) and thyroxine (T4) hormones depends on the conformation, iodination and post-translational modification of TG. Although structural information is available on recombinant and deglycosylated endogenous human thyroglobulin (hTG) from patients with goiters, the structure of native, fully glycosylated hTG remained unknown. Here, we present the cryo-electron microscopy structure of native and fully glycosylated hTG from healthy thyroid glands to 3.2 Å resolution. The structure provides detailed information on hormonogenic and glycosylation sites. We employ liquid chromatography–mass spectrometry (LC-MS) to validate these findings as well as other post-translational modifications and proteolytic cleavage sites. Our results offer insights into thyroid hormonogenesis of native hTG and provide a fundamental understanding of clinically relevant mutations.
Temperature relaxation in strongly-coupled binary ionic mixtures
Authors: Sprenkle R. Tucker , Silvestri L. G. , Murillo M. S. , Bergeson S. D.
Published: January 2022

New facilities such as the National Ignition Facility and the Linac Coherent Light Source have pushed the frontiers of high energy-density matter. These facilities offer unprecedented opportunities for exploring extreme states of matter, ranging from cryogenic solid-state systems to hot, dense plasmas, with applications to inertial-confinement fusion and astrophysics. However, significant gaps in our understanding of material properties in these rapidly evolving systems still persist. In particular, non-equilibrium transport properties of strongly-coupled Coulomb systems remain an open question. Here, we study ion-ion temperature relaxation in a binary mixture, exploiting a recently-developed dual-species ultracold neutral plasma. We compare measured relaxation rates with atomistic simulations and a range of popular theories. Our work validates the assumptions and capabilities of the simulations and invalidates theoretical models in this regime. This work illustrates an approach for precision determinations of detailed material properties in Coulomb mixtures across a wide range of conditions.
Single-atom Cu anchored catalysts for photocatalytic renewable H2 production with a quantum efficiency of 56%
Authors: Zhang Yumin , Zhao Jianhong , Wang Hui , Xiao Bin , Zhang Wen , Zhao Xinbo , Lv Tianping , Thangamuthu Madasamy , Zhang Jin , Guo Yan , Ma Jiani , Lin Lina , Tang Junwang , Huang Rong , Liu Qingju
Published: January 2022

Single-atom catalysts anchoring offers a desirable pathway for efficiency maximization and cost-saving for photocatalytic hydrogen evolution. However, the single-atoms loading amount is always within 0.5% in most of the reported due to the agglomeration at higher loading concentrations. In this work, the highly dispersed and large loading amount (>1 wt%) of copper single-atoms were achieved on TiO2, exhibiting the H2 evolution rate of 101.7 mmol g−1 h−1 under simulated solar light irradiation, which is higher than other photocatalysts reported, in addition to the excellent stability as proved after storing 380 days. More importantly, it exhibits an apparent quantum efficiency of 56% at 365 nm, a significant breakthrough in this field. The highly dispersed and large amount of Cu single-atoms incorporation on TiO2 enables the efficient electron transfer via Cu2+-Cu+ process. The present approach paves the way to design advanced materials for remarkable photocatalytic activity and durability.
Myeloid cell nuclear differentiation antigen controls the pathogen-stimulated type I interferon cascade in human monocytes by transcriptional regulation of IRF7
Authors: Gu Lili , Casserly David , Brady Gareth , Carpenter Susan , Bracken Adrian P. , Fitzgerald Katherine A. , Unterholzner Leonie , Bowie Andrew G.
Published: January 2022

Type I interferons (IFNs) are critical for anti-viral responses, and also drive autoimmunity when dysregulated. Upon viral sensing, monocytes elicit a sequential cascade of IFNβ and IFNα production involving feedback amplification, but how exactly this cascade is regulated in human cells is incompletely understood. Here we show that the PYHIN protein myeloid cell nuclear differentiation antigen (MNDA) is required for IFNα induction in monocytes. Unlike other PYHINs, this is not due to a pathogen sensing role, but rather MNDA regulated expression of IRF7, a transcription factor essential for IFNα induction. Mechanistically, MNDA is required for recruitment of STAT2 and RNA polymerase II to the IRF7 gene promoter, and in fact MNDA is itself recruited to the IRF7 promoter after type I IFN stimulation. These data implicate MNDA as a critical regulator of the type I IFN cascade in human myeloid cells and reveal a new role for human PYHINs in innate immune gene induction.