bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disease-associated KBTBD4 mutations in medulloblastoma elicit neomorphic ubiquitylation activity to promote CoREST degradation
Authors: Chen Zhuoyao , Ioris Rafael M. , Richardson Stacey , Van Ess Ava N. , Vendrell Iolanda , Kessler Benedikt M. , Buffa Francesca M. , Busino Luca , Clifford Steven C. , Bullock Alex N. , D’Angiolella Vincenzo 
Published: April 2022

AbstractMedulloblastoma is the most common malignant brain tumour in children. Genomic studies have identified distinct disease subgroups: wnt/wingless (WNT), sonic hedgehog (SHH), and non-WNT/non-SHH, comprising group 3 and group 4. Alterations in WNT and SHH signalling form the pathogenetic basis for their subgroups, whereas those for non-WNT/non-SHH tumours remain largely elusive. Recent analyses have revealed recurrent in-frame insertions in the E3 ubiquitin ligase adaptor Kelch Repeat and BTB Domain Containing 4 (KBTBD4) in cases of group 3/4 medulloblastoma. Critically, group 3/4 tumours with KBTBD4 mutations typically lack other gene-specific alterations, such as MYC amplification, indicating KBTBD4 insertion mutations as the primary genetic driver. Delineating the role of KBTBD4 mutations thus offers significant opportunities to understand tumour pathogenesis and to exploit the underpinning mechanisms therapeutically. Here, we show a novel mechanism in cancer pathogenesis whereby indel mutations in KBTBD4 drive its recognition of neo-substrates for degradation. We observe that KBTBD4 mutants promote the recruitment and ubiquitylation of the REST Corepressor (CoREST), which forms a complex to modulate chromatin accessibility and transcriptional programmes. The degradation of CoREST promoted by KBTBD4 mutation diverts epigenetic programmes inducing significant alterations in transcription to promote increased stemness of cancer cells. Transcriptional analysis of >200 human group 3 and 4 medulloblastomas by RNA-seq, highlights the presence of CoREST and stem-like signatures in tumours with KBTBD4 mutations, which extend to a further sub-set of non-mutant tumours, suggesting CoREST alterations as a novel pathogenetic mechanism of wide relevance in groups 3 and 4. Our findings uncover KBTBD4 mutation as a novel driver of epigenetic reprogramming in non-WNT/non-SHH medulloblastoma, establish a novel mode of tumorigenesis through gain-of-function mutations in ubiquitin ligases (neo-substrate recruitment) and identify both mutant KBTBD4 and CoREST complexes as new druggable targets for improved tumour-specific therapies.
RAGE-TXNIP axis drives inflammation in Alzheimer’s by targeting Aβ to mitochondria in microglia
Authors: Sbai Oualid , Djelloul Mehdi , Auletta Antonia , Ieraci Alessandro , Vascotto Carlo , Perrone L. 
Published: April 2022

AbstractAlzheimer’s disease (AD) is the most common form of dementia characterized by progressive memory loss and cognitive decline. Although neuroinflammation and oxidative stress are well-recognized features of AD, their correlations with the early molecular events characterizing the pathology are not yet well clarified. Here, we characterize the role of RAGE–TXNIP axis in neuroinflammation in relation to amyloid-beta (Aβ) burden in both in vivo and in vitro models. In the hippocampus of 5xFAD mice microglial activation, cytokine secretion, and glial fibrillary acidic protein-enhanced expression are paralleled with increased TXNIP expression. TXNIP silencing or its pharmacological inhibition prevents neuroinflammation in those mice. TXNIP is also associated with RAGE and Aβ. In particular, RAGE–TXNIP axis is required for targeting Aβ in mitochondria, leading to mitochondrial dysfunction and oxidative stress. Silencing of TXNIP or inhibition of RAGE activation reduces Aβ transport from the cellular surface to mitochondria, restores mitochondrial functionality, and mitigates Aβ toxicity. Furthermore, Aβ shuttling into mitochondria promotes Drp1 activation and exacerbates mitochondrial dysfunction, which induces NLRP3 inflammasome activation, leading to secretion of IL-1β and activation of the pyroptosis-associated protein Gasdermin D (GSDMD). Downregulation of RAGE–TXNIP axis inhibits Aβ-induced mitochondria dysfunction, inflammation, and induction of GSDMD. Herein we unveil a new pathway driven by TXNIP that links the mitochondrial transport of Aβ to the activation of Drp1 and the NLRP3 inflammasome, promoting the secretion of IL-1β and the pyroptosis pathway associated with GSDMD cleavage. Altogether these data shed new light on a novel mechanism of action of RAGE–TXNIP axis in microglia, which is intertwined with Aβ and ultimately causes mitochondria dysfunction and NLRP3 inflammasome cascade activation, suggesting TXNIP as a druggable target to be better deepened for AD.
EIF4EBP1 is transcriptionally upregulated by MYCN and associates with poor prognosis in neuroblastoma
Authors: Voeltzke Kai , Scharov Katerina , Funk Cornelius Maximilian , Kahler Alisa , Picard Daniel , Hauffe Laura , Orth Martin F. , Remke Marc , Esposito Irene , Kirchner Thomas , Schramm Alexander , Rotblat Barak , Grünewald Thomas G. P. , Reifenberger Guido , Leprivier Gabriel 
Published: April 2022

AbstractNeuroblastoma (NB) accounts for 15% of cancer-related deaths in childhood despite considerable therapeutic improvements. While several risk factors, including MYCN amplification and alterations in RAS and p53 pathway genes, have been defined in NB, the clinical outcome is very variable and difficult to predict. Since genes of the mechanistic target of rapamycin (mTOR) pathway are upregulated in MYCN-amplified NB, we aimed to define the predictive value of the mTOR substrate-encoding gene eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1) expression in NB patients. Using publicly available data sets, we found that EIF4EBP1 mRNA expression is positively correlated with MYCN expression and elevated in stage 4 and high-risk NB patients. In addition, high EIF4EBP1 mRNA expression is associated with reduced overall and event-free survival in the entire group of NB patients in three cohorts, as well as in stage 4 and high-risk patients. This was confirmed by monitoring the clinical value of 4EBP1 protein expression, which revealed that high levels of 4EBP1 are significantly associated with prognostically unfavorable NB histology. Finally, functional analyses revealed that EIF4EBP1 expression is transcriptionally controlled by MYCN binding to the EIF4EBP1 promoter in NB cells. Our data highlight that EIF4EBP1 is a direct transcriptional target of MYCN whose high expression is associated with poor prognosis in NB patients. Therefore, EIF4EBP1 may serve to better stratify patients with NB.
ATP6AP2 knockdown in cardiomyocyte deteriorates heart function via compromising autophagic flux and NLRP3 inflammasome activation
Authors: Li Lei , Cui Ya-juan , Liu Yu , Li Hui-xin , Su Yu-dong , Li Sheng-nan , Wang Lan-lan , Zhao Yue-wen , Wang Shuang-xi , Yan Feng , Dong Bo 
Published: April 2022

AbstractModerate autophagy can remove damaged proteins and organelles. In some inflammatory diseases, autophagy plays a protective role by inhibiting the NOD-like receptor family pyrin domain containing 3(NLRP3). (Pro)renin receptor (PRR, or ATP6AP2) is a critical component of the V-ATPase required for autophagy. It remains controversial about ATP6AP2 in the pathological process. The impact of ATP6AP2 on NLRP3 inflammasome and autophagic flux remains unknown under pressure overload stress. This research explores the potential link between ATP6AP2, autophagic flux, and NLRP3. There was upregulation of ATP6AP2 from 5-day post-TAC, and this expression remained at a high level until 8-weeks post-TAC in wild mice. Meanwhile, autophagic flux switched from early compensatory activation to blocking in the heart failure phase. NLRP3 activation can be seen at 8-week post-TAC. Adenovirus-mediated knockdown of ATP6AP2(shR-ATP6AP2) accelerated the progress of heart failure. After TAC was induced, shR-ATP6AP2 significantly deteriorated heart function and fibrosis compared with the shR-Scr group. Meanwhile, there was an elevated expression of NLRP3 and autophagic flux blockage. A transgenic mouse(Tg) with cardio-restricted ATP6AP2/(P)RR overexpression was constructed. Although high expression in cardiac tissue, there were no spontaneous functional abnormalities under the basal state. Cardiac function, fibrosis, hypertrophy remained identical to the control TAC group. However, SQSTM1/P62 was reduced, which indicated the relief of autophagic flux blockage. Further, Neonatal rat ventricular myocyte (NRVMs) transfected with shR-ATP6AP2 showed more susceptibility than sh-Scr NRVMs to phenylephrine-induced cell death. More reactive oxygen species (ROS) or mito-ROS accumulated in the shR-ATP6AP2 group when phenylephrine stimulation. Blocking NLRP3 activation in vivo partly rescued cardiac dysfunction and fibrosis. In conclusion, ATP6AP2 upregulation is a compensatory response to pressure overload. If not effectively compensated, it compromises autophagic flux, leads to dysfunctional mitochondria accumulation, further produces ROS to activate NLRP3, eventually accelerates heart failure.
The engineered CD80 variant fusion therapeutic davoceticept combines checkpoint antagonism with conditional CD28 costimulation for anti-tumor immunity
Authors: Maurer Mark F. , Lewis Katherine E. , Kuijper Joseph L. , Ardourel Dan , Gudgeon Chelsea J. , Chandrasekaran Siddarth , Mudri Sherri L. , Kleist Kayla N. , Navas Chris , Wolfson Martin F. , Rixon Mark W. , Swanson Ryan , Dillon Stacey R. , Levin Steven D. , Kimbung Yengo Raymond , Akutsu Masato , Logan Derek T. , Walse Björn , Swiderek Kristine M. , Peng Stanford L. 
Published: April 2022

AbstractDespite the recent clinical success of T cell checkpoint inhibition targeting the CTLA-4 and PD-1 pathways, many patients either fail to achieve objective responses or they develop resistance to therapy. In some cases, poor responses to checkpoint blockade have been linked to suboptimal CD28 costimulation and the inability to generate and maintain a productive adaptive anti-tumor immune response. To address this, here we utilize directed evolution to engineer a CD80 IgV domain with increased PD-L1 affinity and fuse this to an immunoglobulin Fc domain, creating a therapeutic (ALPN-202, davoceticept) capable of providing CD28 costimulation in a PD-L1-dependent fashion while also antagonizing PD-1 - PD-L1 and CTLA-4–CD80/CD86 interactions. We demonstrate that by combining CD28 costimulation and dual checkpoint inhibition, ALPN-202 enhances T cell activation and anti-tumor efficacy in cell-based assays and mouse tumor models more potently than checkpoint blockade alone and thus has the potential to generate potent, clinically meaningful anti-tumor immunity in humans.
Auxiliary ATP binding sites support DNA unwinding by RecBCD
Authors: Zananiri Rani , Mangapuram Venkata Sivasubramanyan , Gaydar Vera , Yahalom Dan , Malik Omri , Rudnizky Sergei , Kleifeld Oded , Kaplan Ariel , Henn Arnon 
Published: April 2022

AbstractThe RecBCD helicase initiates double-stranded break repair in bacteria by processively unwinding DNA with a rate approaching ∼1,600 bp·s−1, but the mechanism enabling such a fast rate is unknown. Employing a wide range of methodologies — including equilibrium and time-resolved binding experiments, ensemble and single-molecule unwinding assays, and crosslinking followed by mass spectrometry — we reveal the existence of auxiliary binding sites in the RecC subunit, where ATP binds with lower affinity and distinct chemical interactions as compared to the known catalytic sites. The essentiality and functionality of these sites are demonstrated by their impact on the survival of E.coli after exposure to damage-inducing radiation. We propose a model by which RecBCD achieves its optimized unwinding rate, even when ATP is scarce, by using the auxiliary binding sites to increase the flux of ATP to its catalytic sites.
A global temperature control of silicate weathering intensity
Authors: Deng Kai , Yang Shouye , Guo Yulong 
Published: April 2022

AbstractSilicate weathering as an important negative feedback can regulate the Earth’s climate over time, but much debate concerns its response strength to each climatic factor and its evolution with land surface reorganisation. Such discrepancy arises from lacking weathering proxy validation and scarce quantitative paleo-constraints on individual forcing factors. Here we examine the catchment-scale link of silicate weathering intensity with various environmental parameters using a global compilation of modern sediment dataset (n = 3828). We show the primary control of temperature on silicate weathering given the monotonic increase of feldspar dissolution with it (0–30 °C), while controls of precipitation or topographic-lithological factors are regional and subordinate. We interpret the non-linear forcing of temperature on feldspar dissolution as depletion of more reactive plagioclase (relative to orthoclase) at higher temperature. Our results hint at stronger temperature-weathering feedback at lower surface temperature and support the hypothesis of increased land surface reactivity during the late Cenozoic cooling.
Uniaxial pressure induced stripe order rotation in La1.88Sr0.12CuO4
Authors: Wang Qisi , von Arx K. , Mazzone D. G. , Mustafi S. , Horio M. , Küspert J. , Choi J. , Bucher D. , Wo H. , Zhao J. , Zhang W. , Asmara T. C. , Sassa Y. , Månsson M. , Christensen N. B. , Janoschek M. , Kurosawa T. , Momono N. , Oda M. , Fischer M. H. , Schmitt T. , Chang J. 
Published: April 2022

AbstractStatic stripe order is detrimental to superconductivity. Yet, it has been proposed that transverse stripe fluctuations may enhance the inter-stripe Josephson coupling and thus promote superconductivity. Direct experimental studies of stripe dynamics, however, remain difficult. From a strong-coupling perspective, transverse stripe fluctuations are realized in the form of dynamic “kinks”—sideways shifting stripe sections. Here, we show how modest uniaxial pressure tuning reorganizes directional kink alignment. Our starting point is La1.88Sr0.12CuO4 where transverse kink ordering results in a rotation of stripe order away from the crystal axis. Application of mild uniaxial pressure changes the ordering pattern and pins the stripe order to the crystal axis. This reordering occurs at a much weaker pressure than that to detwin the stripe domains and suggests a rather weak transverse stripe stiffness. Weak spatial stiffness and transverse quantum fluctuations are likely key prerequisites for stripes to coexist with superconductivity.
Sirt6 reprograms myofibers to oxidative type through CREB-dependent Sox6 suppression
Authors: Song Mi-Young , Han Chang Yeob , Moon Young Jae , Lee Ju Hyung , Bae Eun Ju , Park Byung-Hyun 
Published: April 2022

AbstractExpanding the exercise capacity of skeletal muscle is an emerging strategy to combat obesity-related metabolic diseases and this can be achieved by shifting skeletal muscle fibers toward slow-twitch oxidative type. Here, we report that Sirt6, an anti-aging histone deacetylase, is critical in regulating myofiber configuration toward oxidative type and that Sirt6 activator can be an exercise mimetic. Genetic inactivation of Sirt6 in skeletal muscle reduced while its transgenic overexpression increased mitochondrial oxidative capacity and exercise performance in mice. Mechanistically, we show that Sirt6 downregulated Sox6, a key repressor of slow fiber specific gene, by increasing the transcription of CREB. Sirt6 expression is elevated in chronically exercised humans, and mice treated with an activator of Sirt6 showed an increase in exercise endurance as compared to exercise-trained controls. Thus, the current study identifies Sirt6 as a molecular target for reprogramming myofiber composition toward the oxidative type and for improving muscle performance.
The PripA-TbcrA complex-centered Rab GAP cascade facilitates macropinosome maturation in Dictyostelium
Authors: Tu Hui , Wang Zhimeng , Yuan Ye , Miao Xilin , Li Dong , Guo Hu , Yang Yihong , Cai Huaqing 
Published: April 2022

AbstractMacropinocytosis, an evolutionarily conserved mechanism mediating nonspecific bulk uptake of extracellular fluid, has been ascribed diverse functions. How nascent macropinosomes mature after internalization remains largely unknown. By searching for proteins that localize on macropinosomes during the Rab5-to-Rab7 transition stage inDictyostelium, we uncover a complex composed of two proteins, which we name PripA and TbcrA. We show that the Rab5-to-Rab7 conversion involves fusion of Rab5-marked early macropinosomes with Rab7-marked late macropinosomes. PripA links the two membrane compartments by interacting with PI(3,4)P2and Rab7. In addition, PripA recruits TbcrA, which acts as a GAP, to turn off Rab5. Thus, the conversion to Rab7 is linked to inactivation of the upstream Rab5. Consistently, disruption of eitherpripAortbcrAimpairs Rab5 inactivation and macropinocytic cargo processing. Therefore, the PripA-TbcrA complex is the central component of a Rab GAP cascade that facilitates programmed Rab switch and efficient cargo trafficking during macropinosome maturation.
Mitochondrial DNA oxidative mutations are elevated in Mexican American women potentially implicating Alzheimer’s disease
Authors: Reid Danielle Marie , Barber Robert C. , Thorpe Roland J. , Sun Jie , Zhou Zhengyang , Phillips Nicole R. 
Published: April 2022

AbstractMexican Americans (MAs) are the fastest-growing Hispanic population segment in the US; as this population increases in age, so will the societal burden of age-related diseases such as Alzheimer’s disease (AD). Mitochondrial DNA (mtDNA) damage may be implicated in MA AD risk since metabolic comorbidities are more prevalent in this group. Oxidative damage to guanosine (8oxoG) is one of the most prevalent DNA lesions and a putative indicator of mitochondrial dysfunction. Testing blood samples from participants of the Texas Alzheimer’s Research and Care Consortium, we found mtDNA 8oxoG mutational load to be significantly higher in MAs compared to non-Hispanic whites and that MA females are differentially affected. Furthermore, we identified specific mtDNA haplotypes that confer increased risk for oxidative damage and suggestive evidence that cognitive function may be related to 8oxoG burden. Our understanding of these phenomena will elucidate population- and sex-specific mechanisms of AD pathogenesis, informing the development of more precise interventions and therapeutic approaches for MAs with AD in the future.
Staphylococcus aureus utilizes environmental RNA as a building material in specific polysaccharide-dependent biofilms
Authors: Chiba Akio , Seki Masahide , Suzuki Yutaka , Kinjo Yuki , Mizunoe Yoshimitsu , Sugimoto Shinya 
Published: April 2022

AbstractBiofilms are surface-bound microbial communities that are typically embedded in a matrix of self-produced extracellular polymeric substances and can cause chronic infections. Extracellular DNA is known to play a crucial role in biofilm development in diverse bacteria; however, the existence and function of RNA are poorly understood. Here, we show that RNA contributes to the structural integrity of biofilms formed by the human pathogen Staphylococcus aureus. RNase A dispersed both fresh and mature biofilms, indicating the importance of RNA at various stages. RNA-sequencing analysis demonstrated that the primary source of RNA in the biofilm matrix was the Brain Heart Infusion medium (>99.32%). RNA purified from the medium promoted biofilm formation. Microscopic and molecular interaction analyses demonstrated that polysaccharides were critical for capturing and stabilizing external RNA in biofilms, which contributes to biofilm organization. These findings provide a basis for exploring the role of externally derived substances in bacterial biofilm organization.
The microbiota-gut-kidney axis mediates host osmoregulation in a small desert mammal
Authors: Nouri Zahra , Zhang Xue-Ying , Khakisahneh Saeid , Degen Abraham Allan , Wang De-Hua 
Published: April 2022

AbstractRegulating sodium and water balances is crucial for survival of small, desert mammals. Studies demonstrate that the gut microbiota and their metabolites are involved in host energy homeostasis, but little is known on the interactions among salt loading, gut microbiota, and osmoregulation. The aim of this study was to fill this gap. Mongolian gerbils (Meriones unguiculatus) were offered drinking water (Con) and either water containing moderate (4%, MS) or high NaCl (8%, HS) ad libitum. Intake of HS reduced α diversity of the microbial community and, at the genus level, reduced the relative abundances of Rikenella and Christensenella but increased Atopobium. To confirm the function of gut microbiota in host osmoregulation, we transplanted caecal microbiota in HS gerbils. To cope with salt loading, the gerbils concentrated urine, resulting in negative energy balance and systemic inflammation. The HS gerbils increased hypothalamic arginine vasopressin and intestinal and renal aquaporin 2 to support water retention, and reduced intestinal and renal epithelial sodium channel α to promote sodium excretion. However, HS gerbils with caecal microbiota transplant (CMT) from Con donors maintained energy balance and osmoregulation, and had a much reduced systemic inflammation. Further, CMT from Con donors to HS recipients reshaped the gut microbiota, particularly by reducing Parabacteroides distasonis and Prevotella copri, and increasing Lactobacillus reuteri abundances, with a resulting increase in bacterial metabolites such as butyrate. These findings highlight a vital role of the microbiota-gut-kidney axis in mediating salt-related osmoregulation, allowing small mammals to adapt to high salt loads in a desert habitat.
Atomic coordination dictates vibrational characteristics and thermal conductivity in amorphous carbon
Authors: Giri Ashutosh , Dionne Connor J. , Hopkins Patrick E. 
Published: April 2022

AbstractWe discuss the role of atomic coordination in dictating the vibrational characteristics and thermal conductivity in amorphous carbon. Our systematic atomistic simulations on amorphous carbon structures at varying mass densities show the significant role played by the ratio of sp2 to sp3 hybridized bonds in dictating the contributions from propagating (phonon-like) and non-propagating vibrational modes and their influence on the overall thermal conductivities of the structures. Specifically, our results show that as the concentration of sp3-bonded carbon atoms increases, the thermal conductivity can be increased by four fold, which is attributed to enhanced contributions from propagating modes in these amorphous structures. Our results shed more light into the role of atomic coordination on dictating heat transfer mechanisms in amorphous materials, and also provide a deeper understanding of the ability to tune the thermal conductivity of amorphous carbon structures through the control of the local atomic coordination.