bluuebunny/crossref_metadata_2025 huggingface dataset:
Big food and drink sponsorship of conferences and speakers: a case study of one multinational company’s influence over knowledge dissemination and professional engagement
Authors: Atli Gunnarsson Jónas , Ruskin Gary , Stuckler David , Steele Sarah
Published: December 2022

Objectives:

Research identifies that multinational corporations, including The Coca-Cola Company (‘Coca-Cola’), seek to influence public health research and policy through scientific events, such as academic and professional conferences. This study aims to understand how different forms of funding and sponsorship impact the relationship between Coca-Cola, academic institutions, public health organisations, academics and researchers.

Design:

The study was conducted using Freedom of Information (FOI) requests and systematic website searches.

Setting:

Data were collected by twenty-two FOI requests to institutions in the USA and UK, resulting in the disclosure of 11 488 pages, including emails and attachments relating to 239 events between 2009 and 2018. We used the Wayback Machine to review historical website data to evaluate evidence from 151 available official conference websites.

Participants:

N/A

Results:

Documents suggest that Coca-Cola provides direct financial support to institutions and organisations hosting events in exchange for benefits, including influence over proceedings. Coca-Cola also provided direct financial support to speakers and researchers, sometimes conditional on media interviews. Also, indirect financial support passed through Coca-Cola-financed non-profits. Often, such financial support was not readily identifiable, and third-party involvement further concealed Coca-Cola funding.

Conclusion:

Coca-Cola exerts direct influence on academic institutions and organisations that convene major public health conferences and events. These events offer Coca-Cola a vehicle for its messaging and amplifying viewpoints favourable to Coca-Cola’s interests. Such corporate-sponsored events should be viewed as instruments of industry marketing. Stronger rules and safeguards are needed to prevent hidden industry influence, such as complete disclosure of all corporate contributions for public health conferences and their speakers.
Monitoring CO2 Injection at the CaMI Field Research Station Using Microseismic Noise Sources
Authors: Li Tianyang , Gu Yu Jeffrey , Lawton Donald C. , Gilbert Hersh , Macquet Marie , Savard Genevieve , Wang Jingchuan , Innanen Kristopher A. , Yu Nian
Published: November 2022

Monitoring subsurface velocity variations due to industrial activities using passive seismic imaging techniques has gained popularity in recent years. In this study, we examine the spatiotemporal variations of persistent, non‐ambient seismic noise during CO2 sequestration at the Containment and Monitoring Institute Field Research Station near Brooks, Alberta, Canada. Based on the temporal migration and power spectral density (PSD) analysis of continuous seismic records from both a dense geophone array and “X”‐shaped geophone lines operated from June to August 2019, we detect two non‐ambient local noise sources correlated with the local industrial activities during the two months: a dominant noise source (1–5 Hz) southeast of the study region and a slightly weaker noise source in the higher frequency range (5–15 Hz) around the injection well. The former noise source overlaps with the operations near a submersible disposal pump. The substantial diurnal variations in noise levels in PSD as a function of time of day, month and location are further evidence of these two noise sources. We propose that the persistent noise source around the injection well originated from the subsurface microtremors caused by the coupled interaction between the injected CO2 fluid and formation rocks. The proposed methods based on passive microseismic noise offer a potentially valuable strategy for long‐term evaluation of the safety of CO2 sequestration, which can be extended to future integrity monitoring of underground energy storage.
Shallow Ice‐Sheet Composite Structure Revealed by Seismic Imaging Near the West Antarctic Ice Sheet (WAIS) Divide Camp
Authors: Zhang Zhendong , Nakata Nori , Karplus Marianne , Kaip Galen , Yi Jia
Published: November 2022

Small‐scale polar ice‐sheet composite structures can influence coarse‐grained climate models. For example, surface melting can hydro‐fracture the ice and may eventually lubricate the base. The drainage process will change the petrophysical properties of the subsurface and is predictable from high‐resolution seismic imaging. Ray‐based imaging methods, though limited by the approximations made, have mapped seismic velocities in 1D, but have yet to offer definitive information about the lateral heterogeneity. Here we use the wave‐equation‐based seismic imaging method to estimate shear‐wave velocities and to image an englacial reflector in 2D. We use 7‐day ambient‐noise data recorded by a linear array near the West Antarctic Ice Sheet (WAIS) Divide drilling site to perform the study. We obtain 2D vertical and horizontal shear‐wave velocity models and observe a lateral variation of the radial anisotropy along the acquisition line. The inverted velocity model is further used to estimate the thicknesses of firn‐air and firn layers. We also observe evident SH reflections and calculate the reflector image using robust zero‐offset imaging and a more precise reverse time migration imaging method. The imaged reflector is at about 1,700 m depth and is dipping to the southwest. We anticipate that a porosity change at that depth may cause this englacial seismic discontinuity near WAIS Divide. Our results demonstrate the feasibility of estimating the petrophysical properties of polar ice using seismic methods. We anticipate our work to be further used for understanding ice dynamics and thermodynamics, such as the stability of ice shelves, the retreat of the Antarctic ice sheet, and restoring the paleo‐sedimentary environment.
Diagnostics in Waldenström’s macroglobulinemia: a consensus statement of the European Consortium for Waldenström’s Macroglobulinemia
Authors: Dogliotti Irene , Jiménez Cristina , Varettoni Marzia , Talaulikar Dipti , Bagratuni Tina , Ferrante Martina , Pérez José , Drandi Daniela , Puig Noemí , Gilestro Milena , García-Álvarez María , Owen Roger , Jurczak Wojciech , Tedeschi Alessandra , Leblond Veronique , Kastritis Efstathios , Kersten Marie José , D’Sa Shirley , Kaščák Michal , Willenbacher Wolfgang , Roccaro Aldo M. , Poulain Stephanie , Morel Pierre , Kyriakou Charalampia , Fend Falko , Vos Josephine M. I. , Dimopoulos Meletios A. , Buske Christian , Ferrero Simone , García-Sanz Ramón
Published: November 2022

The diagnosis of Waldenström’s macroglobulinemia (WM), an IgM-associated lymphoplasmacytic lymphoma, can be challenging due to the different forms of disease presentation. Furthermore, in recent years, WM has witnessed remarkable progress on the diagnostic front, as well as a deeper understanding of the disease biology, which has affected clinical practice. This, together with the increasing variety of tools and techniques available, makes it necessary to have a practical guidance for clinicians to perform the initial evaluation of patients with WM. In this paper, we present the consensus recommendations and laboratory requirements for the diagnosis of WM developed by the European Consortium of Waldenström’s Macroglobulinemia (ECWM), for both clinical practice as well as the research/academical setting. We provide the procedures for multiparametric flow cytometry, fluorescence in situ hybridization and molecular tests, and with this offer guidance for a standardized diagnostic work-up and methodological workflow of patients with IgM monoclonal gammopathy of uncertain significance, asymptomatic and symptomatic WM.
Activation of orphan receptor GPR132 induces cell differentiation in acute myeloid leukemia
Authors: Yi Chunyang , He Jiacheng , Huang Dan , Zhao Yumiao , Zhang Chan , Ye Xiyun , Huang Ying , Nussinov Ruth , Zheng Junke , Liu Mingyao , Lu Weiqiang
Published: November 2022

Blocked cellular differentiation is a critical pathologic hallmark of acute myeloid leukemia (AML). Here, we showed that genetic activation of the orphan GPCR GPR132 significantly induced cell differentiation of AML both in vitro and in vivo, indicating that GPR132 is a potential trigger of myeloid differentiation. To explore the therapeutic potential of GPR132 signaling, we screened and validated a natural product 8-gingerol (8GL) as a GPR132 agonist. Notably, GPR132 activation by 8GL promoted differentiation and reduced colony formation in human AML cell lines with diverse genetic profiles. Mechanistic studies revealed that 8GL treatment inhibits the activation of the mammalian target of rapamycin (mTOR), a regulator of AML cell differentiation blockade, via activating GPR132-Gs-PKA pathway. We further showed that the combination of 8GL and an mTOR inhibitor synergistically elicited AML cell differentiation in vitro. Importantly, 8GL alone or in combination with an mTOR inhibitor remarkably impaired tumor growth and extended mouse survival in an AML xenograft model accompanied by enhanced cell differentiation. Notably, genetic or pharmacological activation of GPR132 triggered the differentiation of human primary AML cells. In summary, this study demonstrated that activation of orphan GPR132 represents a potential strategy for inducing myeloid differentiation in AML patients.
High-confidence cancer patient stratification through multiomics investigation of DNA repair disorders
Authors: Mkrtchyan Garik V. , Veviorskiy Alexander , Izumchenko Evgeny , Shneyderman Anastasia , Pun Frank W. , Ozerov Ivan V. , Aliper Alex , Zhavoronkov Alex , Scheibye-Knudsen Morten
Published: November 2022

Multiple cancer types have limited targeted therapeutic options, in part due to incomplete understanding of the molecular processes underlying tumorigenesis and significant intra- and inter-tumor heterogeneity. Identification of novel molecular biomarkers stratifying cancer patients with different survival outcomes may provide new opportunities for target discovery and subsequent development of tailored therapies. Here, we applied the artificial intelligence-driven PandaOmics platform (https://pandaomics.com/) to explore gene expression changes in rare DNA repair-deficient disorders and identify novel cancer targets. Our analysis revealed that CEP135, a scaffolding protein associated with early centriole biogenesis, is commonly downregulated in DNA repair diseases with high cancer predisposition. Further screening of survival data in 33 cancers available at TCGA database identified sarcoma as a cancer type where lower survival was significantly associated with high CEP135 expression. Stratification of cancer patients based on CEP135 expression enabled us to examine therapeutic targets that could be used for the improvement of existing therapies against sarcoma. The latter was based on application of the PandaOmics target-ID algorithm coupled with in vitro studies that revealed polo-like kinase 1 (PLK1) as a potential therapeutic candidate in sarcoma patients with high CEP135 levels and poor survival. While further target validation is required, this study demonstrated the potential of in silico-based studies for a rapid biomarker discovery and target characterization.
GOLPH3 protein controls organ growth by interacting with TOR signaling proteins in Drosophila
Authors: Frappaolo Anna , Karimpour-Ghahnavieh Angela , Cesare Giuliana , Sechi Stefano , Fraschini Roberta , Vaccari Thomas , Giansanti Maria Grazia
Published: November 2022

The oncoprotein GOLPH3 (Golgi phosphoprotein 3) is an evolutionarily conserved phosphatidylinositol 4-phosphate effector, mainly localized to the Golgi apparatus, where it supports organelle architecture and vesicular trafficking. Overexpression of human GOLPH3 correlates with poor prognosis in several cancer types and is associated with enhanced signaling downstream of mTOR (mechanistic target of rapamycin). However, the molecular link between GOLPH3 and mTOR remains elusive. Studies inDrosophila melanogasterhave shown that Translationally controlled tumor protein (Tctp) and 14-3-3 proteins are required for organ growth by supporting the function of the small GTPase Ras homolog enriched in the brain (Rheb) during mTORC1 (mTOR complex 1) signaling. Here we demonstrate thatDrosophilaGOLPH3 (dGOLPH3) physically interacts with Tctp and 14-3-3ζ. RNAi-mediated knockdown of dGOLPH3 reduces wing and eye size and enhances the phenotypes ofTctpRNAi. This phenotype is partially rescued by overexpression of Tctp, 14-3-3ζ, or Rheb. We also show that the Golgi localization of Rheb inDrosophilacells depends on dGOLPH3. Consistent with dGOLPH3 involvement in Rheb-mediated mTORC1 activation, depletion of dGOLPH3 also reduces levels of phosphorylated ribosomal S6 kinase, a downstream target of mTORC1. Finally, the autophagy flux and the expression of autophagic transcription factors of the TFEB family, which anti correlates with mTOR signaling, are compromised upon reduction of dGOLPH3. Overall, our data provide the first in vivo demonstration that GOLPH3 regulates organ growth by directly associating with mTOR signaling proteins.
Identification of a group of bisbenzylisoquinoline (BBIQ) compounds as ferroptosis inhibitors
Authors: Fan Yipu , Zhang Yihan , Shi Kunyu , Cheng Shan , Pei Duanqing , Shu Xiaodong
Published: November 2022

Ferroptosis induced by detrimental accumulation of lipid peroxides has been recently linked to a variety of pathological conditions ranging from acute tissue injuries to chronic degenerative diseases and suppression of ferroptosis by small chemical inhibitors is beneficial to the prevention and treatment of these diseases. However, in vivo applicable small chemical ferroptosis inhibitors are limited currently. In this study, we screened an alkaloid natural compound library for compounds that can inhibit RSL3-induced ferroptosis in HT1080 cells and identified a group of bisbenzylisoquinoline (BBIQ) compounds as novel ferroptosis-specific inhibitors. These BBIQ compounds are structurally different from known ferroptosis inhibitors and they do not appear to regulate iron homeostasis or lipid ROS generation pathways, while they are able to scavenge 1,1-diphenyl-2-picryl-hydrazyl (DPPH) in cell-free reactions and prevent accumulation of lipid peroxides in living cells. These BBIQ compounds demonstrate good in vivo activities as they effectively protect mice from folic acid-induced renal tubular ferroptosis and acute kidney injury. Several BBIQ compounds are approved drugs in Japan and China for traditional uses and cepharanthine is currently in clinical trials against SARS-CoV-2, our discovery of BBIQs as in vivo applicable ferroptosis inhibitors will expand their usage to prevent ferroptotic tissue damages under various pathological conditions.
Mutual regulation between phosphofructokinase 1 platelet isoform and VEGF promotes glioblastoma tumor growth
Authors: Lim Je Sun , Shi YuJie , Park Su Hwan , Jeon So Mi , Zhang Chuanbao , Park Yun-Yong , Liu Rui , Li Jing , Cho Wan-Seob , Du Linyong , Lee Jong-Ho
Published: November 2022

Glioblastoma (GBM) is a highly vascular malignant brain tumor that overexpresses vascular endothelial growth factor (VEGF) and phosphofructokinase 1 platelet isoform (PFKP), which catalyzes a rate-limiting reaction in glycolysis. However, whether PFKP and VEGF are reciprocally regulated during GBM tumor growth remains unknown. Here, we show that PFKP can promote EGFR activation-induced VEGF expression in HIF-1α-dependent and -independent manners in GBM cells. Importantly, we demonstrate that EGFR-phosphorylated PFKP Y64 has critical roles in both AKT/SP1-mediated transcriptional expression ofHIF-1αand in the AKT-mediated β-catenin S552 phosphorylation, to fully enhanceVEGFtranscription, subsequently promoting blood vessel formation and brain tumor growth. Levels of PFKP Y64 phosphorylation in human GBM specimens are positively correlated with HIF-1α expression, β-catenin S552 phosphorylation, and VEGF expression. Conversely, VEGF upregulates PFKP expression in a PFKP S386 phosphorylation-dependent manner, leading to increased PFK enzyme activity, aerobic glycolysis, and proliferation in GBM cells. These findings highlight a novel mechanism underlying the mutual regulation that occurs between PFKP and VEGF for promoting GBM tumor growth and also suggest that targeting the PFKP/VEGF regulatory loop might show therapeutic potential for treating GBM patients.
Metabolic regulation of cholestatic liver injury by D-2-hydroxyglutarate with the modulation of hepatic microenvironment and the mammalian target of rapamycin signaling
Authors: Tian Xinbei , Wang Ying , Lu Ying , Wu Bo , Chen Shanshan , Du Jun , Cai Wei , Xiao Yongtao
Published: November 2022

Biliary atresia (BA) is a cholestatic liver disease in neonates with devastating obstructive intrahepatic and extrahepatic biliary ducts. Owing to the lack of an early diagnostic marker and limited understanding of its pathogenesis, BA often leads to death within 2 years. Therefore, this study aimed to develop early diagnostic methods and investigate the underlying pathogenesis of liver injury in BA using metabolomics. Metabolomics and organoid combined energy metabolism analysis was used to obtain new insights into BA diagnosis and pathobiology using patient samples, mice liver organoids, and a zebrafish model. Metabolomics revealed that D-2-hydroxyglutarate (D-2-HG) levels were significantly elevated in the plasma and liver of patients with BA and closely correlated with liver injuries and impaired liver regeneration. D-2-HG suppressed the growth and expansion of liver organoids derived from the intrahepatic biliary ducts. The energy metabolism analysis demonstrated that D-2-HG inhibited mitochondrial respiration and ATP synthase; however, it increased aerobic glycolysis in organoids. In addition, D-2-HG exposure caused liver degeneration in zebrafish larvae. Mechanistically, D-2-HG inhibited the activation of protein kinase B and the mammalian target of rapamycin signaling. These findings reveal that D-2-HG may represent a novel noninvasive diagnostic biomarker and a potential therapeutic target for infants with BA.
Extrinsic cell death pathway plasticity: a driver of clonal evolution in cancer?
Authors: Seidel Eric , von Karstedt Silvia
Published: November 2022

Human cancers are known to adhere to basic evolutionary principles. During their journey from early transformation to metastatic disease, cancer cell populations have proven to be remarkably adaptive to different forms of intra- and extracellular selective pressure, including nutrient scarcity, oxidative stress, and anti-cancer immunity. Adaption may be achieved via the expansion of clones bearing driver mutations that optimize cellular fitness in response to the specific selective scenario, e.g., mutations facilitating evasion of cell death, immune evasion or increased proliferation despite growth suppression, all of which constitute well-established hallmarks of cancer. While great progress concerning the prevention, diagnosis and treatment of clinically apparent disease has been made over the last 50 years, the mechanisms underlying cellular adaption under selective pressure via the immune system during early carcinogenesis and its influence on cancer cell fate or disease severity remain to be clarified. For instance, evasion of cell death is generally accepted as a hallmark of cancer, yet recent decades have revealed that the extrinsic cell death machinery triggered by immune effector cells is composed of an astonishingly complex network of interacting—and sometimes compensating—modes of cell death, whose role in selective processes during early carcinogenesis remains obscure. Based upon recent advances in cell death research, here we propose a concept of cell death pathway plasticity in time shaping cancer evolution prior to treatment in an effort to offer new perspectives on how cancer cell fate may be determined by cell death pathway plasticity during early carcinogenesis.
Proteomic and functional profiling of platelet-derived extracellular vesicles released under physiological or tumor-associated conditions
Authors: Vismara Mauro , Manfredi Marcello , Zarà Marta , Trivigno Silvia Maria Grazia , Galgano Luca , Barbieri Silvia Stella , Canobbio Ilaria , Torti Mauro , Guidetti Gianni Francesco
Published: November 2022

During hemostasis, thrombosis, and inflammation, activated blood platelets release extracellular vesicles (PEVs) that represent biological mediators of physiological and pathological processes. We have recently demonstrated that the activation of platelets by breast cancer cells is accompanied by a massive release of PEVs, evidence that matches with the observation that breast cancer patients display increased levels of circulating PEVs. A core concept in PEVs biology is that their nature, composition and biological function are strongly influenced by the conditions that induced their release. In this study we have performed a comparative characterization of PEVs released by platelets upon activation with thrombin, a potent thrombotic stimulus, and upon exposure to the breast cancer cell line MDA-MB-231. By nanoparticle tracking analysis and tandem mass spectrometry we have characterized the two populations of PEVs, showing that the thrombotic and tumoral stimuli produced vesicles that largely differ in protein composition. The bioinformatic analysis of the proteomic data led to the identification of signaling pathways that can be differently affected by the two PEVs population in target cells. Specifically, we have demonstrated that both thrombin- and cancer-cell-induced PEVs reduce the migration and potentiate Ca2+-induced apoptosis of Jurkat cells, but only thrombin-derived PEVs also potentiate cell necrosis. Our results demonstrate that stimulation of platelets by thrombotic or tumoral stimuli induces the release of PEVs with different protein composition that, in turn, may elicit selective biological responses in target cells.
Mesenchymal stem cells alleviate systemic sclerosis by inhibiting the recruitment of pathogenic macrophages
Authors: Gong Pixia , Ding Yayun , Sun Rongrong , Jiang Zishan , Li Wen , Su Xiao , Tian Ruifeng , Zhou Yipeng , Wang Tingting , Jiang Junjie , Li Peishan , Shao Changshun , Shi Yufang
Published: November 2022

Systemic sclerosis (SSc) is a recalcitrant autoimmune disease for which there is no cure. Mesenchymal stem cell (MSC)-based treatment has emerged as a promising therapeutic option for several autoimmune diseases. Previously, we found that the immunoregulatory potential of MSCs can be greatly enhanced by IFN-γ and TNF-α. Here, we found that IFN-γ- and TNF-α-pretreated MSCs significantly alleviated skin fibrosis in a bleomycin (BLM)-induced SSc model. Macrophages were found to be the predominant profibrotic immune cell population in the pathogenesis of SSc. The accumulation of macrophages was significantly decreased by MSC treatment. Importantly, MSCs primarily reduced the population of maturing macrophages with high CCR2 expression by inhibiting the generation of CCL2 from fibroblasts and macrophages. This finding may help to improve MSC-based clinical treatments for SSc patients.
Modular stimuli-responsive hydrogel sealants for early gastrointestinal leak detection and containment
Authors: Anthis Alexandre H. C. , Abundo Maria Paulene , Neuer Anna L. , Tsolaki Elena , Rosendorf Jachym , Rduch Thomas , Starsich Fabian H. L. , Weisse Bernhard , Liska Vaclav , Schlegel Andrea A. , Shapiro Mikhail G. , Herrmann Inge K.
Published: November 2022

Millions of patients every year undergo gastrointestinal surgery. While often lifesaving, sutured and stapled reconnections leak in around 10% of cases. Currently, surgeons rely on the monitoring of surrogate markers and clinical symptoms, which often lack sensitivity and specificity, hence only offering late-stage detection of fully developed leaks. Here, we present a holistic solution in the form of a modular, intelligent suture support sealant patch capable of containing and detecting leaks early. The pH and/or enzyme-responsive triggerable sensing elements can be read out by point-of-need ultrasound imaging. We demonstrate reliable detection of the breaching of sutures, in as little as 3 hours in intestinal leak scenarios and 15 minutes in gastric leak conditions. This technology paves the way for next-generation suture support materials that seal and offer disambiguation in cases of anastomotic leaks based on point-of-need monitoring, without reliance on complex electronics or bulky (bio)electronic implantables.
Geometrical congruence, greedy navigability and myopic transfer in complex networks and brain connectomes
Authors: Cannistraci Carlo Vittorio , Muscoloni Alessandro
Published: November 2022

We introduce in network geometry a measure of geometrical congruence (GC) to evaluate the extent a network topology follows an underlying geometry. This requires finding all topological shortest-paths for each nonadjacent node pair in the network: a nontrivial computational task. Hence, we propose an optimized algorithm that reduces 26 years of worst scenario computation to one week parallel computing. Analysing artificial networks with patent geometry we discover that, different from current belief, hyperbolic networks do not show in general high GC and efficient greedy navigability (GN) with respect to the geodesics. The myopic transfer which rules GN works best only when degree-distribution power-law exponent is strictly close to two. Analysing real networks—whose geometry is often latent—GC overcomes GN as marker to differentiate phenotypical states in macroscale structural-MRI brain connectomes, suggesting connectomes might have a latent neurobiological geometry accounting for more information than the visible tridimensional Euclidean.
Predicting protein function and orientation on a gold nanoparticle surface using a residue-based affinity scale
Authors: Xu Joanna Xiuzhu , Alom Md. Siddik , Yadav Rahul , Fitzkee Nicholas C.
Published: November 2022

The orientation adopted by proteins on nanoparticle surfaces determines the nanoparticle’s bioactivity and its interactions with living systems. Here, we present a residue-based affinity scale for predicting protein orientation on citrate-gold nanoparticles (AuNPs). Competitive binding between protein variants accounts for thermodynamic and kinetic aspects of adsorption in this scale. For hydrophobic residues, the steric considerations dominate, whereas electrostatic interactions are critical for hydrophilic residues. The scale rationalizes the well-defined binding orientation of the small GB3 protein, and it subsequently predicts the orientation and active site accessibility of two enzymes on AuNPs. Additionally, our approach accounts for the AuNP-bound activity of five out of six additional enzymes from the literature. The model developed here enables high-throughput predictions of protein behavior on nanoparticles, and it enhances our understanding of protein orientation in the biomolecular corona, which should greatly enhance the performance and safety of nanomedicines used in vivo.
Improved bounds on Lorentz violation from composite pulse Ramsey spectroscopy in a trapped ion
Authors: Dreissen Laura S. , Yeh Chih-Han , Fürst Henning A. , Grensemann Kai C. , Mehlstäubler Tanja E.
Published: November 2022

In attempts to unify the four known fundamental forces in a single quantum-consistent theory, it is suggested that Lorentz symmetry may be broken at the Planck scale. Here we search for Lorentz violation at the low-energy limit by comparing orthogonally oriented atomic orbitals in a Michelson-Morley-type experiment. We apply a robust radiofrequency composite pulse sequence in the 2F7/2 manifold of an Yb+ ion, extending the coherence time from 200 μs to more than 1 s. In this manner, we fully exploit the high intrinsic susceptibility of the 2F7/2 state and take advantage of its exceptionally long lifetime. We match the stability of the previous best Lorentz symmetry test nearly an order of magnitude faster and improve the constraints on the symmetry breaking coefficients to the 10−21 level. These results represent the most stringent test of this type of Lorentz violation. The demonstrated method can be further extended to ion Coulomb crystals.
Chern Fermi pocket, topological pair density wave, and charge-4e and charge-6e superconductivity in kagomé superconductors
Authors: Zhou Sen , Wang Ziqiang
Published: November 2022

The recent discovery of novel charge density wave (CDW) and pair density wave (PDW) in kagomé lattice superconductorsAV3Sb5(A = K, Rb, Cs) hints at unexpected time-reversal symmetry breaking correlated and topological states whose physical origin and broader implications are not understood. Here, we make conceptual advances toward a mechanism behind the striking observations and new predictions for novel macroscopic phase coherent quantum states. We show that the metallic CDW state with circulating loop currents is a doped orbital Chern insulator near van Hove filling. The emergent Chern Fermi pockets (CFPs) carry concentrated Berry curvature and orbital magnetic moment. We find that the pairing of electrons on the CFPs leads to a superconducting state with an emergent vortex-antivortex lattice and the formation of a complex triple-QPDW. A plethora of correlated and topological states emerge, including a never-before-encountered chiral topological PDW superconductor, a loop-current pseudogap phase, and vestigial charge-4eand charge-6esuperconductivity in staged melting of the vortex-antivortex lattice and hexatic liquid crystal. Our findings reveal previously unknown nature of the superconducting state of a current-carrying Chern metal, with broad implications for correlated and topological materials.
How mono- and diphosphine ligands alter regioselectivity of the Rh-catalyzed annulative cleavage of bicyclo[1.1.0]butanes
Authors: Chen Pan-Pan , Wipf Peter , Houk K. N.
Published: November 2022

Rh(I)-catalyzed cycloisomerizations of bicyclo[1.1.0]butanes provide a fruitful approach to cyclopropane-fused heterocycles. Products and stereochemical outcome are highly dependent on catalyst. The triphenylphosphine (PPh3) ligand provides pyrrolidines, placing substituents anti to the cyclopropyl group. The 1,2-bis(diphenylphosphino)ethane (dppe) ligand yields azepanes with substituents syn to the cyclopropyl group. In this work, quantum mechanical DFT calculations pinpoint a reversal of regio- and diastereoselectivity, suggesting a concerted (double) C−C bond cleavage and rhodium carbenoid formation, driven by strain-release. The ligand-influenced cleavage step determines the regioselectivity of carbometalation and product formation, and suggests new applications of bicyclobutanes.
Characterisation of SARS-CoV-2 genomic variation in response to molnupiravir treatment in the AGILE Phase IIa clinical trial
Authors: Donovan-Banfield I’ah , Penrice-Randal Rebekah , Goldswain Hannah , Rzeszutek Aleksandra M. , Pilgrim Jack , Bullock Katie , Saunders Geoffrey , Northey Josh , Dong Xiaofeng , Ryan Yan , Reynolds Helen , Tetlow Michelle , Walker Lauren E. , FitzGerald Richard , Hale Colin , Lyon Rebecca , Woods Christie , Ahmad Shazaad , Hadjiyiannakis Dennis , Periselneris Jimstan , Knox Emma , Middleton Calley , Lavelle-Langham Lara , Shaw Victoria , Greenhalf William , Edwards Thomas , Lalloo David G. , Edwards Christopher J. , Darby Alistair C. , Carroll Miles W. , Griffiths Gareth , Khoo Saye H. , Hiscox Julian A. , Fletcher Thomas
Published: November 2022

Molnupiravir is an antiviral, currently approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for treating at-risk COVID-19 patients, that induces lethal error catastrophe in SARS-CoV-2. How this drug-induced mechanism of action might impact the emergence of resistance mutations is unclear. To investigate this, we used samples from the AGILE Candidate Specific Trial (CST)−2 (clinical trial number NCT04746183). The primary outcomes of AGILE CST-2 were to measure the drug safety and antiviral efficacy of molnupiravir in humans (180 participants randomised 1:1 with placebo). Here, we describe the pre-specified exploratory virological endpoint of CST-2, which was to determine the possible genomic changes in SARS-CoV-2 induced by molnupiravir treatment. We use high-throughput amplicon sequencing and minor variant analysis to characterise viral genomics in each participant whose longitudinal samples (days 1, 3 and 5 post-randomisation) pass the viral genomic quality criteria (n = 59 for molnupiravir and n = 65 for placebo). Over the course of treatment, no specific mutations were associated with molnupiravir treatment. We find that molnupiravir significantly increased the transition:transversion mutation ratio in SARS-CoV-2, consistent with the model of lethal error catastrophe. This study highlights the utility of examining intra-host virus populations to strengthen the prediction, and surveillance, of potential treatment-emergent adaptations.
Shape morphing of plastic films
Authors: Zhang Feilong , Li Dong , Wang Changxian , Liu Zhihua , Yang Man , Cui Zequn , Yi Junqi , Wang Ming , Jiang Ying , Lv Zhisheng , Wang Shutao , Gao Huajian , Chen Xiaodong
Published: November 2022

Three-dimensional (3D) architectures have qualitatively expanded the functions of materials and flexible electronics. However, current fabrication techniques for devices constrain their substrates to 2D geometries and current post-shape transformation strategies are limited to heterogenous or responsive materials and are not amenable to free-standing inert plastic films such as polyethylene terephthalate (PET) and polyimide (PI), which are vital substrates for flexible electronics. Here, we realize the shape morphing of homogeneous plastic films for various free-standing 3D frameworks from their 2D precursors by introducing a general strategy based on programming the plastic strain in films under peeling. By modulating the peeling parameters, previously inaccessible free-standing 3D geometries ranging from millimeter to micrometer were predicted theoretically and obtained experimentally. This strategy is applicable to most materials capable of plastic deformation, including polymers, metals, and composite materials, and can even enable 4D transformation with responsive plastic films. Enhanced performance of 3D circuits and piezoelectric systems demonstrates the enormous potential of peeling-induced shape morphing for 3D devices.
ARID1A loss induces polymorphonuclear myeloid-derived suppressor cell chemotaxis and promotes prostate cancer progression
Authors: Li Ni , Liu Qiuli , Han Ying , Pei Siyu , Cheng Bisheng , Xu Junyu , Miao Xiang , Pan Qiang , Wang Hanling , Guo Jiacheng , Wang Xuege , Zhang Guoying , Lian Yannan , Zhang Wei , Zang Yi , Tan Minjia , Li Qintong , Wang Xiaoming , Xiao Yichuan , Hu Guohong , Jiang Jun , Huang Hai , Qin Jun
Published: November 2022

Chronic inflammation and an immunosuppressive microenvironment promote prostate cancer (PCa) progression and diminish the response to immune checkpoint blockade (ICB) therapies. However, it remains unclear how and to what extent these two events are coordinated. Here, we show that ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, functions downstream of inflammation-induced IKKβ activation to shape the immunosuppressive tumor microenvironment (TME). Prostate-specific deletion ofArid1acooperates withPtenloss to accelerate prostate tumorigenesis. We identify polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) as the major infiltrating immune cell type that causes immune evasion and reveal that neutralization of PMN-MDSCs restricts the progression ofArid1a-deficient tumors. Mechanistically, inflammatory cues activate IKKβ to phosphorylate ARID1A, leading to its degradation via β-TRCP. ARID1A downregulation in turn silences the enhancer ofA20deubiquitinase, a critical negative regulator of NF-κB signaling, and thereby unleashes CXCR2 ligand-mediated MDSC chemotaxis. Importantly, our results support the therapeutic strategy of anti-NF-κB antibody or targeting CXCR2 combined with ICB for advanced PCa. Together, our findings highlight that the IKKβ/ARID1A/NF-κB feedback axis integrates inflammation and immunosuppression to promote PCa progression.
Decoding molecular programs in melanoma brain metastases
Authors: Radke Josefine , Schumann Elisa , Onken Julia , Koll Randi , Acker Güliz , Bodnar Bohdan , Senger Carolin , Tierling Sascha , Möbs Markus , Vajkoczy Peter , Vidal Anna , Högler Sandra , Kodajova Petra , Westphal Dana , Meier Friedegund , Heppner Frank , Kreuzer-Redmer Susanne , Grebien Florian , Jürchott Karsten , Redmer Torben
Published: November 2022

Melanoma brain metastases (MBM) variably respond to therapeutic interventions; thus determining patient’s prognosis. However, the mechanisms that govern therapy response are poorly understood. Here, we use a multi-OMICS approach and targeted sequencing (TargetSeq) to unravel the programs that potentially control the development of progressive intracranial disease. Molecularly, the expression of E-cadherin (Ecad) or NGFR, the BRAF mutation state and level of immune cell infiltration subdivides tumors into proliferative/pigmented and invasive/stem-like/therapy-resistant irrespective of the intracranial location. The analysis of MAPK inhibitor-naive and refractory MBM reveals switching from Ecad-associated into NGFR-associated programs during progression. NGFR-associated programs control cell migration and proliferation via downstream transcription factors such as SOX4. Moreover, global methylome profiling uncovers 46 differentially methylated regions that discriminate BRAFmut and wildtype MBM. In summary, we propose that the expression of Ecad and NGFR sub- classifies MBM and suggest that the Ecad-to-NGFR phenotype switch is a rate-limiting process which potentially indicates drug-response and intracranial progression states in melanoma patients.
Structural basis for lipid and copper regulation of the ABC transporter MsbA
Authors: Lyu Jixing , Liu Chang , Zhang Tianqi , Schrecke Samantha , Elam Nicklaus P. , Packianathan Charles , Hochberg Georg K. A. , Russell David , Zhao Minglei , Laganowsky Arthur
Published: November 2022

A critical step in lipopolysaccharide (LPS) biogenesis involves flipping lipooligosaccharide, an LPS precursor, from the cytoplasmic to the periplasmic leaflet of the inner membrane, an operation carried out by the ATP-binding cassette transporter MsbA. Although LPS binding to the inner cavity of MsbA is well established, the selectivity of MsbA-lipid interactions at other site(s) remains poorly understood. Here we use native mass spectrometry (MS) to characterize MsbA-lipid interactions and guide structural studies. We show the transporter co-purifies with copper(II) and metal binding modulates protein-lipid interactions. A 2.15 Å resolution structure of an N-terminal region of MsbA in complex with copper(II) is presented, revealing a structure reminiscent of the GHK peptide, a high-affinity copper(II) chelator. Our results demonstrate conformation-dependent lipid binding affinities, particularly for the LPS-precursor, 3-deoxy-D-manno-oct-2-ulosonic acid (Kdo)2-lipid A (KDL). We report a 3.6 Å-resolution structure of MsbA trapped in an open, outward-facing conformation with adenosine 5’-diphosphate and vanadate, revealing a distinct KDL binding site, wherein the lipid forms extensive interactions with the transporter. Additional studies provide evidence that the exterior KDL binding site is conserved and a positive allosteric modulator of ATPase activity, serving as a feedforward activation mechanism to couple transporter activity with LPS biosynthesis.
Structural characterization of protective non-neutralizing antibodies targeting Crimean-Congo hemorrhagic fever virus
Authors: Durie Ian A. , Tehrani Zahra R. , Karaaslan Elif , Sorvillo Teresa E. , McGuire Jack , Golden Joseph W. , Welch Stephen R. , Kainulainen Markus H. , Harmon Jessica R. , Mousa Jarrod J. , Gonzalez David , Enos Suzanne , Koksal Iftihar , Yilmaz Gurdal , Karakoc Hanife Nur , Hamidi Sanaz , Albay Cansu , Spengler Jessica R. , Spiropoulou Christina F. , Garrison Aura R. , Sajadi Mohammad M. , Bergeron Éric , Pegan Scott D.
Published: November 2022

Crimean-Congo Hemorrhagic Fever Virus (CCHFV) causes a life-threatening disease with up to a 40% mortality rate. With no approved medical countermeasures, CCHFV is considered a public health priority agent. The non-neutralizing mouse monoclonal antibody (mAb) 13G8 targets CCHFV glycoprotein GP38 and protects mice from lethal CCHFV challenge when administered prophylactically or therapeutically. Here, we reveal the structures of GP38 bound with a human chimeric 13G8 mAb and a newly isolated CC5-17 mAb from a human survivor. These mAbs bind overlapping epitopes with a shifted angle. The broad-spectrum potential of c13G8 and CC5-17 and the practicality of using them against Aigai virus, a closely related nairovirus were examined. Binding studies demonstrate that the presence of non-conserved amino acids in Aigai virus corresponding region prevent CCHFV mAbs from binding Aigai virus GP38. This information, coupled with in vivo efficacy, paves the way for future mAb therapeutics effective against a wide swath of CCHFV strains.
Kinetochore- and chromosome-driven transition of microtubules into bundles promotes spindle assembly
Authors: Matković Jurica , Ghosh Subhadip , Ćosić Mateja , Eibes Susana , Barišić Marin , Pavin Nenad , Tolić Iva M.
Published: November 2022

Mitotic spindle assembly is crucial for chromosome segregation and relies on bundles of microtubules that extend from the poles and overlap in the middle. However, how these structures form remains poorly understood. Here we show that overlap bundles arise through a network-to-bundles transition driven by kinetochores and chromosomes. STED super-resolution microscopy reveals that PRC1-crosslinked microtubules initially form loose arrays, which become rearranged into bundles. Kinetochores promote microtubule bundling by lateral binding via CENP-E/kinesin-7 in an Aurora B-regulated manner. Steric interactions between the bundle-associated chromosomes at the spindle midplane drive bundle separation and spindle widening. In agreement with experiments, theoretical modeling suggests that bundles arise through competing attractive and repulsive mechanisms. Finally, perturbation of overlap bundles leads to inefficient correction of erroneous kinetochore-microtubule attachments. Thus, kinetochores and chromosomes drive coarsening of a uniform microtubule array into overlap bundles, which promote not only spindle formation but also chromosome segregation fidelity.
Epigenetic regulation of white adipose tissue plasticity and energy metabolism by nucleosome binding HMGN proteins
Authors: Nanduri Ravikanth , Furusawa Takashi , Lobanov Alexei , He Bing , Xie Carol , Dadkhah Kimia , Kelly Michael C. , Gavrilova Oksana , Gonzalez Frank J. , Bustin Michael
Published: November 2022

White adipose tissue browning is a key metabolic process controlled by epigenetic factors that facilitate changes in gene expression leading to altered cell identity. We find that male mice lacking the nucleosome binding proteins HMGN1 and HMGN2 (DKO mice), show decreased body weight and inguinal WAT mass, but elevated food intake, WAT browning and energy expenditure. DKO white preadipocytes show reduced chromatin accessibility and lower FRA2 and JUN binding at Pparγ and Pparα promoters. White preadipocytes and mouse embryonic fibroblasts from DKO mice show enhanced rate of differentiation into brown-like adipocytes. Differentiating DKO adipocytes show reduced H3K27ac levels at white adipocyte-specific enhancers but elevated H3K27ac levels at brown adipocyte-specific enhancers, suggesting a faster rate of change in cell identity, from white to brown-like adipocytes. Thus, HMGN proteins function as epigenetic factors that stabilize white adipocyte cell identity, thereby modulating the rate of white adipose tissue browning and affecting energy metabolism in mice.
Observation of a transient intermediate in the ultrafast relaxation dynamics of the excess electron in strong-field-ionized liquid water
Authors: Low Pei Jiang , Chu Weibin , Nie Zhaogang , Bin Mohd Yusof Muhammad Shafiq , Prezhdo Oleg V. , Loh Zhi-Heng
Published: November 2022

A unified picture of the electronic relaxation dynamics of ionized liquid water has remained elusive despite decades of study. Here, we employ sub-two-cycle visible to short-wave infrared pump-probe spectroscopy and ab initio nonadiabatic molecular dynamics simulations to reveal that the excess electron injected into the conduction band (CB) of ionized liquid water undergoes sequential relaxation to the hydrated electron s ground state via an intermediate state, identified as the elusive p excited state. The measured CB and p-electron lifetimes are 0.26 ± 0.02 ps and 62 ± 10 fs, respectively. Ab initio quantum dynamics yield similar lifetimes and furthermore reveal vibrational modes that participate in the different stages of electronic relaxation, with initial relaxation within the dense CB manifold coupled to hindered translational motions whereas subsequent p-to-s relaxation facilitated by librational and even intramolecular bending modes of water. Finally, energetic considerations suggest that a hitherto unobserved trap state resides ~0.3-eV below the CB edge of liquid water. Our results provide a detailed atomistic picture of the electronic relaxation dynamics of ionized liquid water with unprecedented time resolution.
Seroepidemiology of enterovirus A71 infection in prospective cohort studies of children in southern China, 2013-2018
Authors: Yang Juan , Liao Qiaohong , Luo Kaiwei , Liu Fengfeng , Zhou Yonghong , Zou Gang , Huang Wei , Yu Shuanbao , Wei Xianglin , Zhou Jiaxin , Dai Bingbing , Qiu Qi , Altmeyer Ralf , Hu Hongan , Paireau Juliette , Luo Li , Gao Lidong , Nikolay Birgit , Hu Shixiong , Xing Weijia , Wu Peng , van Doorn H. Rogier , Horby Peter W. , Simmonds Peter , Leung Gabriel M. , Cowling Benjamin J. , Cauchemez Simon , Yu Hongjie
Published: November 2022

Enterovirus A71 (EV-A71)–related hand, foot, and mouth disease (HFMD) imposes a substantial clinical burden in the Asia Pacific region. To inform policy on the introduction of the EV-A71 vaccine into the National Immunization Programme, we investigated the seroepidemiological characteristics of EV-A71 in two prospective cohorts of children in southern China conducted between 2013 and 2018. Our results show that maternal antibody titres declined rapidly in neonates, with over half becoming susceptible to EV-A71 at 1 month of age. Between 6 months and 2 years of age, over 80% of study participants were susceptible, while one third remained susceptible at 5 years old. The highest incidence of EV-A71 infections was observed in children aged 5-6 months. Our findings support EV-A71 vaccination before 6 months for birth cohorts in southern China, potentially with a one-time catch-up vaccination for children 6 months-5 years old. More regionally representative longitudinal seroepidemiological studies are needed to further validate these findings.