bluuebunny/crossref_metadata_2025_split huggingface dataset:
E3 ligase MG53 suppresses tumor growth by degrading cyclin D1
Authors: Fang Meng , Wu Hong-Kun , Pei Yumeng , Zhang Yan , Gao Xiangyu , He Yanyun , Chen Gengjia , Lv Fengxiang , Jiang Peng , Li Yumei , Li Wenwen , Jiang Peng , Wang Lin , Ji Jiafu , Hu Xinli , Xiao Rui-Ping 
Published: July 2023

AbstractDue to the essential role of cyclin D1 in regulating transition from G1 to S phase in cell cycle, aberrant cyclin D1 expression is a major oncogenic event in many types of cancers. In particular, the dysregulation of ubiquitination-dependent degradation of cyclin D1 contributes to not only the pathogenesis of malignancies but also the refractory to cancer treatment regiments with CDK4/6 inhibitors. Here we show that in colorectal and gastric cancer patients, MG53 is downregulated in more than 80% of tumors compared to the normal gastrointestinal tissues from the same patient, and the reduced MG53 expression is correlated with increased cyclin D1 abundance and inferior survival. Mechanistically, MG53 catalyzes the K48-linked ubiquitination and subsequent degradation of cyclin D1. Thus, increased expression of MG53 leads to cell cycle arrest at G1, and thereby markedly suppresses cancer cell proliferation in vitro as well as tumor growth in mice with xenograft tumors or AOM/DSS induced-colorectal cancer. Consistently, MG53 deficiency results in accumulation of cyclin D1 protein and accelerates cancer cell growth both in culture and in animal models. These findings define MG53 as a tumor suppressor via facilitating cyclin D1 degradation, highlighting the therapeutic potential of targeting MG53 in treating cancers with dysregulated cyclin D1 turnover.
Synergistic, long-term effects of glutamate dehydrogenase 1 deficiency and mild stress on cognitive function and mPFC gene and miRNA expression
Authors: Asraf Kfir , Zaidan Hiba , Natoor Baylasan , Gaisler-Salomon Inna 
Published: July 2023

AbstractGlutamate abnormalities in the medial prefrontal cortex (mPFC) are associated with cognitive deficits. We previously showed that homozygous deletion of CNS glutamate dehydrogenase 1 (Glud1), a metabolic enzyme critical for glutamate metabolism, leads to schizophrenia-like behavioral abnormalities and increased mPFC glutamate; mice heterozygous for CNSGlud1deletion (C-Glud1+/−mice) showed no cognitive or molecular abnormalities. Here, we examined the protracted behavioral and molecular effects of mild injection stress on C-Glud1+/−mice. We found spatial and reversal learning deficits, as well as large-scale mPFC transcriptional changes in pathways associated with glutamate and GABA signaling, in stress-exposed C-Glud1+/−mice, but not in their stress-naïve or C-Glud1+/+littermates. These effects were observed several weeks following stress exposure, and the expression levels of specific glutamatergic and GABAergic genes differentiated between high and low reversal learning performance. An increase in miR203-5p expression immediately following stress may provide a translational regulatory mechanism to account for the delayed effect of stress exposure on cognitive function. Our findings show that chronic glutamate abnormalities interact with acute stress to induce cognitive deficits, and resonate with gene x environment theories of schizophrenia. Stress-exposed C-Glud1+/−mice may model a schizophrenia high-risk population, which is uniquely sensitive to stress-related ‘trigger’ events.
Quality of life, mentalization, and perception of challenging patient encounters in dentistry: A cross-sectional study
Authors: Johnsen Jan-Are K. , Haukefer Sunniva B. , Korsan Sofie. J. , Larsen Maria , Holde Gro Eirin 
Published: July 2023

Abstract
Objective
This study investigated how exposure to challenging patient encounters influenced participants’ self-reported quality of life, and how participants’ mentalization capabilities affected the perceptions of challenging patients encounters among Norwegian dentists and dental students.

Materials and Methods
Data was collected with an online questionnaire, and a total of 165 dentists (n = 126) and dental students (n = 39) responded.

Results
Participants who reported higher total exposure of challenging encounters reported lower quality of life (QoL). Mentalization tendencies affected the perception of challenging encounters with specific types of patients; critical and anxious; as well as the estimation of the total exposure to challenging patient encounters. Participants that were overconfident with regards to the mental states of others found these patient types less challenging and they reported less overall exposure to challenging patients than underconfident participants. Also, overconfident participants reported higher QoL than underconfident participants.

Conclusions
Mentalization capabilities of dental practitioners interact with the perception of challenging encounters in dental practice, and how practitioners respond to these challenges. Measures should be undertaken to increase the awareness of metacognitive skills in dentistry with the dual goal of improving patient care as well as the quality of life of dental practitioners.
A novel CTLA-4 blocking strategy based on nanobody enhances the activity of dendritic cell vaccine-stimulated antitumor cytotoxic T lymphocytes
Authors: Yang Wenli , Pang Yanyang , Wang Xi , Lai Zhiheng , Lu Yanda , Zheng Shaojiang , Wang Wu 
Published: July 2023

AbstractDespite the great success of CTLA-4 blocking in cancer treatment, the use of anti-CTLA-4 monoclonal antibodies still faces many limitations. Now, immune checkpoint blocking coupled with adoptive cell therapy is gaining much attention. In this paper, we reported a strategy on the basis of anti-CTLA-4 nanobody (Nb)-modified liposomes to improve these obstacles. An Nb36/liposome complex was constructed and utilized as a blocker of the CTLA-4/B7 signal pathway in a combination with dendritic cell (DC)/tumor fusion vaccine to enhance the CD8+ T cell cytokine secretion, activation, proliferation, as well as specific cytotoxicity. Moreover, the CD8+ T cells induced by LPS-Nb36 and DC/tumor fusion vaccine led to higher CD8+ T cell effector function in vivo, which significantly retarded tumor growth and lengthened survival of tumor-bearing mice (HepG2, A549, and MGC-803). Our data demonstrate that the anti-CTLA-4 Nb-modified liposomes in connection with DC/tumor fusion vaccines enhance the CD8+ T cell antitumor activity in vitro and in vivo, and is expected to be an alternative therapy for patients with malignancies that have T cell dysfunction or have poor treatment against anti-CTLA-4 mAb.
Central macular choriocapillaris impairment as a manifestation of microvascular disease in eyes with subretinal drusenoid deposits
Authors: Abdolrahimzadeh Solmaz , Zweifel Sandrine Anne , Di Pippo Mariachiara , Bajka Anahita , Scuderi Gianluca , Lotery Andrew John 
Published: July 2023

Abstract
Background/Objectives
Microvascular alterations and choroidal impairment are emerging as a pathologic pathway in age-related macular degeneration (AMD). This study aimed to evaluate the central macular choriocapillaris (CC) in eyes with subretinal drusenoid deposits (SDD) and the retinal microvasculature in patients with early AMD phenotypes.

Subjects/Methods
This was an institutional, multicentric observational cross-sectional study. Ninety-nine eyes of 99 subjects; 33 eyes with SDD only, 33 eyes with conventional drusen (CD) only, and 33 eyes of healthy age-matched subjects were included. Comprehensive ophthalmologic examination and optical coherence tomography angiography (OCTA) was performed. The central macular flow area of the CC was analysed in the SDD group and the vessel density of the retinal superficial capillary plexus (SCP) and deep capillary plexus (DCP) was analysed in the SDD and CD groups using automated OCTA output parameters.

Results
The flow area of the CC in the SDD group was significantly reduced (p ≤ 0.001) with respect to the healthy control group. There was a trend of reduction of vessel density of the SCP and the DCP in the SDD and CD group with respect to controls, although this did not reach statistical significance.

Conclusions
OCTA data in the present report corroborate the role of vascular damage in early AMD with CC impairment in the central macular area in eyes with SDD.
Highly efficient platelet generation in lung vasculature reproduced by microfluidics
Authors: Zhao Xiaojuan , Alibhai Dominic , Walsh Tony G. , Tarassova Nathalie , Englert Maximilian , Birol Semra Z. , Li Yong , Williams Christopher M. , Neal Chris R. , Burkard Philipp , Cross Stephen J. , Aitken Elizabeth W. , Waller Amie K. , Beltrán José Ballester , Gunning Peter W. , Hardeman Edna C. , Agbani Ejaife O. , Nieswandt Bernhard , Hers Ingeborg , Ghevaert Cedric , Poole Alastair W. 
Published: July 2023

AbstractPlatelets, small hemostatic blood cells, are derived from megakaryocytes. Both bone marrow and lung are principal sites of thrombopoiesis although underlying mechanisms remain unclear. Outside the body, however, our ability to generate large number of functional platelets is poor. Here we show that perfusion of megakaryocytes ex vivo through the mouse lung vasculature generates substantial platelet numbers, up to 3000 per megakaryocyte. Despite their large size, megakaryocytes are able repeatedly to passage through the lung vasculature, leading to enucleation and subsequent platelet generation intravascularly. Using ex vivo lung and an in vitro microfluidic chamber we determine how oxygenation, ventilation, healthy pulmonary endothelium and the microvascular structure support thrombopoiesis. We also show a critical role for the actin regulator Tropomyosin 4 in the final steps of platelet formation in lung vasculature. This work reveals the mechanisms of thrombopoiesis in lung vasculature and informs approaches to large-scale generation of platelets.
Molecular profiling of aromatase inhibitor sensitive and resistant ER+HER2- postmenopausal breast cancers
Authors: Schuster Eugene F. , Lopez-Knowles Elena , Alataki Anastasia , Zabaglo Lila , Folkerd Elizabeth , Evans David , Sidhu Kally , Cheang Maggie Chon U. , Tovey Holly , Salto-Tellez Manuel , Maxwell Perry , Robertson John , Smith Ian , Bliss Judith M. , Dowsett Mitch 
Published: July 2023

AbstractAromatase inhibitors (AIs) reduce recurrences and mortality in postmenopausal patients with oestrogen receptor positive (ER+) breast cancer (BC), but >20% of patients will eventually relapse. Given the limited understanding of intrinsic resistance in these tumours, here we conduct a large-scale molecular analysis to identify features that impact on the response of ER + HER2- BC to AI. We compare the 15% of poorest responders (PRs, n = 177) as measured by proportional Ki67 changes after 2 weeks of neoadjuvant AI to good responders (GRs, n = 190) selected from the top 50% responders in the POETIC trial and matched for baseline Ki67 categories. In this work, low ESR1 levels are associated with poor response, high proliferation, high expression of growth factor pathways and non-luminal subtypes. PRs having high ESR1 expression have similar proportions of luminal subtypes to GRs but lower plasma estradiol levels, lower expression of estrogen response genes, higher levels of tumor infiltrating lymphocytes and immune markers, and more TP53 mutations.
Expanded vacuum-stable gels for multiplexed high-resolution spatial histopathology
Authors: Bai Yunhao , Zhu Bokai , Oliveria John-Paul , Cannon Bryan J. , Feyaerts Dorien , Bosse Marc , Vijayaragavan Kausalia , Greenwald Noah F. , Phillips Darci , Schürch Christian M. , Naik Samuel M. , Ganio Edward A. , Gaudilliere Brice , Rodig Scott J. , Miller Michael B. , Angelo Michael , Bendall Sean C. , Rovira-Clavé Xavier , Nolan Garry P. , Jiang Sizun 
Published: July 2023

AbstractCellular organization and functions encompass multiple scales in vivo. Emerging high-plex imaging technologies are limited in resolving subcellular biomolecular features. Expansion Microscopy (ExM) and related techniques physically expand samples for enhanced spatial resolution, but are challenging to be combined with high-plex imaging technologies to enable integrative multiscaled tissue biology insights. Here, we introduce Expand and comPRESS hydrOgels (ExPRESSO), an ExM framework that allows high-plex protein staining, physical expansion, and removal of water, while retaining the lateral tissue expansion. We demonstrate ExPRESSO imaging of archival clinical tissue samples on Multiplexed Ion Beam Imaging and Imaging Mass Cytometry platforms, with detection capabilities of > 40 markers. Application of ExPRESSO on archival human lymphoid and brain tissues resolved tissue architecture at the subcellular level, particularly that of the blood-brain barrier. ExPRESSO hence provides a platform for extending the analysis compatibility of hydrogel-expanded biospecimens to mass spectrometry, with minimal modifications to protocols and instrumentation.
Amphetamine disrupts dopamine axon growth in adolescence by a sex-specific mechanism in mice
Authors: Reynolds Lauren M. , Hernandez Giovanni , MacGowan Del , Popescu Christina , Nouel Dominique , Cuesta Santiago , Burke Samuel , Savell Katherine E. , Zhao Janet , Restrepo-Lozano Jose Maria , Giroux Michel , Israel Sonia , Orsini Taylor , He Susan , Wodzinski Michael , Avramescu Radu G. , Pokinko Matthew , Epelbaum Julia G. , Niu Zhipeng , Pantoja-Urbán Andrea Harée , Trudeau Louis-Éric , Kolb Bryan , Day Jeremy J. , Flores Cecilia 
Published: July 2023

AbstractInitiating drug use during adolescence increases the risk of developing addiction or other psychopathologies later in life, with long-term outcomes varying according to sex and exact timing of use. The cellular and molecular underpinnings explaining this differential sensitivity to detrimental drug effects remain unexplained. The Netrin-1/DCC guidance cue system segregates cortical and limbic dopamine pathways in adolescence. Here we show that amphetamine, by dysregulating Netrin-1/DCC signaling, triggers ectopic growth of mesolimbic dopamine axons to the prefrontal cortex, only in early-adolescent male mice, underlying a male-specific vulnerability to enduring cognitive deficits. In adolescent females, compensatory changes in Netrin-1 protect against the deleterious consequences of amphetamine on dopamine connectivity and cognitive outcomes. Netrin-1/DCC signaling functions as a molecular switch which can be differentially regulated by the same drug experience as function of an individual’s sex and adolescent age, and lead to divergent long-term outcomes associated with vulnerable or resilient phenotypes.
Photoswitchable dynamic conjugate addition-elimination reactions as a tool for light-mediated click and clip chemistry
Authors: Lu Hanwei , Ye Hebo , Zhang Meilan , Liu Zimu , Zou Hanxun , You Lei 
Published: July 2023

AbstractPhototriggered click and clip reactions can endow chemical processes with high spatiotemporal resolution and sustainability, but are challenging with a limited scope. Herein we report photoswitchable reversible covalent conjugate addition-elimination reactions toward light-addressed modular covalent connection and disconnection. By coupling between photochromic dithienylethene switch and Michael acceptors, the reactivity of Michael reactions was tuned through closed-ring and open-ring forms of dithienylethene, allowing switching on and off dynamic exchange of a wide scope of thiol and amine nucleophiles. The breaking of antiaromaticity in transition states and enol intermediates of addition-elimination reactions provides the driving force for photoinduced change in kinetic barriers. To showcase the versatile application, light-mediated modification of solid surfaces, regulation of amphiphilic assemblies, and creation/degradation of covalent polymers on demand were achieved. The manipulation of dynamic click/clip reactions with light should set the stage for future endeavors, including responsive assemblies, biological delivery, and intelligent materials.
Signatures of VH1-69-derived hepatitis C virus neutralizing antibody precursors defined by binding to envelope glycoproteins
Authors: Capella-Pujol Joan , de Gast Marlon , Radić Laura , Zon Ian , Chumbe Ana , Koekkoek Sylvie , Olijhoek Wouter , Schinkel Janke , van Gils Marit J. , Sanders Rogier W. , Sliepen Kwinten 
Published: July 2023

AbstractAn effective preventive vaccine for hepatitis C virus (HCV) remains a major unmet need. Antigenic region 3 (AR3) on the E1E2 envelope glycoprotein complex overlaps with the CD81 receptor binding site and represents an important epitope for broadly neutralizing antibodies (bNAbs) and is therefore important for HCV vaccine design. Most AR3 bNAbs utilize the VH1-69 gene and share structural features that define the AR3C-class of HCV bNAbs. In this work, we identify recombinant HCV glycoproteins based on a permuted E2E1 trimer design that bind to the inferred VH1-69 germline precursors of AR3C-class bNAbs. When presented on nanoparticles, these recombinant E2E1 glycoproteins efficiently activate B cells expressing inferred germline AR3C-class bNAb precursors as B cell receptors. Furthermore, we identify critical signatures in three AR3C-class bNAbs that represent two subclasses of AR3C-class bNAbs that will allow refined protein design. These results provide a framework for germline-targeting vaccine design strategies against HCV.
Ultra-short pulse laser acceleration of protons to 80 MeV from cryogenic hydrogen jets tailored to near-critical density
Authors: Rehwald Martin , Assenbaum Stefan , Bernert Constantin , Brack Florian-Emanuel , Bussmann Michael , Cowan Thomas E. , Curry Chandra B. , Fiuza Frederico , Garten Marco , Gaus Lennart , Gauthier Maxence , Göde Sebastian , Göthel Ilja , Glenzer Siegfried H. , Huang Lingen , Huebl Axel , Kim Jongjin B. , Kluge Thomas , Kraft Stephan , Kroll Florian , Metzkes-Ng Josefine , Miethlinger Thomas , Loeser Markus , Obst-Huebl Lieselotte , Reimold Marvin , Schlenvoigt Hans-Peter , Schoenwaelder Christopher , Schramm Ulrich , Siebold Mathias , Treffert Franziska , Yang Long , Ziegler Tim , Zeil Karl 
Published: July 2023

AbstractLaser plasma-based particle accelerators attract great interest in fields where conventional accelerators reach limits based on size, cost or beam parameters. Despite the fact that particle in cell simulations have predicted several advantageous ion acceleration schemes, laser accelerators have not yet reached their full potential in producing simultaneous high-radiation doses at high particle energies. The most stringent limitation is the lack of a suitable high-repetition rate target that also provides a high degree of control of the plasma conditions required to access these advanced regimes. Here, we demonstrate that the interaction of petawatt-class laser pulses with a pre-formed micrometer-sized cryogenic hydrogen jet plasma overcomes these limitations enabling tailored density scans from the solid to the underdense regime. Our proof-of-concept experiment demonstrates that the near-critical plasma density profile produces proton energies of up to 80 MeV. Based on hydrodynamic and three-dimensional particle in cell simulations, transition between different acceleration schemes are shown, suggesting enhanced proton acceleration at the relativistic transparency front for the optimal case.
Quantifying disorder one atom at a time using an interpretable graph neural network paradigm
Authors: Chapman James , Hsu Tim , Chen Xiao , Heo Tae Wook , Wood Brandon C. 
Published: July 2023

AbstractQuantifying the level of atomic disorder within materials is critical to understanding how evolving local structural environments dictate performance and durability. Here, we leverage graph neural networks to define a physically interpretable metric for local disorder, called SODAS. This metric encodes the diversity of the local atomic configurations as a continuous spectrum between the solid and liquid phases, quantified against a distribution of thermal perturbations. We apply this methodology to four prototypical examples with varying levels of disorder: (1) grain boundaries, (2) solid-liquid interfaces, (3) polycrystalline microstructures, and (4) tensile failure/fracture. We also compare SODAS to several commonly used methods. Using elemental aluminum as a case study, we show how our paradigm can track the spatio-temporal evolution of interfaces, incorporating a mathematically defined description of the spatial boundary between order and disorder. We further show how to extract physics-preserved gradients from our continuous disorder fields, which may be used to understand and predict materials performance and failure. Overall, our framework provides a simple and generalizable pathway to quantify the relationship between complex local atomic structure and coarse-grained materials phenomena.
Molecular mechanism of plasmid-borne resistance to sulfonamide antibiotics
Authors: Venkatesan Meenakshi , Fruci Michael , Verellen Lou Ann , Skarina Tatiana , Mesa Nathalie , Flick Robert , Pham Chester , Mahadevan Radhakrishnan , Stogios Peter J. , Savchenko Alexei 
Published: July 2023

AbstractThe sulfonamides (sulfas) are the oldest class of antibacterial drugs and inhibit the bacterial dihydropteroate synthase (DHPS, encoded by folP), through chemical mimicry of its co-substrate p-aminobenzoic acid (pABA). Resistance to sulfa drugs is mediated either by mutations in folP or acquisition of sul genes, which code for sulfa-insensitive, divergent DHPS enzymes. While the molecular basis of resistance through folP mutations is well understood, the mechanisms mediating sul-based resistance have not been investigated in detail. Here, we determine crystal structures of the most common Sul enzyme types (Sul1, Sul2 and Sul3) in multiple ligand-bound states, revealing a substantial reorganization of their pABA-interaction region relative to the corresponding region of DHPS. We use biochemical and biophysical assays, mutational analysis, and in trans complementation of E. coli ΔfolP to show that a Phe-Gly sequence enables the Sul enzymes to discriminate against sulfas while retaining pABA binding and is necessary for broad resistance to sulfonamides. Experimental evolution of E. coli results in a strain harboring a sulfa-resistant DHPS variant that carries a Phe-Gly insertion in its active site, recapitulating this molecular mechanism. We also show that Sul enzymes possess increased active site conformational dynamics relative to DHPS, which could contribute to substrate discrimination. Our results reveal the molecular foundation for Sul-mediated drug resistance and facilitate the potential development of new sulfas less prone to resistance.
A supramolecular metalloenzyme possessing robust oxidase-mimetic catalytic function
Authors: Xu Shichao , Wu Haifeng , Liu Siyuan , Du Peidong , Wang Hui , Yang Haijun , Xu Wenjie , Chen Shuangming , Song Li , Li Jikun , Shi Xinghua , Wang Zhen-Gang 
Published: July 2023

AbstractEnzymes fold into unique three-dimensional structures to distribute their reactive amino acid residues, but environmental changes can disrupt their essential folding and lead to irreversible activity loss. The de novo synthesis of enzyme-like active sites is challenging due to the difficulty of replicating the spatial arrangement of functional groups. Here, we present a supramolecular mimetic enzyme formed by self-assembling nucleotides with fluorenylmethyloxycarbonyl (Fmoc)-modified amino acids and copper. This catalyst exhibits catalytic functions akin those of copper cluster-dependent oxidases, and catalytic performance surpasses to date-reported artificial complexes. Our experimental and theoretical results reveal the crucial role of periodic arrangement of amino acid components, enabled by fluorenyl stacking, in forming oxidase-mimetic copper clusters. Nucleotides provide coordination atoms that enhance copper activity by facilitating the formation of a copper-peroxide intermediate. The catalyst shows thermophilic behavior, remaining active up to 95 °C in an aqueous environment. These findings may aid the design of advanced biomimetic catalysts and offer insights into primordial redox enzymes.